Infectious Diseases

Section Editor: Dr. Mark Joffe

Fever of Unknown Origin

Infect Dis Clin North Am 2007;21:4

Differential Diagnosis

This list is not exclusive, but highlights some important causes of FUO after the common causes of fever have been excluded:

INFECTIONS — TB (pulmonary, extrapulmonary, miliary), abscess (liver, splenic, perinephric, psoas, diverticular, pelvis), osteomyelitis , endocarditis

NEOPLASTIC — hematologic (lymphoma, leukemia, multiple myeloma, myelodysplastic syndrome), solid tumors (renal cell, hepatoma)

COLLAGEN-VASCULAR — vasculitis (giant cell arteritis, Still’s disease, polyarteritis nodosa, Takayasu’s arteritis, Wegener’s granulomatosis, mixed cryoglobulinemia), lupus , rheumatoid arthritis

DRUGS — antimicrobials (sulfonamides, penicillins, nitrofurantoin, antimalarials), antihistamines , antiepileptics (barbiturate, phenytoin), NSAIDs/ASA , antihypertensives (hydralazine, methyldopa), antiarrhythmics (quinidine, procainamide), antithyroid , iodides , quinine , illicit (cocaine)

UNCOMMON CAUSES OF FUO—central fever , endocrine (hypothalamic dysfunction, hyperthyroidism, pheochromocytoma, adrenal insufficiency), infections (dental abscess, Q fever, leptospirosis, psittacosis, tularemia, melioidosis, syphilis, gonococcemia, chronic meningococcemia, Whipple’s disease, yersiniosis, brucellosis), hereditary periodic fever syndromes (familial Mediterranean fever, PFAPA syndrome [Periodic Fever with Aphthous Stomatitis and Adenitis], TNFR-1-associated periodic syndrome, hyper-IgD syndrome, Muckle–Wells syndrome, familial cold auto-inflammatory syndrome), alcoholic hepatitis , hematoma , factitious fever

Pathophysiology

Definitions

fever of unknown origin (FUO) classic definition (1961) —≥38.3°C [≥101°F], duration ≥3 weeks, diagnosis uncertain after 7 days of investigation in hospital new definitions FUO —≥38.3°C [≥101°F], duration ≥3 weeks, diagnosis uncertain after 3 days in hospital or three outpatient visits nosocomial FUO —hospitalized patients, ≥38.3°C [≥101°F], diagnosis uncertain after 3 days and infection not present or incubating on admission immune-deficient (neutropenic) FUO —>38.3°C [≥101°F], >3 days, neutrophil count ≤500/mm 3 . See p. 234 for details HIV -related FUO —HIV patients, ≥38.3°C [≥101°F], duration ≥3 weeks for outpatients or ≥3 days for inpatients fever, NYD —persistent fever that has not yet met the definition for FUO

Clinical Features

HISTORY —pattern and duration of fever, associated symptoms (cough, dyspnea, hemoptysis, chest pain, diarrhea, abdominal pain, dysuria, urethral discharge, hematuria, neck stiffness, headache), rash (palpable purpura, exanthem), exposure (food, water, plants, animals, insects, infected human secretions), weight loss, night sweats, travel history, sexual history, HIV risk factors, immunizations, past medical history (rheumatologic disorders, malignancy, alcohol), medications

PHYSICAL —vitals (tachycardia, tachypnea, hypotension, fever, hypoxemia), oral ulcers, lymphadenopathy, nuchal rigidity, respiratory and cardiac examination (murmurs), temporal artery, abdominal examination (hepatosplenomegaly), prostate examination, skin lesions (morphology, distribution), tick bite marks, joint examination

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, LDH, CK, serum protein electrophoresis, urinalysis, ESR, CRP, ANA, ENA, RF, C3, C4, ANCA, cryoglobulin

microbiology —blood C&S (including Mycobacteria ), sputum Gram stain/AFB/C&S, urine C&S, stool C&S, O&P, serology (HBV, HCV, HIV, monospot, CMV IgM, endemic fungi)

imaging —CXR, echocardiogram (if suspect endocarditis), CT chest/abd/pelvis as guided by symptoms

Special

ECG

T uberculin skin test

biopsy —affected tissue

Diagnosis and Prognostic Issues

DIAGNOSIS —the most important diagnostic strategy is a careful history and physical examination with frequent reassessment

prognosis —up to 30–50% will not have a diagnosis despite detail workup; adults who remain undiagnosed have good prognosis

Management

EMPIRIC ANTIBIOTICS —ONLY if suspect infectious etiology and therapy cannot be delayed due to severity of patient’s disease (see EMPIRIC ANTIBIOTICS p. 257). In general, therapeutic trials of antimicrobials or steroids are discouraged

TREAT UNDERLYING CAUSE

Fever and Rash

Differential Diagnosis

Infections

gram-positive cocci —scarlet fever, toxic shock syndrome, staphylococcal scalded skin syndrome, acute rheumatic fever (erythema marginatum, subcutaneous nodules)

gram-negative cocci —meningococcemia (purpura), disseminated gonococcal infection

gram-negative bacilli — S almonella typhi, Pseudomonas (ecythema gangrenosum), Vibrio vulnificus

endocarditis

spirochetes — Borrelia burgdorferi (Lyme erythema migrans), Treponema pallidum (chancre, secondary syphilis)

rickettsial —Rocky Mountain spotted fever, ehrlichiosis, typhus

viral exanthem —acute HIV, mononucleosis, rubella, measles, roseola, erythema infectiosum, chickenpox, shingles, coxsackie virus, echovirus

fungal —Blastomyces, Coccidioides, Histoplasma

Rheumatologic

seropositive —lupus, dermatomyositis

seronegative —inflammatory bowel disease, reactive arthritis

vasculitis —Wegener’s, polyarteritis nodosa

B ehcet’s disease

MALIGNANCY —lymphoma, leukemia, metastatic, paraneoplastic

MEDICATIONS —penicillins, cephalosporins, sulfas, barbiturates, phenytoin, procainamide, quinidine

OTHERS —sarcoidosis, erythema nodosum; Sweet’s syndrome (acute febrile neutrophilic dermatosis)

Clinical Features

Settings

age —viral exanthems, scarlet fever, and acute rheumatic fever are more likely in children. Mononucleosis is more common in young adults

season —tick-borne diseases are more common in spring and summer. Coxsackie virus and echovirus are more common in summer and fall. Meningococcus and parvovirus are more common in winter and spring

geographic location —Lyme disease in Pacific northwest, the Midwest, and the northeast USA and some southern Canadian locations. RMSF in south-central and Atlantic states. Ehrlichiosis in midwestern, south-central, and southeastern states. Tularemia in western, southeastern, and south-central states and Canada. Relapsing fever ( Borrelia hermsii ) in mountainous areas of the western USA. Endemic fungal infections include Blastomyces dermatitidis (southeastern states, Manitoba, and Ontario), Coccidioides immitis (southwestern states), and Histoplasma capsulatum (Mississippi, Ohio River valleys, and Quebec)

HISTORY —pattern and duration of fever, associated symptoms (cough, dyspnea, chest pain, diarrhea, abdominal pain, dysuria, urethral discharge, neck stiffness, headache), rash (prodrome, location, progression, treatment), exposure (food, water, plants, animals, infected human secretions), weight loss, night sweats, travel history, sexual history, immunizations, past medical history (rheumatologic disorders, malignancy), medications

PHYSICAL —vitals (tachycardia, tachypnea, hypotension, fever, hypoxemia), oral ulcers, lymphadenopathy, nuchal rigidity, respiratory and cardiac examination (murmurs), abdominal examination (hepatosplenomegaly), skin lesions (morphology, distribution), tick bite marks, joint examination

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, ESR, urinalysis

microbiology —blood C&S, sputum Gram stain/AFB/C&S, urine C&S, monospot test, CMV IgM, EBV, HIV, and other serologies

Special

lumbar puncture —if suspect meningococcus

skin biopsy —dermatology consult

inflammatory workup —CRP, ANA, ENA, RF

Management

ISOLATION PRECAUTIONS —droplet/airborne plus contact precautions for uncertain diagnosis; for purpura with bacterial sepsis, institute droplet and contact isolation precautions. See p. 269 for more details

TREAT UNDERLYING CAUSE

Specific Entities

Rickettsial Infections (Within North America)

themes —all transmitted by ticks, except Q fever. All associated with a rash, myalgias, and headache, except Q fever and ehrlichiosis. All involve some degree of vasculitis and DIC as part of pathogenesis. All can be treated with doxycycline

R ocky M ountain spotted fever — Rickettsia rickettsii transmitted by ticks. Most common in mid-Atlantic states. Rash begins on extremities and moves centrally. Treat with doxycycline

murine typhus —flea vector. Rash begins centrally and moves peripherally. Treat with doxycycline or chloramphenicol

ehrlichia — E. chaffeensis (human monocytic ehrlichiosis) transmitted by lone star tick. Peaks in May to July. Infects lymphocytes, monocytes, and neutrophils intracellularly. Fever, headache, myalgia, leukopenia, thrombocytopenia, and elevated transaminases; maculopapular or petechial rash in one-third. Human granulocytic anaplasmosis is caused by a related Ehrlichia and produces similar illness without rash. Transmitted by Ixodes tick and co-infection with Lyme disease possible. Treat with doxycycline

Q fever — Coxiella burnetii transmitted by respiratory spread from infected animal body fluids (e.g. cattle, sheep, goats, cats). No rash. Fever, pneumonitis, hepatitis, endocarditis, CNS symptoms. Treat with doxycycline

Lyme Disease

pathophysiology — Borrelia burgdorferi transmitted by tick bite after attachment for >24 h; think about concomitant tick borne diseases

clinical features —most common tick-borne disease in USA, particularly coastal Atlantic States and California during spring and summer stage 1 (early) —first 3–30 days, erythema migrans, fever, meningismus, lymphadenopathy stage 2 (disseminated) —weeks to months, hematogenous spread with neurological symptoms (facial nerve palsy, lymphocytic meningitis, encephalitis, chorea, myelitis, radiculitis, peripheral neuropathy) and carditis (AV block, dilated cardiomyopathy); may have multiple skin lesions of erythema migrans stage 3 (late) —months to years, mono- or oligoarthritis, acrodermatitis chronica atrophicans (in Europe), progressive encephalitis, dementia. Not amenable to antibiotic therapy May develop post-Lyme syndrome with musculoskeletal pain, neurocognitive symptoms, dysesthesias and fatigue

diagnosis —seology (anti-B. burgdorferi ELISA). If positive, confirm with Western blot

prevention —protective clothing and tick repellants. After tick bite (>36 h in hyperendemic area), consider doxycycline 200 mg ×1 dose within 72 h of the tick bite

treatments — stage 1 ( doxycycline 100 mg PO BID ×10–21 days, or cefuroxime 500 mg PO BID × 10–21 days). Lyme carditis ( ceftriaxone 2 g IV ×14–21 days if third degree AV block; otherwise, same as stage I with oral antibiotics). Neurologic Lyme ( ceftriaxone 2 g IV ×14–21 days). Lyme arthritis ( doxycycline 100 mg BID ×28 days, amoxicillin)

J arisch– H erxheimer reaction —up to 15% of patients may experience transient worsening of symptoms during first 24 h of treatment. This results from the host immune response to antigen release from dying organisms (typically Lyme and syphilis) causing fever, chills, myalgias, and exacerbation of rash

Babesiosis (malaria like; does not cause rash)

pathophysiology — B. microti (USA) or B. divergens (Europe) transmitted by Ixodes ticks (which also transmit Lyme disease and Ehrlichia ) → fever, chills, sweats, malaise, myalgias, arthralgias, headache 5–33 days after, particularly in immunosuppressed individuals

clinical features —endemic in southern New England, southern New York, Wisconsin, and Minnesota

diagnosis —blood smear, PCR, serology

treatments —atovaquone plus azithromycin

Related Topic

Exanthematous Lesions (p. 364)

Fever and Joint Pain

See JOINT PAIN AND FEVER (p. 276)

Sepsis

See SEPSIS (p. 97)

Febrile Neutropenia

IDSA Guidelines 2002

Differential Diagnosis

Bacterial

gram positive — S. aureus , coagulase-negative staphylococci, Streptococcus pneumoniae , corynebacterium

gram negative — Enterobacter, Escherichia. coli, K. pneumoniae, Pseudomonas, C. difficile, anaerobes

TB

VIRAL —HSV, VZV, CMV, EBV, HHV6, enterovirus, RSV

FUNGAL —Candida, Aspergillus, Cryptococcus, Fusarium

REACTIVATION OF LATENT INFECTION —Histoplasma, Coccidioides, Toxoplasma, Tuberculosis

Pathophysiology

DEFINITION —single temp >38.3°C [101°F] or >38°C [100.4°F] for >1 h, ANC <0.5×10 9 /L or <1.0×10 9 /L + expected nadir <0.5×10 9 /L

absolute neutrophil count (ANC) —neutrophils + bands

PATHOGENESIS —chemotherapy-induced injury to mucosal barriers, immune defects due to drugs or underlying disease and invasive devices. With the attenuated immune response, patients may be relatively asymptomatic until they decompensate due to overwhelming infection. Fever is sometimes the only warning sign and should always be taken seriously in patients at risk of developing neutropenia

NEUTROPENIA-ASSOCIATED FEBRILE EPISODES —most commonly idiopathic; bacterial source identified in approximately 30% of episodes, usually from patient’s own endogenous flora. Fungal infections replace bacterial infections in prominence after 7 days. Fever usually abates with return of neutrophils. If fever persists or returns after neutropenia resolves, consider hepatosplenic candidiasis

Clinical Features

HISTORY —patients usually asymptomatic other than fever. Determine severity and duration of fever, associated signs and symptoms (cough, dyspnea, chest pain, diarrhea, abdominal pain, dysuria, urethral discharge, neck stiffness, headache, rash), recent chemotherapy (nadir of neutrophil counts usually 10–14 days post-treatment), weight loss, night sweats, travel history, sexual history, immunizations, past medical history (malignancy, rheumatologic disorders), medications (chemotherapy, GCSF)

PHYSICAL —vitals (tachycardia, tachypnea, hypotension, fever, hypoxemia), oral ulcers, lymphadenopathy, nuchal rigidity, respiratory and cardiac examination (murmurs), abdominal examination (hepatosplenomegaly), skin lesions (morphology, distribution). Important sites to examine include venous access devices, sinuses, and perianal region for abscess. Digital rectal examination is not recommended as potential rectal tear

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, urinalysis

microbiology —blood C&S×2 (culture peripheral blood in addition to central line ports, sputum Gram stain/AFB/C&S, urine C&S, stool C&S, O&P, C. difficile toxin (if diarrhea)

imaging —CXR

Special

sinus X-ray

Management

low risk (ANC >0.1×10 9 /L, peak temperature <39°C [102.2°F], no significant symptoms or signs, no significant comorbidities, nearly normal renal and hepatic function, neutropenia <7 days)— ciprofloxacin 500 mg PO BID + amoxicillin–clavulanate 500 mg PO q8h. May send home with follow-up

high risk —admit for intravenous antibiotics

first line —one of imipenem 500 mg IV q6 h, meropenem 2 g IV q8h, ceftazidime 2 g IV q8h, cefepime 2 g IV q8h, piperacillin/tazobactam 4.5 g IV q8h, piperacillin 3 g IV q4h plus tobramycin 2–2.5 mg/kg IV q8h, clindamycin 600 mg IV q8h plus tobramycin 7 mg/kg IV q24h, or piperacillin/tazobactam 4.5 g IV q8h plus gentamicin 2–2.5 mg/kg IV q8h

second line —add vancomycin 1 g IV q12 h if suspect line infection, known colonization MRSA, Gram-positive blood culture, or hypotension

third line —add antifungal if febrile after 5 days ( fluconazole 400 mg IV daily, itraconazole 200 mg IV daily, amphotericin B 0.5–1 mg/kg IV daily over 4 h, caspofungin 70 mg on first day followed by 50 mg IV daily)

GCSF SUPPORT —see TREATMENT ISSUES below

catheter removal —necessary for most patients with bacteremia/candidemia with organisms other than coagulase-negative Staphylococci

Treatment Issues

Modification of Therapy During First Week of Treatment

if patient becomes afebrile in 3–5 days known organism —switch to specific antibiotics unknown etiology and low risk —switch to ciprofloxacin plus amoxicillin–clavulanate after afebrile for 48 h unknown etiology and high risk —continue same antibiotics

if persistent fever during first 3–5 days clinically stable by day 3 —continue antibiotics, stop vancomycin if cultures negative progressive disease by day 3 —change antibiotics febrile after day 5 —add antifungal

duration of antibiotic treatment

if afebrile by day 3 stop antibiotics —if (1) ANC ≥0.5×10 9 /L for 2 consecutive days, afebrile for ≥48 h, cultures negative, and no obvious signs of infection, or if (2) ANC <0.5×10 9 /L by day 7, but afebrile for 5–7 days, patient initially at low risk, and no subsequent complications continue antibiotics —if above criteria not met

if persistent fever on day 3 stop antibiotics —if ANC ≥0.5×10 9 /L for 4–5 consecutive days continue antibiotics —if ANC <0.5×10 9 /L, reassess and continue antibiotics for 2 weeks. Consider stopping therapy if no disease site is found and condition is stable

pre-medications for amphotericin b — meperidine 50 mg IV, acetaminophen 2 tabs PO, hydrocortisone 25 mg IV 30 min before dose, and repeat ×1 1–2 h after administration

ASCO 2006 guideline for GCSF use

primary prophylaxis —GCSF is recommended for the prevention of febrile neutropenia if high-risk patients —based on age (>65), medical history (poor performance status, previous febrile neutropenia, extensive prior treatment, poor nutrition, open wounds, active infections), disease characteristics (bone marrow involvement), and myelotoxicity of the chemotherapy regimen (chemoradiation) chemotherapy regimens —20% or higher risk of febrile neutropenia or dose dense regimens

secondary prophylaxis —GCSF is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (in which primary prophylaxis was not received), in which a reduced dose may compromise disease-free survival overall survival, or treatment outcome

treatment of patients with febrile neutropenia —GCSF should be given to those with high risk of developing complications, including expected prolonged (>10 days) and profound (<0.1×10 9 /L) neutropenia, age >65 years, uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction (sepsis), invasive fungal infection, being hospitalized at the time of the development of fever

special situations stem cell transplant —to mobilize peripheral blood progenitor cell often in conjunction with chemotherapy. Also administered after autologous, but not allogeneic, stem cell transplantation DLBCL —prophylactic GCSF should be given for patients with diffuse aggressive lymphoma age 65 and older treated with curative chemotherapy (CHOP or more aggressive regimens) AML —may be given shortly after completion of the initial induction chemotherapy to modestly decrease the duration of neutropenia ALL —recommended after the completion of the initial first few days of chemotherapy of the initial induction or first post-remission course, thus shortening the duration of neutropenia by approximately 1 week MDS —may be used to increase the ANC in neutropenic patients. Intermittent administration of CSFs may be considered in a subset of patients with severe neutropenia and recurrent infections post-radiation —GCSF should be given to patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs

J Clin Oncol 2006 24:19

Specific Entities

Necrotizing Enterocolitis (typhlitis)

pathophysiology —mucosal injury in patients with profound neutropenia → impaired host defense → necrosis of bowel wall, involving cecum extending into ascending colon and terminal ileum

clinical features —abdominal pain (especially RLQ) in neutropenic patients

diagnosis —CT abd. Avoid barium enema and colonoscopy

treatments —bowel rest, NG suction, IV fluids, nutritional support, broad spectrum antibiotics (including metronidazole for C. difficile and amphotericin B/fluconazole for fever >72 h), GCSF. Surgical indications include peritonitis, perforation, persistent GI bleeding, or clinical deterioration

Related Topics

Chemotherapy (p. 226)

Neutropenia (p. 148)

Sepsis (p. 97)

Stem Cell Transplant (p. 180)

Fever with Travel History

NEJM 2002 347:7 http://www.cdc.gov

Differential Diagnosis

Fever with CNS Involvement

bacterial —meningococcal, typhoid fever, rickettsial, leptospirosis

mycobacterial —tuberculosis

viral —Japanese encephalitis, West Nile encephalitis, tick-borne encephalitis, poliomyelitis, rabies

fungal —coccidioidomycosis

parasitic —malaria, angiostrongyliasis, trypanosomiasis

Fever with Respiratory Involvement

bacterial — S. pneumoniae , mycoplasma, Legionella, Q fever, typhoid fever, scrub typhus

mycobacterial —tuberculosis

viral —influenza, parainfluenza, metapneumovirus, respiratory syncytial virus, adenovirus, dengue

fungal —histoplasmosis, coccidioidomycosis

parasitic —malaria, Loeffler’s syndrome (migration of larval helminths such as ascaris, strongyloides, and hookworm)

fever with rash —see FEVER AND RASH (p. 234)

Hemorrhagic Fever

bacterial —rickettsial, meningococcemia, leptospirosis

viral —dengue, yellow fever, Ebola fever, Lassa fever

parasitic —malaria

FEVER WITH SEXUAL OR BLOOD EXPOSURES —syphilis, CMV, EBV, HIV, HBV

FEVER WITH EOSINOPHILIA —parasitic (acute hookworm, ascaris, strongyloides, acute schistosomiasis, visceral larva migrans, lymphatic filariasis, acute trichinosis)

FEVER WITH THROMBOCYTOPENIA —malaria, typhoid fever, dengue shock syndrome, ehrlichiosis, Rocky Mountain spotted fever

Acute Traveler’s Diarrhea ± Fever

bacterial —Enterotoxigenic or enteroaggregative E. coli , Campylobacter jejuni , Salmonella, Shigella, Vibrio, Aeromonas, Plesiomonas, C. difficile

viral —Caliciviruses (Norwalk, Norwalk-like), rotaviruses, enteroviruses

parasitic — Giardia lamblia, Cryptosporidium parvum, Entamoeba histolytica, Cyclospora cayetanensis, Isospora belli, E. polecki, Balantidium coli, Trichinella spiralis

Chronic Traveler’s Diarrhea ± Fever

bacterial —Enteroaggregative or enteropathogenic E. coli, C. jejuni, Shigella, Salmonella, Yersinia enterocolitica, Aeromonas, Plesiomonas, C. difficile, Tropheryma whippelii

mycobacterial —tuberculosis, M. avium complex

fungal — Paracoccidioides brasiliensis, Histoplasma capsulatum

parasitic — G. lamblia, E. histolytica, C. parvum, C. cayetanensis, Trichuris trichiura, Strongyloides stercoralis , Schistosomiasis, Capillaria philippinensis, Fasciolopsis buski, Metagonimus yokogawai, Echinostoma

non-infectious —small-bowel overgrowth syndrome, disaccharidase deficiency, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, cancer, laxative use, endocrinopathy, dysmotility, idiopathic

www.phac-aspc.gc.ca/publicat/ccdr-rmtc/06vol32/acs-01/index-eng.php

Clinical Features

HISTORY —pattern and duration of fever, associated symptoms (cough, dyspnea, chest pain, diarrhea, abdominal pain, dysuria, urethral discharge, neck stiffness, headache), weight loss, night sweats, travel history (specific itinerary, activities and exposures including food and fresh/saltwater history, incubation period), sexual history, immunization status, antimalarial chemoprophylaxis (medications, degree of adherence), past medical history (rheumatologic disorders, malignancy), medications

PHYSICAL —vitals (tachycardia, tachypnea, hypotension, fever, hypoxemia), oral ulcers, lymphadenopathy, nuchal rigidity, respiratory and cardiac examination (murmurs), abdominal examination (hepatosplenomegaly), skin lesions (morphology, distribution), tick bite marks, joint examination

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, urinalysis

microbiology —blood C&S, sputum Gram stain/AFB/C&S, urine C&S, stool C&S, O&P, C. diff toxin A/B, malaria thick and thin smear (repeat ×1 within 12–24 h if initially negative result), serologies (HIV, dengue, rickettsiae, schistosomiasis, strongyloidiasis, leptospira, HAV, HBV, HCV, Hepatitis E)

imaging —CXR, U/S abd guided by symptoms

Special

lumbar puncture

Pre-Travel Considerations

vaccinations —standard regardless of travel (influenza, pneumococcal if age >65, hepatitis B, MMR, DPT), developing countries (hepatitis A), specific countries (meningococcal, Japanese encephalitis, yellow fever), high-risk activity (rabies), outbreaks (cholera)

malaria prophylaxis —see below

diarrhea prophylaxis —ciprofloxacin and imodium if diarrhea develops

Specific Entities

PRIORITY —focus on those illnesses that are potentially fatal or may be public health threats

top travel-related infections —malaria, typhoid fever, dengue fever, diarrheal disease, respiratory infections, Lyme disease, Q fever, brucellosis

schistosomiasis

pathophysiology —trematode worms S. haematobium, S. mansoni, S. intercalatum in sub-Saharan Africa, S. mansoni in part of South America, S. japonicum in Asia, S. mekongi in Cambodia. Freshwater exposure → cercariae penetrate skin → larvae migrate to lung through venous circulation → migrate to heart → migrate to liver, where they mature and pair off → migrate to mesenteric venules of bowel ( S. mansoni, mekongi, japonicum, and intercalatum ) bladder ( S. hematobium ), where females lay eggs → excreted into feces or urine → mature to cercariae

clinical features —initial penetration of skin may cause pruritus. Acute schistosomiasis (Katayama fever) includes fever, headache, myalgias, RUQ pain, bloody diarrhea, and dyspnea. Chronic schistosomiasis with granuloma formation is due to host’s immune response to schistosome eggs, leading to hepatic (cirrhosis), intestinal (diarrhea, occult blood, fibrosis) or genitourinary tract symptoms (hematuria, dysuria, calcification, fibrosis), and rarely CNS (seizures, focal deficit, transverse myelitis) involvement

diagnosis —serology, schistosome eggs in feces or urine, biopsy of rectum or bladder

treatments — praziquantel 20 mg/kg PO q8h ×2 doses (3 doses for S. japonicum and mekongi ); adjunctive corticosteroids for Katyama fever

MALARIA —the most important cause of fever in returning travelers. P. falciparum can be rapidly fatal and must be ruled out in all febrile travelers returning from malaria-endemic regions. It has the shortest incubation period and >90% of affected travelers will become ill within 30 days of return

pathophysiology —anopheline mosquito bite transmits sporozoites → travel to liver and invade hepatocytes → divide and form schizonts which contain merozoites (asymptomatic) → rupture after 6–16 days and release merozoites into the bloodstream → infect erythrocytes and mature from ring forms to trophozoites to mature schizonts (asexual form) over 48 ( P. vivax, P. ovale, P. falciparum ) or 72 ( P. malariae ) hours → merozoites released from erythrocytes (fever, anemia, lactic acidosis, cytokine release) and infect new red cells → few merozoites differentiate into male or female gametocytes (sexual forms) can circulate in blood until ingested by mosquito. P. vivax and P. ovale may stay dormant in the liver as hypnozoites and may cause late relapse by reactivating after many months. In contrast, P. falciparum and P. malariae have no liver stage and do not cause relapse. P. falciparum specifically can induce obstruction of microvascular blood flow, and may lead to organ dysfunction (e.g. cerebral malaria, renal failure, ARDS, hypoglycemia, anemia, DIC, and gastroenteritis)

clinical features — P. falciparum is acquired mostly from sub-Saharan Africa, while P. vivax is mostly from Asia or Latin America. Symptoms include spiking fevers, chills, headache, back pain, cough, GI problems. Splenomegaly and thrombocytopenia without leukocytosis may be present. Cerebral malaria ( P. falciparum ) presents as altered level of consciousness or seizures and is universally fatal if untreated

diagnosis —thick and thin smear (need to repeat over 48 h to rule out malaria)

prophylaxis —the relative risk of contracting malaria varies by geographic region: Caribbean 4, North Africa 7, South America 8, Southeast Asia 12, Central America 38, South Asia 54, Oceania 77, and sub-Saharan Africa 208. Travelers should be advised to wear long sleeves/pants between dusk and dawn, use mosquito repellents containing 30–50% DEET, and consider permethrin-treated mosquito nets. Chloroquine may be used for travel to destinations with chloroquine-sensitive P . falciparum (e.g. most of Central America and parts of the Middle East). For destinations where chloroquine-resistant P. falciparum is present, chemoprophylaxis with atovaquone–proguanil, mefloquine, or doxycycline should be used. Give atovaquone–proguanil or doxycycline for travel to destinations with P. falciparum resistance to chloroquine, mefloquine, and sulfonamides (e.g. regions of Thailand, Cambodia, China, Laos, and Vietnam). Atavaquone–proguanil associated with fewest side effects. Mefloquine has ease of weekly dosing. Doxycycline is the cheapest, but requires prolonged course and causes sun sensitization. CDC 2010 risk assessment and prophylaxis recommendations are available online at http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria-risk-information-and-prophylaxis.aspx

treatments —artesunate has emerged as the treatment of choice for complicated malaria. Other options include quinine–doxycycline, atovaquone–proguanil, and mefloquine. Chloroquine–primaquine for non-falciparum

NEJM 2008 359:6

www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/35s1/index-eng.php

Rickettsial Infections (Outside of North America)

pathophysiology —African tick typhus ( Rickettsia africae ), Mediterranean tick typhus (R. conorii), and scrub typhus ( Orientia tsutsugamushi ) are all transmitted by ticks

clinical features —tick bite ± inoculation eschar with a triad of fever, headache, and myalgia. Rash may be present. Lymphadenopathy, leukopenia, and thrombocytopenia

diagnosis —serology

treatments —doxycycline

Rickettsial Infections (within of North America)—see FEVER AND RASH (p. 234)

Leptospirosis

pathophysiology — Leptospira interrogans , zoonosis more common in tropical areas

clinical features —history of exposure to freshwater. Fever, headache, myalgia, rash, conjunctival suffusion. May be associated with aseptic meningitis, uveitis, elevated transaminases, jaundice, proteinuria, and microscopic hematuria; fulminant syndrome with jaundice, renal failure, and hemorrhage (Weil’s Disease)

diagnosis —serology; culture of blood, urine, and CSF

treatments —doxycycline or amoxicillin for mild disease; penicillin/ampicillin or ceftriaxone/cefotaxime IV for severe disease

Typhoid Fever

pathophysiology —acquired after exposure to food or water contaminated by Salmonella typhi

clinical features —mainly in developing countries. Fever, chills, headache, myalgia, abdominal pain and constipation (uncommonly diarrhea), relative bradycardia, splenomegaly, and rose spots (faint salmon-colored macules on the abdomen and trunk). Septic symptoms from intestinal perforation may occur in second week

diagnosis —blood, stool, urine, or bone marrow (highest sensitivity) culture; CBC may show leukopenia

treatments —fluoroquinolones, ceftriaxone, azithromycin

BRUCELLOSIS (undulant fever, Mediterranean fever)

pathophysiology —Gram-negative facultative intracellular coccobacilli

clinical features —transmitted by drinking or eating infected animal products (milk), inhalation, or direct animal contact through skin wounds. Other than fever, may involve any organ system, particularly joints (sacroiliitis), GU (epididymo-orchitis), CNS (meningitis), eyes (uveitis), cardiac (endocarditis), pulmonary (pneumonitis, pleural effusion, empyema), and can cause abscesses (hepatic, splenic, thyroid, epidural). May develop into chronic hepatosplenic disease

diagnosis —blood cultures, serology

treatments —doxycycline plus streptomycin or rifampin

Dengue Fever (break-bone fever)

pathophysiology —flavivirus transmitted by mosquito → flu-like illness 4–7 days later → may develop lymphadenopathy, maculopapular/petechial rash → dengue shock syndrome and dengue hemorrhagic fever if previously exposed to other serotypes

clinical features —acquired mostly from tropical and subtropical areas. Fever, headache, retro-orbital pain, severe myalgia/arthralgia. Leukopenia and thrombocytopenia

diagnosis —serology

treatments —supportive

Chikungunya Fever

pathophysiology —mosquito-borne viral infection acquired in Africa and Asia. Large outbreaks ongoing in Indian Ocean islands and India

clinical features —fever (usually within 2–4 days of exposure) with severe joint pains involving small joints of hands, wrists, and ankles; may be prolonged. Leukopenia, thrombocytopenia, and elevated transaminases may be seen

diagnosis —serology (acute and convalescent)

treatments —symptomatic with NSAIDs

NEJM 2007 356:8

Pneumonia

See Pneumonia (p. 6)

Endocarditis

See Endocarditis (p. 52)

Meningitis

NEJM 2006 354:1

Differential Diagnosis for Fever and Neurological Symptoms

★DIMS★

drugs —neuroleptic malignant syndrome, serotonin syndrome, sympathomimetics, alcohol withdrawal

Infectious

meningitis —bacterial ( S. pneumoniae, N. meningitidis, H. influenzae, L. monocytogenes, Klebsiella, E. coli, Serratia, Pseudomonas ), viral (enterovirus, VZV, influenza, mumps, HIV), TB, fungal ( Cryptococcus )

encephalitis —HSV, West Nile, St. Louis, Equine, La Crosse

abscess —bacterial

METABOLIC —thyroid storm

Structural

hemorrhage —subarachnoid, epidural, subdural, intracerebral

cerebral infarct

tumor

pituitary apoplexy

vascular —TTP/HUS, lupus, vasculitis, granulomatous angiitis

Pathophysiology

Associations with Specific Organisms

age 0–4 weeks — S. agalactiae, E. coli, Listeria monocytogenes, K. pneumoniae

age 1–23 months — S. agalactiae, E. coli, S. pneumoniae, H. influenzae, N. meningitidis

age 2–50 years — S. pneumoniae, N. meningitidis

age >50 years — S. pneumoniae, N. meningitidis, L. monocytogenes , aerobic Gram-negative bacilli*

immunocompromised — Listeria , aerobic Gram-negative bacilli*

neurosurgery/head trauma — S. aureus, S. epidermidis , aerobic Gram-negative bacilli*

CSF shunt — S. aureus, S. epidermidis , aerobic Gram negative bacilli*, diphtheroids

basilar skull fracture — S. pneumoniae , H. influenzae , group A Streptococci

*aerobic Gram-negative bacilli include Klebsiella, E. coli, Serratia, and Pseudomonas

RISK FACTORS FOR S. pneumoniae —pneumonia, otitis media, mastoiditis, sinusitis, endocarditis, head trauma with CSF leak, alcoholism, splenectomy

RISK FACTORS FOR L. monocytogenes —extremes of age, alcoholism, malignancy, immunosuppression, diabetes, hepatic failure, renal failure, iron overload, collagen vascular disease, HIV

COMPLICATIONS —neurologic complications include herniation, stroke, vasculitis, acute cerebral hemorrhage, and aneurysm formation of cerebral vessels, with symptoms such as seizures, hearing loss, and neuropsychological impairment. Systemic complications include septic shock, pneumonia, and ARDS

Clinical Features

Investigations

Basic

labs —CBCD, lytes, Cr/urea, INR, PTT, AST, ALT, ALP, bilirubin, fibrinogen, urinalysis

microbiology —blood C&S, sputum Gram stain/AFB/C&S, urine C&S

imaging —CXR, head CT (see below)

lumbar puncture —(1) cell count and differential; (2) Gram stain, C&S and AFB; (3) cell count and differential; (4) protein, glucose, lactate; (5) PCR for HSV, VZV, enteroviruses; (6) cytology

Diagnostic and Prognostic Issues

lumbar puncture —suspect bacterial infection if high neutrophils, low glucose, high protein, with culture. Suspect viral infection if high lymphocytes, normal glucose, and normal/high protein ( NEJM 2006 355:e12 )

opening pressure —normal is 60–250 mmH 2 O. Causes of elevated opening pressure include meningitis, pseudotumor cerebri, intracranial hemorrhage, tumors, and idiopathic

cell count and differential —normal WBC is <5/mm 3 . This can increase to 1000–5000/mm 3 for bacterial meningitis (neutrophils mainly) and 50–1000/mm 3 for viral meningitis (lymphocytes mainly). Other causes include seizure, intracerebral hemorrhage, tumor, and "traumatic tap" (correct by +1 WBC for every 500–1000 RBCs)

xanthochromia —lysed RBC. Present in >90% of patients within 12 h of subarachnoid hemorrhage onset

gram stain —sensitivity is 60–80% in untreated bacterial meningitis and 40–60% in partially treated cases

culture —gold standard with sensitivity of 70–85% in untreated bacterial meningitis and 50% in partially treated cases. Viral, TB, and fungal cultures may be done as well

protein —normal is 0.18–0.58 g/L. Significantly elevated in bacterial meningitis and obstruction, variably elevated in fungal and TB infections, and only sometimes elevated in viral infections. Other causes include tumors, intracranial hemorrhages, multiple sclerosis, and Guillain–Barre syndrome

glucose —normal is 2/3 of serum level, up to 16.7 mM [300 mg/dL]. Significantly lower in bacterial meningitis, mildly lower in fungal and TB infections, and usually normal in viral infections

CT head —indicated before lumbar puncture only if age >60, immunocompromised, history of CNS disease, seizures within 1 week, focal neurological abnormalities, papilloedema, obtunded or unconscious, inability to answer two questions correctly, or inability to follow two commands correctly

NEJM 2001 345:24

PROGNOSIS —mortality rate is 19–26% for S. pneumoniae meningitis and 3–13% for N. meningitidis meningitis. Factors conferring poor prognosis include systemic compromise, ↓ level of consciousness, and S. pneumoniae

NEJM 2004 351:18

Management

acute —ABC, O 2 , IV, intubation. Droplet precautions for suspect N. meningitidis infection

EMPIRIC ANTIBIOTICS — steroid if acute bacterial meningitis and 15–20 min before first dose of antibiotics ( dexamethasone 0.15 mg/kg or 10 mg IV q6 h ×4days). Cefotaxime 2 g IV q6 h or ceftriaxone 2 g IV q12 h. Add vancomycin 500–750 mg IV q6 h if concerned about penicillin-resistant Pneumococci. Add ampicillin 2 g IV q4h if age >50 for Listeria coverage. If neurosurgery/trauma, CSF shunt, or basilar skull fracture, give ceftazidime 2 g IV q8h plus vancomycin . If HSV encephalitis, give acyclovir 10 mg/kg IV q8h

SPECIFIC ANTIBIOTICS — S. pneumoniae (penicillin G or ampicillin if MIC <0.1 μg/mL, ceftriaxone or cefotaxime ± vancomycin ×10–14 days if MIC >1.0 μg/mL), N. meningitidis (ceftriaxone, penicillin G or ampicillin ×7 days), L. monocytogenes (ampicillin or penicillin G, plus gentamicin ×14–21 days), H. influenzae (ampicillin, ceftriaxone, or cefotaxime ×7 days), Enterobacteriaceae (ceftriaxone or cefotaxime ×7 days)

Specific Entities

CHRONIC MENINGITIS (>4 weeks symptoms and persistent CSF abnormalities)—consider TB, fungal infections, neurosarcoidosis, lymphoma, and leptomeningeal carcinomatosis

RECURRENT MENINGITIS — congenital predisposition (myelomeningocele, dermal sinus), acquired (trauma, tumor, shunt), immunologic defects (complement defects, antibody defects, splenectomy)

Hsv Encephalitis

pathophysiology —usually infects the temporal lobe → subacute illness with fever, focal neurologic abnormalities, aphasia, mental status changes, and seizures. May have long-term sequelae

diagnosis —lumbar puncture (mild lymphocytic pleocytosis <500 cells/µL, erythrocytes, xanthochromia, ↑ protein, normal glucose, PCR for HSV1 and HSV2), MRI (hyperintense lesion in the inferior medial temporal lobe, often extending into the insula)

treatments — acyclovir 30 mg/kg/day ×14 days

West Nile Virus Encephalitis

pathophysiology —flavivirus West Nile virus transmitted by mosquitoes between late spring and early autumn

clinical features —wide spectrum from asymptomatic to severe neurologic disorder. Fever, erythematous rash, meningitis, encephalitis, and flaccid paralysis. Risk of progression to severe neurological disease about 1/150, highest in the elderly

diagnosis —lumbar puncture (viral picture, PCR for West Nile virus), IgM antibody to West Nile virus in serum or cerebrospinal fluid (samples from the acute and convalescent phases, submitted at least two weeks apart)

treatments —supportive. Prevention is key

Related Topics

Delirium (p. 380)

Infection Control (p. 269)

Urinary Tract Infections and Sexually Transmitted Infections

Urol Clin N Am 2008;35:1; Can J Infect Dis Med Microbiol 2005;16:6; www.phac-aspc.gc.ca/std-mts/sti-its/guide-lignesdir-eng.php

Differential Diagnosis of Dysuria

★SUV★

S EXUALLY TRANSMITTED DISEASES — Chlamydia trachomatis , Neisseria gonorrhoeae , HSV

U RINARY TRACT INFECTIONS (urethritis, cystitis, pyelonephritis, perinephric abscess)— bacterial (★ KEEPS ★ K lebsiella, E . coli, E nterococci, P roteus, S taphylococcus saprophyticus )

V aginal infections — Candida albicans , Trichomonas, bacterial vaginosis

Pathophysiology of Urinary Tract Infections

COMPLICATED UTI —presence of functional or anatomic abnormality of the urinary tract (polycystic kidney disease, nephrolithiasis, neurogenic bladder, diabetes, immunosuppression, pregnancy, indwelling urinary catheter, recent urinary tract instrumentation)

UNCOMPLICATED UTI —absence of risk factors above. In women, uncomplicated UTIs are usually treated for 3 days (or 5–7 days with nitrofurantoin)

PYELONEPHRITIS —usually 18–40-year-old women, fever, costovertebral angle tenderness, blood and urine cultures indicated. Challenges differentiating between cystitis and pyelonephritis

Risk Factors for UTI

young women —frequent or recent sexual activity

elderly women —age, estrogen deficiency, incontinence, diabetes, cystoceles, previous GU surgery

PATHOPHYSIOLOGY OF CATHETER-ASSOCIATED BACTERIURIA —bacteria establish biofilm in or on catheter and enter bladder intra- or extraluminally. Common organisms include E. coli and enterococci. Responsible for 80% of urosepsis. Risk factors include duration of catheterization, errors in catheter care, diabetes mellitus, and female sex

Clinical Features of Urinary Tract Infections

Investigations for Urinary Tract Infections

Basic

labs —CBCD, lytes, Cr/urea

microbiology —urinalysis (nitrite or leukocyte esterase sens 75%, spc 82%), urine C&S (pyuria sens 95%, spc 71%; bacteria sens 40–70%, spc 85–95%. Not necessary if symptomatic uncomplicated UTI)

Diagnostic Issues for Urinary Tract Infections

NUMBER OF BACTERIA —significant bacteria (>10 5 /mL) in clean catch suggests UTI (sens 50%). If using lower threshold to >10 3 /mL for women with symptoms, sensitivity increases and specificity only decreases slightly

URINE CULTURE —not always needed if symptomatic and biochemical evidence (i.e. leukocyte esterase) of uncomplicated UTI (see Clinical Features). However, antimicrobial resistance is increasing, so culture and sensitivity may become more important

Management of Urinary Tract Infections

UNCOMPLICATED UTI in women — trimethoprim–sulfamethoxazole (DS-160/800 mg) 1 tab PO BID ×3 days, ciprofloxacin 250–500 mg PO BID ×3 days, levofloxacin 250–500 mg PO daily ×3 days, nitrofurantoin macrocrystals 50 mg PO QID ×5–7 days, nitrofurantoin monohydrate macrocrystals 100 mg PO BID ×5–7 days, amoxicillin–clavulanate 500 mg PO BID ×7 days, fosfomycin trometamol 3 g PO ×1 dose

COMPLICATED UTI —treatment duration 7–14 days

RECURRENT UTI (consider below measures if >3 episode of UTI/year)— daily low-dose prophylaxis ( trimethoprim–sulfamethoxazole DS ½ tab PO qhs or 1 tab 3×/week ×6 months, nitrofurantoin 50 mg or macrocrystals 100 mg PO qhs ×6 months), post-coital prophylaxis ( trimethoprim–sulfamethoxazole DS ½-1 tab PO post-coital, nitrofurantoin 50 mg PO or macrocrystals 100 mg PO post-coital), patient-initiated treatment (start standard dose of antibiotics with onset of UTI symptoms)

SYMPTOM CONTROL — phenazopyridine 100–200 mg PO TID ×2 days

ACUTE UNCOMPLICATED PYELONEPHRITIS —treat empircally with oral fluoroquinolones ×7 d ( ciprofloxacin 500 mg PO BID or levofloxacin 750 mg PO daily). If isolate susceptible, may treat with trimethoprim–sulfamethoxazole, amoxicillin, or amoxicillin–clavulanate ×14 d. Most otherwise healthy, non-pregnant women with pyelonephritis can be treated on an outpatient basis. Otherwise, treat with IV antibiotics, at least initially (aminoglycoside ± ampicillin, third-generation cephalosporin, or carbapenem)

catheter-associated bacteriuria —remove or replace catheter and initiate antibiotics for symptomatic infection; switch to intermittent catheterization

pregnancy and UTI —urinalysis for all pregnant women at 16 weeks. Treat all bacteriuria with amoxicillin or nitrofurantoin ×3–7 days even if asymptomatic as there is a 20–40% risk of pyelonephritis. Avoid fluoroquinolones

Vaginitis

CANDIDA —vulvovaginitis with cheesy vaginal discharge, intense itch. Diagnosis by microscopy with 10% KOH showing hyphae and budding yeast, pH 4–4.5 (normal). Treat with vaginal antifungal cream (3–14 days) or fluconazole 150 mg PO ×1 dose

TRICHOMONIASIS —profuse purulent greenish vaginal discharge, strawberry cervix. Diagnosis by microscopy showing motile trichomonads, pH 5–6. Treat with oral metronidazole 2 g as a single dose

BACTERIAL VAGINOSIS —gray, fishy-smelling vaginal discharge. Diagnosis made by amine odor when KOH added to the discharge, pH >4.5 and clue cells (vaginal epithelial cells coated with bacteria) seen on microscopy. Treat if symptomatic or pregnant with metronidazole or clindamycin, orally or vaginally

Sexually Transmitted Infections (STI s )

Urethritis in Men/Cervicitis in Women

pathophysiology — N. gonorrhea , Chlamydia trachomatis, and other non-gonococcal ( Ureaplasma urealyticum , Mycoplasma genitalium, Trichomonas vaginalis , HSV)

diagnosis —Gram stain of discharge, urine for chlamydia/gonorrhea (nucleic acid amplification test, NAAT) or urethral/cervical swab for gonorrhea culture; offer syphilis and HIV testing

treatments —anti-gonococcal ( cefixime 400 mg PO ×1, ceftriaxone 125 mg IM ×1), anti-chlamydial ( azithromycin 1 g PO ×1, or doxycycline 100 mg PO BID ×7 days). If gonorrhea identified, empirically treat for both gonococcus and chlamydia since dual infection is common. Trace and treat all partners within the last 60 days

Syphilis

pathophysiology — Treponema pallidum infection. Risk factors include men who have sex with men (MSM), sex trade, HIV infection primary syphilis —presents as chancre (painless, indurated, non-purulent ulcer) within 3–90 days secondary syphilis —develops within 2 weeks to 6 months, with symptoms such as fever, maculopapular rash, mucocutaneous lesions, alopecia, lymphadenopathy, meningitis, uveitis, and cranial neuritis tertiary syphilis —develops after year(s) and may involve the heart (aortitis), eyes (iritis, Argyll Robertson pupil), bones/soft tissues (gummas), and neurologic system (general paresis, a rapidly progressive dementia with psychotic features and tabes dorsalis which affects posterior columns of the spinal cord and the dorsal roots, leading to pain episodes, decreased vibration and proprioception, absent reflexes, and bowel/bladder dysfunction)

diagnosis —first-line diagnostic test of choice for a primary syphilitic chancre should be either DFA or PCR, if available. Otherwise, treponemal serologies are more sensitive and become positive earlier than non-treponemal serologies and would be preferred if primary syphilis is a consideration

treatments —for primary, secondary and early latent (<1 year) syphilis, benzathine penicillin G 2.4 M units IM ×1 (preferred) or doxycycline 100 mg PO BID ×2 weeks. For late latent (>1 year) syphilis, gummatous and cardiovascular syphilis, benzathine penicillin G 2.4 M units IM q7days ×3 weeks. For neurosyphilis or syphilitic eye disease, give benzathine penicillin G 3–4 M units q4h IV ×10–14 days. Follow-up is essential. Treatment failure is defined as persistent symptoms or failure of serologic test to decline by 4 fold within 6 months

JAMA 2003 290:11

Pelvic Inflammatory Disease

pathophysiology —includes endometritis, tubo-ovarian abscess, salpingitis, and pelvic peritonitis. Most commonly due to N. gonorrhoeae, C. trachomatis, M. hominis, U. urealyticum; may involve endogenous (gut) organisms including anaerobes . Complications include infertility, ectopic pregnancy, and chronic pelvic pain

clinical features —lower abdominal pain, abnormal vaginal bleeding/discharge, and dyspareunia may be mild and non-specific. Findings include lower abdominal tenderness, adnexal tenderness, and cervical motion tenderness

diagnosis —high index of clinical suspicion. Cervical swab and urine NAAT for Chlamydia and gonorrhea. Ultrasound. Pregnancy test

treatments — outpatients ( ceftriaxone 250 mg IM ×1 and doxycycline 100 mg PO BID ×14 days, or levofloxacin 500 mg PO daily ×14 days); add metronidazole 500 mg PO BID ×14 days if there are risk factors for anaerobic pathogens. Inpatients ( doxycycline 100 mg PO q12 h and cefoxitin 2 g IV q6 h ×14 days, or clindamycin 900 mg IV q8h and gentamicin 1.5 mg/kg IV q8h ×14 days)

Soft Tissue Infections

NEJM 2004 350:9; NEJM 2007 357:4; CID 2005 41:10

Differential Diagnosis

DISCRETE, LOCALIZED CUTANEOUS INFECTIONS — superficial (impetigo, folliculitis, furunculosis), deep (carbuncles, subcutaneous abscesses)

SPREADING, DIFFUSE CUTANEOUS INFECTIONS (involves deeper dermis and subcutaneous tissues)—erysipelas, cellulitis

DEEP SOFT TISSUE INFECTIONS —necrotizing fasciitis (polymicrobial, S. pyogenes ), gas gangrene ( C. perfringens )

Pathophysiology

Risk Factors for Cellulitis

compromised skin —trauma, IDU, psoriasis, eczema, fungal disease (especially tinea pedis)

compromised sensory/proprioceptive nerves —diabetic neuropathy

compromised blood/lymphatic vessels —diabetes, malignancy, lymphatic or venous insufficiency, venectomy, radiation, prior cellulitis

CELLULITIS —acute spreading infection involving the dermis and subcutaneous tissue, mostly caused by Staphylococci and group A S treptococcus . It usually presents as a swollen, erythematous plaque with ill-defined border

ERYSIPELAS —superficial cellulitis involving the upper dermis and lymphatics, mostly caused by group A Streptococcus . It usually presents as a raised, erythematous plaque with well-demarcated border. It occurs more commonly in infants and elderly

RISK FACTORS FOR SKIN AND SOFT TISSUE INFECTIONS DUE TO MRSA/CA-MRSA —previous MRSA infection or household contacts of known MRSA; street involved/shelters/incarceration, injection drug use, athletes, children/day care

Common Pathogens Causing Cellulitis

most common — S. pyogenes (β-hemolytic group A Streptococcus ), S. aureus , other β-hemolytic streptococci (B, C, G, and F)

surgical wound — S. aureus, S. pyogenes

human bite —oral anaerobes, Eikenella corrodens

animal bite — Pasteurella multocida, Capnocytophaga canimorsus

tick bite — Borrelia burgdorferi , Tularemia

freshwater — Aeromonas hydrophila

seawater — Vibrio vulnificus

fish exposure — Erysipelothrix rhusiopathiae, Streptococcus iniae

hot tub — Pseudomonas aeruginosa folliculitis

Investigations

Basic

labs —CBCD, lytes, urea, Cr, lactate (if suspicion of necrotizing fasciitis)

microbiology —swab of portal of entry or any open wound for Gram stain and C&S, blood C&S

Management

treat underlying cause — incision and drainage of abscesses. Elevation of affected area if possible, compression and skin hydration. Antibiotics for mild cellulitis ( cephalexin 500 mg PO QID, dicloxacillin 500 mg PO QID, or clindamycin 150–300 mg PO QID ×5–14 days); for systemic toxicity or severe cellulitis ( cefazolin 1–2 g IV q8h, ceftriaxone 1 g IV q24h, nafcillin 1–2 g IV q4–6 h ×7–14 days). For MRSA-associated skin infections, consider vancomycin 1–2 g IV q12 h, clindamycin 600 mg IV TID or 300 mg PO QID, daptomycin 4–6 mg/kg IV daily, tigecycline 100 mg loading dose, then 50 mg IV q12 h, doxycycline 100 mg PO BID, linezolid 600 mg PO/IV q12 h or quinupristin–dalfopristin 7.5 mg/kg IV q8–12 h. For mild erysipelas , consider penicillin 500 mg PO QID or amoxicillin 500 mg PO TID. For severe erysipelas with fevers and chills , consider ceftriaxone 1 g IV q24h or cefazolin 1–2 g IV q8h ×5–14 days

Specific Entities

Necrotizing Fasciitis

types — type 1 (polymicrobial infections including Enterococci, E. coli , non-group A Streptococcus , Klebsiella , anaerobes. Mixed infections occurring postoperatively or in those with diabetes or peripheral vascular disease, e.g. Fournier’s gangrene of perineum in diabetics), type 2 (monomicrobial Streptococcus pyogenes “Group A strep”; rarely, CA-MRSA. May occur at any age and in healthy hosts following minor trauma, penetrating injury, laceration, varicella, IDU, or childbirth)

pathophysiology (type 1) —inoculation of ischemic or devitalized tissue → host immune system and antibiotics relatively ineffective → rapid spreading of infection to surrounding tissue → late signs include fever, crepitus, shock → complications include compartment syndrome, acute renal failure, sepsis. May be limb or life-threatening. May happen over a few hours

associations —host (age >50, cancer, alcoholism, immunocompromised state, malnutrition, obesity), compromised skin (burns, trauma, postoperative infection), compromised blood vessels (peripheral vascular disease, diabetes)

clinical features —typically happens over body areas with limited fibrous tissue (trunk, extremities). Pain disproportionate to physical findings. Gangrenous skin changes, bullae, tense edema, and crepitus may be seen as late signs

diagnosis —high index of suspicion (pain >>physical findings). Plain X-ray to check for gas with type 1 necrotizing fasciitis. CT or MRI maybe useful. Early deep incisional biopsy is gold standard

treatments —urgent surgical debridement of all necrotic tissue. Consider IVIG if significant hypotension in Group A S treptococcus necrotizing fasciitis. Polymicrobial ( cefotaxime 2 g IV q8h plus clindamycin 600–900 mg IV q8h [note: clindamycin inhibits toxic protein production], Piperacillin–tazobactam 4.5 g IV q8h, or ampicillin/penicillin G plus ciprofloxacin plus metronidazole). Streptococcus ( penicillin G 4 MU IV q4h plus clindamycin 600–900 mg IV q8h)

Osteomyelitis

Differential Diagnosis

hematogenous (monomicrobial)— S. aureus , coagulase-negative staphylococci, Gram-negative bacilli ( P. aeruginosa, Serratia, E. coli ), TB, fungi

CONTIGUOUS SPREAD FROM SOFT TISSUE OR JOINTS (polymicrobial)— S. aureus , coagulase-negative Staphylococci, S. pyogenes, Enterococcus , Gram-negative bacilli, anaerobes

CONTIGUOUS SPREAD WITH GENERALIZED VASCULAR INSUFFICIENCY (polymicrobial)— S. aureus, Streptococcus, Enterococcus, Proteus mirabilis, P. aeruginosa , anaerobes

DIRECT INOCULATION THROUGH TRAUMA OR SURGERY (monomicrobial or polymicrobial)—may involve skin or environmental commensal organisms

Pathophysiology

Route of Infection

hematogenous —mainly central (vertebrae, sternoclavicular, sacroiliac) and sometimes long bones (femur, tibia, humerus)

contiguous spread from soft tissue infections —trauma, surgery, orthopedic prosthesis, decubitus ulcer

contiguous spread from soft tissue infections with generalized vascular insufficiency —ischemic ulcers, diabetic ulcers

Risk Factors for Osteomyelitis

systemic —diabetes, sickle cell disease (Salmonella)

local —vascular compromise (arterial insufficiency, neuropathy venous stasis), orthopedic surgery

Clinical Features

diabetic foot ulcer —either probing of bone or ulcer area above 2 cm 2 is associated with ∼90% chance of having underlying osteomyelitis (sens 66%, spc 85%, PPV 89%, NPV 56%). Further non-invasive testing is unlikely to improve accuracy of diagnosis

Symptoms

acute osteomyelitis (<2 weeks)—typically associated with bone pain, tenderness, warmth, swelling, febrile, and chills. Hip, vertebrae, and pelvis tend to manifest few signs and symptoms

subacute osteomyelitis (weeks to few months)—longer duration of above symptoms, but less severe. Over time, draining sinus tracts, deformity, instability, and vascular/neurologic changes may develop

chronic osteomyelitis (>few months)—similar to subacute osteomyelitis

Investigations

Basic

labs —CBCD, ESR (monitor disease progress if elevated), urinalysis

microbiology —blood C&S, urine C&S

imaging —plain films (specific but insensitive), three-phase bone scan (sensitive), CT, MRI (most sensitive and specific, particularly spine and diabetic foot), indium-labeled WBC scan (specific), U/S, bone marrow scan, dual tracer scan

Special

ulcer probing

bone biopsy —C&S, AFB, TB culture, fungal culture, histology; generally required for vertebral osteomyelitis (CT-guided biopsy can provide microbiological diagnosis to guide therapy)

ankle brachial index —ischemic ulcers suspected

Diagnostic Issues

PLAIN FILMS —soft tissue swelling and gas, cortical destruction, periosteal new bone formation, foreign bodies, deformities, fractures, and soft tissue gas. Usually the first imaging to investigate for osteomyelitis. However, may not detect changes until after 2–3 weeks of infection. May help make diagnosis of osteomyelitis but never excludes it (sens 61%, spc 72%, PPV 80% for diabetic foot osteomyelitis)

BONE SCAN —more sensitive but less specific than plain films (sens 70–100%, spc 36% for diabetic foot osteomyelitis). Useful for ruling out osteomyelitis, but cannot make the diagnosis

INDIUM-LABELED LEUKOCYTE SCAN —better sensitivity and specificity (but still poor) than bone scans in diabetic foot. Since WBC accumulates in the marrow, the scan is less sensitive in areas with red marrow (vertebrae, pelvis). Excellent for fracture nonunion osteomyelitis (sens 91%, spc 97%)

MRI —provides great anatomic details, more sensitive and specific than bone scan. Imaging of choice for specific body sites (vertebrae, diabetic foot) (sens 72%)

ULTRASOUND —fluid collection adjacent to the bone without intervening soft tissue, elevation of the periosteum by >2 mm, and thickening of the periosteum. Sensitivity and specificity uncertain

BONE BIOPSY —gold standard for osteomyelitis and generally required in vertebral osteomyelitis. Positive blood cultures and corresponding radiologic findings may support diagnosis and sometimes replace bone biopsy. Consider holding off antibiotic therapy if not life-threatening infection to facilitate identification of organisms. Organisms from skin swabs have little correlation with the actual organisms growing inside the bone, except for S. aureus

Related Topic

Diabetes Mellitus (p. 337)

Management

HEMATOGENOUS —for vertebral osteomyelitis, need blood and bone cultures, then start empiric antibiotics with cloxacillin 2 g IV q4–6 h or cefazolin 2 g IV q8h. Consider vancomycin 15 mg/kg IV q12 h if high local MRSA rates. Once organism identified, treat with specific antibiotic (total 6–12 weeks of antibiotics guided by susceptibility from time of biopsy or definitive surgery, with at least 2 weeks of IV therapy). If failed therapy, consider bone/soft tissue debridement and another 4–6 weeks of antibiotics after definitive surgery

CONTIGUOUS SPREAD WITHOUT VASCULAR INSUFFICIENCY —after orthopedic surgery and specimen collection, start vancomycin 15 mg/kg IV q12 h ± ceftazidime 2 g IV q8h. For sternal osteomyelitis, give vancomycin 15 mg/kg IV q12 h, then switch to specific antibiotics (total 6 weeks of antibiotics from time of definitive surgery, usually intravenous for the duration)

contiguous spread with vascular insufficiency —polymicrobial. Base therapy on bone culture, empirical coverage should include anaerobes (e.g. carbapenems, piperacillin–tazobactam)

Specific Entities

Vertebral Osteomyelitis

pathophysiology —usually results from disc-space seeding through hematogenous dissemination, seeding from urinary tract, trauma, extension of infection from adjacent structures, or as a complication of spine and disc surgery. Risk factors include extraspinal infection site, urinary tract instrumentation, vascular catheter, hemodialysis, intravenous drug abuse, cancer, and diabetes mellitus

clinical features —severe back pain, limited function, and fever (52%)

diagnosis —MRI, blood cultures. Bone biopsy generally required for confirmation and microbiological diagnosis to guide therapy

treatments — cloxacillin 2 g IV q4–6 h or cefazolin 2 g IV q8h. Consider vancomycin 15 mg/kg IV q12 h if high local MRSA rates

Prosthetic Joint Infections

pathophysiology —most commonly due to coagulase-negative staphylococci

treatments —debridement with retention of prosthesis may be possible with early-onset infection (within 3 months of surgery), short duration of symptoms (<3 weeks) with no sinus tract, a stable implant and a causative organism susceptible to quinolones (or trimethoprim–sulfamethoxazole) and rifampin, which are given for 3 months (hips) to 6 months (knees) after an initial course of appropriate IV antibiotic therapy for at least 2 weeks. If debridement and retention are not appropriate, removal of the infected prosthesis with one-stage or two-stage exchange; IV antibiotic therapy is also provided for 6 weeks following the initial surgery

NEJM 2009 361:8

Septic Arthritis

See SEPTIC ARTHRITIS (p. 273)

Tuberculosis: Pulmonary

NEJM 1999 340:5; NEJM 2001 345:3; NEJM 2004 350:20

Pathophysiology

ORGANISMS —genus Mycobacterium consists of >50 species. TB is caused by M. tuberculosis complex including M. tuberculosis, M. bovis, and others. The cell envelope contains mycolic acid → resists destaining by acid alcohol, thus termed acid fast bacilli

TRANSMISSION —TB transmission is almost exclusively airborne through inhalation of minute droplet nuclei. Therefore, lungs are the primary focus. However, any organs can become infected during the bacteremia that follows initial lung infection

LATENT TB infection (ltbi) —follows initial infection; asymptomatic; detected by tuberculin skin test. Risk of active infection generally is 5% in the first 2 years with 5% risk of reactivation thereafter

FACTORS THAT INCREASE THE RISK OF INFECTION —1/3 of the world’s population is infected with TB. Birth in endemic area (less commonly travel) is the major risk factor; other risk factors include aboriginal populations and racial/ethnic minorities, household/institutional contacts and crowding (healthcare workers, long-term care, correctional facilities, substance abuse, and shelters)

FACTORS INCREASING THE RISK OF REACTIVATION OF LTBI —HIV infection (most important risk factor, always test those with active TB for HIV), fibronodular disease on CXR, chronic renal failure, increasing age, malignancy, transplant/immunosuppression, silicosis, chronic steroid use, TNF-α inhibitors, alcohol abuse, malnutrition, liver or kidney disease, poorly controlled diabetes, smoking, gastrectomy, jejunoileal bypass

Clinical Features

Primary Tb

symptoms —fever, night sweats, pleuritic chest pain, chronic cough, anorexia, weight loss, fatigue, erythema nodosum

signs —often none. Primary TB usually involves the mediastinal lymph nodes; hilar lymphadenopathy in the presence of RML collapse is the most common radiologic finding (2/3) with pleural effusion in 1/3. Lung infiltrates may be seen and involve lower lungs or middle lung fields most commonly with possible cavitation in areas of consolidation

Reactivation Tb (active pulmonary)

symptoms —cough, yellow-green sputum (increases over time), hemoptysis (25%), chest pain/dyspnea (33%), fever/night sweats (50%), fatigue (50–66%), weight loss

signs —reactivation TB usually involves the apical-posterior segments of upper lobes (80–90%), cavitation (19–40%), hilar lymphadenopathy (more likely than cavitation in AIDS patients)

elderly with reactivation TB —presents with fever, night sweats, or hemoptysis less often. Lesions less often cavitary and less often TST positive

COMPLICATIONS OF PULMONARY TB —hemoptysis (rarely massive), pneumothorax (more common in endemic countries), bronchiectasis, and pulmonary destruction (rare)

Related Topic

Tuberculosis in Pregnancy (p. 412)

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, albumin, urinalysis

microbiology —blood C&S with mycobacterial culture, sputum Gram stain/AFB/C&S, urine AFB/C&S, HIV serology

imaging —CXR, CT chest

Special

skin test —see Diagnostic Issues for details

interferon gamma release assays —QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and T-SPOT TB assay

PCR

molecular fingerprinting —tracing outbreaks

susceptibility testing —1 extra week

thoracentesis —if effusion. Send for fluid AFB and TB culture

pleural biopsy

CSF —AFB, TB culture

Diagnostic Issues

tuberculin skin test (TST) —gold standard for diagnosing latent tuberculosis (epidemiologic tool), but not sensitive or specific to include or exclude active pulmonary TB. Given as 5 units TST-S (purified protein derivative) intradermally, measure extent of induration after 48–72 h. Skin test reaction cutoffs and corresponding population groups when test considered positive (in North America) are as follows:

≥5 mm —HIV positive, recent TB contact, CXR signs, prior TB

≥10 mm —other risk factors for infection (endemic, immigrant, aboriginal, homeless, injection drug user, healthcare worker, silicosis, kidney or liver disease, gastrectomy, ileal bypass)

≥15 mm —no risk factors

Sputum Smear

utility —morning sputum ×3 days (AFB, TB culture), induced sputum if necessary, bronchoscopic lavage if cannot obtain sputum. Three consecutive AFB-negative sputum samples support that patient is non-infectious and can come off isolation

limitations —smear only detects 50% of culture-positive TB, and in non-endemic areas positive smear may represent non-TB mycobacterium

staining agents —standard is Ziehl–Neelsen (acid fast stain); Auramine–Rhodamine or Auramine O fluorescence staining improves sensitivity but must be confirmed with acid fast

SPUTUM CULTURE —2–8 weeks in egg media, 4–14 days if radiometric (sens 80–85%, spc 98–99%)

POLYMERASE CHAIN REACTION (PCR)—more useful in non-endemic countries to rule out other common mycobacteria. High specificity but variable sensitivity (if AFB positive, sens 94–96%, spc 99.7–100%. If AFB positive, sens 9–100%, spc 25–100%)

INTERFERON GAMMA RELEASE ASSAYS —sensitivity >95%; not affected by prior BCG vaccination. Most useful for evaluation of latent TB in those with positive TST and previously vaccinated with BCG

Management

LATENT TB infection — isoniazid 300 mg PO daily ×6–12 months or rifampin 600 mg PO daily ×4 months. A "decision to tuberculin test is a decision to treat” with no age cutoff for treatment and regardless of BCG vaccination status. Exclude active TB with sputum culture and CXR before treatment. HIV, immunosuppressed, and newly infected patients should be priority for treatment of latent TB

PRIMARY OR REACTIVATION TB —patients should be isolated in single rooms with negative air pressure. TB therapy should be undertaken in consultation with an expert. Susceptibility testing is necessary to guide treatment. Directly observed treatment (DOT) is the standard of care for all patients. TB therapy consists of an intensive phase of daily therapy followed by a continuation phase of twice- or thrice-weekly therapy. ★ RIPE ★ Rifampin 10 mg/kg or 600 mg PO daily, isoniazid 5 mg/kg or 300 mg PO daily, pyrazinamide 20–25 mg/kg PO daily ×8 weeks. Ethambutol 15–20 mg/kg PO daily is added until drug susceptibility results are available. This is followed by isoniazid and rifampin daily, twice weekly, or three times weekly for 16 more weeks. Alternatives include isoniazid, rifampin, pyrazinamide, plus ethambutol or streptomycin three times weekly for 24 weeks, or isoniazid, rifampin, pyrazinamide, plus ethambutol for 2 weeks, then twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 16 weeks (see guidelines for exceptions and alternate regimens when faced with resistance or drug intolerance)

Treatment Issues

VACCINATION WITH BCG (Bacillus Calmette-Guerin)—decreases miliary and meningeal TB by 75–86% and pulmonary TB by 50% in children. However, BCG leads to false-positive skin test, which may compromise contact tracing and decision to treat latent TB infection

DIRECTLY OBSERVED TREATMENT —most effective method to prevent multi-drug-resistant tuberculosis according to the WHO

Medication Details

rifampin (RIF)—bactericidal. Side effects include hepatic toxicity (less than INH, but induces hepatic microsomal enzymes → ↑ clearance and ↓ effects of many drugs), flu-like symptoms, red-orange urine, sweat, tears

isoniazid (INH)—bactericidal and inexpensive. Side effects include hepatitis (↑ with increased age and alcohol use), peripheral neuropathy (↓ with pyridoxine 10 mg PO daily or 25 mg PO daily if HIV, diabetes, malnourished, renal failure, pregnancy, or breast feeding)

pyrazinamide (PZA)—bactericidal at acidic pH in cells. Side effects include GI intolerance, hepatic injury, hyperuricemia due to ↓ renal excretion, arthraligias

ethambutol —mostly bacteriostatic. Main side effect is optic neuritis

Drug Monitoring

baseline —platelet, Cr, AST, ALP, bilirubin, uric acid (pyrazinamide), visual acuity, and red-green color discrimination (ethambutol)

follow-up —symptoms of hepatotoxicity and visual disturbance

TREATMENT OF CO-INFECTION WITH TB and HIV —similar treatment outcome with or without HIV, but treatment of active TB infection in HIV patients should be extended beyond 6 months if bacteriologic or clinical response is slow or suboptimal. Also beware of TB and HIV drug interactions (protease inhibitors and non-nucleoside reverse transcriptase inhibitors may cause toxic levels of rifampin, which should be replaced by rifabutin)

CANADIAN TUBERCULOSIS STANDARDS —see http://www.phac-aspc.gc.ca/tbpc-latb/index-eng.php for more information

Approach to Gram Stain, Culture, and Sensitivity

Gram-Positive Cocci

Clusters (catalase positive) (Staphylococci)

coagulase positive — S. aureus

coagulase negative — S. epidermidis, S. saprophyticus, S. hominis, S. lugdunesis, S. schleiferi

Pairs/Chains (catalase negative)

α-hemolytic streptococci — S. pneumoniae , viridians group streptococci, enterococcus (Group D strep)

β-hemolytic streptococci — S. pyogenes (Group A strep), S. agalactiae (Group B strep), group C, F, G strep

others — Abiotrophia , Granulicatella (“nutrient variant Strep”), Leuconostoc , Lactococcus , Aerococcus

anaerobic — Peptostreptococcus , Streptococcus , Peptococcus , Anaerococcus

Gram-Positive Bacilli

ACID FAST (mycobacterium)— M. tuberculosis, M. leprae, M. avium-intracellulare complex, or non-tuberculous Mycobacteria (NTM, also known as mycobacteria other than TB (MOTT)). These organisms have Gram-positive-type cell walls, but do not stain Gram-positive due to the waxy mycolic acids in the cell envelope

Spore Forming

aerobic — Bacillus anthrax, Bacillus cereus

anaerobic — Clostridium perfringens, C. difficile, C. botulinum

Non-Spore Forming

aerobic, facultative, aerotolerant — Corynebacterium /diphtheroids, Lactobacillus, Listeria, Gardenerella, Nocardia

anaerobic — Actinomyces, Propionibacterium, Eubacterium

BRANCHING BACILLI —★ ABCD-LMN ★ A ctinomyces (acid fast negative), B acillus, C lostridium , D iphtheroids, L isteria, L actobacillus, M ycobacterium (Modified and Ziehl–Neelsen acid fast), N ocardia (modified acid fast)

Gram-Negative Cocci

neisseria — N. meningitidis (diplococci), N. gonorrhoeae (diplococci), other Neisseria

moraxella — M. catarrhalis

Gram-Negative Bacilli

Aerobic

glucose fermenting and lactose fermenting —a number of Enterobacteriaceae including E. coli, Citrobacter, Enterobacter, Klebsiella, Serratia

glucose fermenting but non-lactose fermenting — Shigella, Salmonella, Hafnia, Morganella, Proteus, Yersinia, Edwardsiella, Vibrio (oxidase positive), Aeromonas (oxidase positive), Pleisiomonas (oxidase positive)

non-glucose and non-lactose fermenting oxidase positive — Pseudomonas, Ralstonia, Burkholderia, Roseomonas, Sphingomonas oxidase negative — Stenotrophomonas, Acinetobacter, Chryseomonas

anaerobic — Bacteroides fragilis, Fusobacterium, Prevotella, Porphyromonas

others — Eikenella*, Pasteurella (cats), Capnocytophaga (dogs), Kingella *, Actinobacillus *, Cardiobacterium *, Haemophilus * (coccobacilli, pleomorphic), Legionella (BCYE agar), Campylobacter (boomerang)

*HACEK organisms in endocarditis

Specific Organisms

NON-GRAM-STAINABLE —Chlamydia, Mycoplasma, Ureaplasma, Rickettsia, Treponema, Coxiella, Ehrlichia, Mycobacteria

Antibiotic Susceptibility and Resistance

GROUP A S TREPTOCOCCAL INFECTIONS —cellulitis, erysipelas, necrotizing fasciitis, pharyngitis, bacteremia, Streptococcal toxic shock syndrome, scarlet fever, acute rheumatic fever (post-streptococcal glomerulonephritis)

STREPTOCOCCUS PNEUMONIAE —may develop resistance to penicillin by altered penicillin-binding protein

S. AUREUS (MSSA)—may develop resistance to penicillin by β-lactamase

P SEUDOMONAS —various intrinsic mechanisms conferring resistance. Need to treat with dual antibiotic therapy for serious infections if therapy for >2 weeks or if susceptibility not yet available

VRE —vancomycin-resistant enterococci

MRSA — S. aureus that is resistant not only to penicillin, but also penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin). In general, hospital MRSA strains have broader resistance (e.g. clindamycin, trimethoprim–sulfamethoxazole, tetracyclines) than community-associated MRSA strains (CA-MRSA). Risk factors for hospital MRSA infections include frequent hospital visits and contact with MRSA-infected individuals; CA-MRSA is associated with crowding, acute and chronic skin disease, poor hygiene, sharing of contaminated items, contact sports, and IDU

β-LACTAMASE-RESISTANT BACTERIA — constitutive ( E. coli*, Klebsiella*, Haemophilus, Neisseria, bacteroides ), inducible ( S. aureus , S erratia †*, P rovidencia †, P seudomonas , I ndole-positive Proteus †*, C itrobacter †*, E nterobacter †*, M organella †*)

†★ SPICE-M ★ organisms with inducible, chromosomally mediated cephalosporinases (AmpC type β-lactamases) resistant to penicillins, first and second generation cephalosporins, cephamycins, and β-lactamase inhibitors

*these organisms may have extended spectrum β-lactamase (ESBL) resistant to all β-lactams except carbapenems

Antibiotics

Gentamicin and Tobramycin Dosing

TOXICITY —nephrotoxicity, ototoxicity, neuromuscular blockade (rare). Serum aminoglycoside levels correlate with nephrotoxicity

LOADING DOSE (TRADITIONAL DOSING: Q8H) —dependent on indication. For mild infection, uncomplicated UTI, synergy with β-lactams for Gram positive infections, give 0.6–1.2 mg/kg IV q8h. For serious Gram-positive infection or sepsis, give 2.5 mg/kg IV. For life-threatening infections, give 3.0 mg/kg IV

Maintenance Dose (Traditional Dosing: Q8H)

start —1.7 mg/kg IV q8h. Monitor serum levels after steady state reached; i.e. 3–5 half-lives (after third dose). Monitor renal function and ototoxicity every 3 days

peak levels —obtain 30–45 min after end of infusion. Should be 4.2–8.4 μmol/L [2–4 μg/mL] when drug is being given for synergy or uncomplicated infections, 12.6–16.8 μmol/L [6–8 μg/mL] for serious Gram-negative infection or sepsis, and 14.7–18.9 μmol/L [7–9 μg/mL] for life-threatening infections

trough levels —obtain 0–30 min prior to scheduled dose. Should be <4.2 μmol/L [<2 μg/mL] to prevent toxicity

adjustments —dosing interval is dependent on renal function (CrCl >60 mL/min, q8h; 40–60 mL/min, q12h; 20–40 mL/min, q24h; <20 mL/min single dose then measure serum concentration and give PRN). Changes in dose without changes in interval will result in proportional changes in both peak and trough serum drug concentrations. Prolongation of dosing interval will also reduce both, but particularly trough level

Once-Daily Gentamicin and Tobramycin Dosing

RATIONALE —optimize treatment of Gram-negative infections with less nephrotoxicity than q8h dosing. Similar ototoxicity and neuromuscular toxicity

NOT RECOMMENDED —monotherapy for infections outside urinary tract, pregnant patients, dialysis patients, endocarditis, CNS infections, osteomyelitis, ophthalmologic infections, surgical prophylaxis, patients with rapid drug clearance (e.g. burns >20% BSA), Gram-positive infections, patients receiving concurrent ototoxins (e.g. furosemide) neonates, pediatric patients with significant renal dysfunction, duration of therapy >14 days

LOADING DOSE —5–7 mg/kg IV

MAINTENANCE DOSE (5–7 mg/kg IV q24–48 h)

start —monitor serum level 6–14 h after first dose. Monitor renal function and ototoxicity q3d

adjustments —dosing interval (q24–48 h) is based on 6–14 h serum level (Hartford nomogram, Antimicrob Agents Chemother 1995 39:3 ). Pharmacy consult to assist with dosing (Once-daily dosing provides peak levels of 15–31–46 μmol/L [22 μg/mL] and trough levels <2.1 μmol/L [<1 μg/mL] to prevent toxicity. Peak and trough levels do not need to be monitored)

DOSING WEIGHT FOR AMINOGLYCOSIDES —for obese patient (i.e. actual body weight (BW) >125% of ideal body weight (IBW)), use adjusted body weight (ABW) for dose determination:

ABW (kg)=IBW +0.4(BW-IBW)

Note: 1 kg=2.2 lbs. See p. 406 for IBW calculation

Related Topic

Drug Eruptions (p. 372)

Vancomycin Toxicity and Dosing

TOXICITY —rash, infusion-related red man syndrome, rarely nephrotoxicity (especially combined with aminoglycoside), and ototoxicity. However, serum vancomycin levels do not predict toxicity

LOADING DOSE —15–20 mg/kg (usually 1–1.5 g) IV

MAINTENANCE DOSE —30 mg/kg (actual body weight) per day divided into 2–4 doses (maximum usually 1.5 g/dose)

start —monitoring after steady state, i.e. after third dose normally, or after second dose if dosing interval >48 hour. Monitor only if >14 days in patients with stable renal function and mild/moderate infection, or >4 days in patients with unstable renal function or severe infection

trough levels —obtained 30–60 min before next scheduled dose. Should be at least 6.9–10.4 μmol/L [10–15 μg/mL]; adjust to 10.4–13.8 μmol/L [15–20 μg/mL] for serious infections (endocarditis, osteomyelitis)

peak levels —there is no correlate for efficacy or toxicity and therefore should not be monitored

adjustments —dosing interval is dependent on renal function (CrCl >100 mL/min, q12h; 80–100 mL/min, q18h; 60–80 mL/min, q24h; 40–60 mL/min, q36 h; 25–40 mL/min q48h; <25 mL/min, single dose then measure serum concentration and give PRN). Changes in dose without changes in interval will result in proportional changes in both peak and trough serum drug concentrations. Prolongation of dosing interval will also reduce both, particularly trough level

Penicillin Allergy

HISTORY —characterize reaction (age when reaction occurred, timing of reaction after penicillin administration, type of reaction, route of administration, reason for penicillin, any other medications at the time, resolution), any similar antibiotics since

CROSS-REACTIVITY —incidence of cross-reactivity to cephalosporins when patient has penicillin allergy by history is <2%. Carbapenems and first/second-generation cephalosporins have higher cross-reactivity in the penicillin allergic than third-generation cephalosporins and aztreonam. It is often safe to use these medications, with the first dose monitored. If safety unclear, skin testing provides reassurance. For patients with a history of penicillin allergy, those with positive and negative skin test have 5.6% and 1.7% chance of developing cross-reactivity with cephalosporin, respectively

NEJM 2006 354:6

Rational Clinical Examination Series: Is This Patient Allergic To Penicillin?

HISTORY —history of penicillin allergy (LR+ 1.9, LR− 0.5)

Types of Allergic Reactions

★ ACID ★ A ntibody-mediated (IgE), C ytotoxic (antibody-dependent), I mmune-complex-mediated, D elayed hypersensitivity reaction

type I —immediate <1 h, IgE antibodies mediated, anaphylaxis, hypotension, laryngeal edema, wheezing, angioedema, urticaria

type II —>72 h, IgG and complement mediated, increased clearance of RBC and platelets by lymphoreticular system

type III —>72 h, IgG and IgM immune complexes mediated, serum sickness, tissue injury

type IV —>72 h, contact dermatitis

others —>72 h, maculopapular or morbilliform rashes

approach —“only 10–20% of patients reporting a history of penicillin allergy are truly allergic when assessed by skin testing. Taking a detailed history of a patient’s reaction to penicillin may allow clinicians to exclude true penicillin allergy, allowing these patients to receive penicillin. Patients with a concerning history of type I penicillin allergy who have a compelling need for a drug containing penicillin should undergo skin testing. Virtually all patients with a negative skin test result can take penicillin without serious sequelae”

JAMA 2001 285:19

Approach to Empiric Antibiotics

General Approach

CHOICE OF EMPIRIC ANTIBIOTIC —based on the most likely and deadly organisms for each type of infection. Thus, a good understanding of the pathophysiology of each infection and the local resistance pattern of various organisms is essential

CULTURE AND SUSCEPTIBILITY —should always be performed to facilitate targeted antibiotic treatment except for mild infections. However, the specific organism may not be identified even if multiple cultures are taken. In this case, the clinician must rely on clinical judgment and continue treatment with empiric antibiotic(s)

Specific Infections and Empiric Antibiotic Choices

SEPSIS —depending on the suspected source. For pulmonary source, respiratory fluoroquinolone plus ceftriaxone ± vancomycin if community setting, anti-pseudomonal plus ciprofloxacin if hospital setting. For urinary source, ceftriaxone or carbapenem or fluoroquinolone or aminoglycoside. For intra-abdominal source, pipericillin–tazobactam plus aminoglycoside. Duration of treatment is at least 10–14 days with rationalization of antibiotics when susceptibility results available. See p. 97 for details

meningitis ( S. pneumoniae, N. meningitidis, Listeria , HSV)—ceftriaxone/cefotaxime ± ampicillin ± vancomycin. Add acyclovir if CSF suggests viral picture. Duration of treatment is 7–21 days. See p. 241 for details

COMMUNITY–ACQUIRED PNEUMONIA ( S. pneumoniae, Klebsiella, Mycoplasma )—macrolides ± cefotaxime or respiratory fluoroquinolones. Duration of treatment is usually 7 days. See p. 6 for details

ASPIRATION PNEUMONIA (anaerobes, Staph, GNB)—cefotaxime ± clindamycin or metronidazole. Duration of treatment is usually at least 7 days. See p. 6 for details

ICU /VENTILATOR-ASSOCIATED PNEUMONIA (GNB, Pseudomonas )—ciprofloxacin plus ceftazidime or pipericillin–tazobactam or carbapenem. Duration of treatment is usually 8 days (p. 94)

ENDOCARDITIS ( S. aureus , S. viridans, Enterococcus ). Duration of treatment is highly variable. See AHA guidelines and p. 52 for details

native valve disease —ampicillin + cloxacillin/nafcillin or vancomycin plus gentamicin

injection drug use —cloxacillin or vancomycin plus gentamicin

prosthetic valve disease —vancomycin plus gentamicin

ACUTE BLOODY DIARRHEA ( Salmonella, Shigella, Campylobacter )—ciprofloxacin. Duration of treatment is 3 days. See p. 122 for details

ANTIBIOTIC-ASSOCIATED DIARRHEA ( C. difficile )—oral metronidazole. Duration of treatment is 10 days. See p. 123 for details

PERITONITIS/INTRA-ABDOMINAL SEPSIS (coliforms, anaerobes)—pipericillin–tazobactam, imipenem, or ampicillin plus ciprofloxacin plus metronidazole. Treat until WBC/peritonitis resolved

FEVER IN SPLENECTOMIZED patient ( H. influenza, N. meningitidis, S. pneumoniae, Capnocytophaga canimorsus )—cefotaxime/ceftriaxone. Duration of treatment is usually 10–14 days. See p. 148 for further information

URINARY TRACT INFECTION ( E. coli, Klebsiella, Enterococcus, Proteus, S. saprophyticus )—nitrofurantoin, trimethoprim–sulfamethoxazole, ciprofloxacin. Duration of treatment is 3 days if uncomplicated UTI, otherwise 14–21 days. See p. 244 for details

CELLULITIS ( Staphylococcus, Streptococcus )—cefazolin, cloxacillin, or cephalexin. Duration of treatment is usually 7–10 days. See p. 247 for details

HUMAN BITE (Gram positive, Eikenella , anaerobes)—amoxicillin–clavulanate, or clindamycin plus Ciprofloxacin

DIABETIC FOOT (polymicrobial)—amoxicillin–clavulanate or ciprofloxacin plus clindamycin, or trimethoprim–sulfamethoxazole plus metronidazole. Treat until resolution. May require IV antibiotics with Pseudomonas coverage (e.g. pipericillin–tazobactam; carbapenem). Osteomyelitis likely if ulcer >2 cm 2 or probe touches bone. See p. 248 for details

NECROTIZING FASCIITIS —surgical treatment is mandatory. For polymicrobial infection, cefotaxime plus clindamycin, pipericillin–tazobactam, or ampicillin/penicillin G plus ciprofloxacin/gentamicin plus metronidazole. For Streptococcus , penicillin G plus clindamycin. See p. 247 for details

OSTEOMYELITIS (Gram positive, Gram negative, anaerobes)—for Gram-positive coverage, clindamycin, cefazolin, or vancomycin. For Gram-negative coverage, cefotaxime or ciprofloxacin. For Pseudomonas , piperacillin or carbapenem or ceftazidime, plus ciprofloxacin or aminoglycoside. Duration of therapy usually at least 6 weeks. See p. 248 for details

SEPTIC ARTHRITIS —vancomycin, cloxacillin, or cefazolin for Gram-positive coverage, ciprofloxacin or ceftriaxone for Gram-negative coverage. Usual duration 4 weeks. See p. 273 for details

Hepatitis B

See HEPATITIS B (p. 130)

Hepatitis C

See HEPATITIS C (p. 131)

Herpes Simplex Virus Infection

See HERPES SIMPLEX VIRUS (p. 366)

Human Immunodeficiency Virus

NEJM 2005 353:16; MMWR 2009 58:RR-4; www.aidsinfo.nih.gov/Guidelines/

Risk Factors for HIV

SEXUAL CONTACT —homosexual, heterosexual

PARENTERAL —IDU, transfusion, or unsafe needle use in developing world, health workers

MATERNAL–FETAL —in-utero, delivery, breast feeding

Acute HIV Infection

STRAINS —HIV1 globally; HIV2 mainly in West Africa

SYMPTOMS —acute febrile “mononucleosis-like” illness, lymphadenopathy, pharyngitis, rash and headache within 1 – 6 weeks post-exposure. Hematologic (lymphopenia, thrombocytopenia) and liver enzyme abnormalities

DIAGNOSIS —ELISA assay (sens ∼100%, spc <100%) → if positive, repeat ELISA → if positive, Western blot → if indeterminate, repeat Western blot 4–6 weeks, 3 months, and 6 months later. If worrying about window period (2–6 weeks post-exposure), may perform viral load testing

BASIC WORKUP FOR THE NEWLY DIAGNOSED

HIV status —viral load, CD4 count, genotype antiretroviral drug resistance testing

baseline —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, fasting lipid profile, amylase, lipase, CK, HLA B5701, βhCG, CXR, ECG

co-existing/opportunistic infections —HAV serology, HBV testing (HBsAg, HBsAb, HBcAb. If HBsAg or HBcAb positive, check HBV DNA as well), HCV testing (HCV antibodies, if negative but CD4 <200/mm 3 and liver enzymes abnormal, consider HCV RNA testing. If HCV positive, assess genotype ± liver biopsy), Pap smear, anal screening for HPV in gay men (no consensus yet), Chlamydia and gonorrhea screen, RPR (syphilis), TB skin test, toxoplasma serology, CMV serology

Natural History of HIV

viral load —rate of progression (speed of train). Indicates activity of viral replication. Critical measure of effect of antiretroviral therapy, once started

CD4 count —progress and stage of disease (distance to crash). Indicates relative health of immune system and risk of opportunistic complication

follow-up —viral load and CD4 count (usually 3–4-month intervals, or q2–8weeks if change of HAART)

AIDS —CD4 <200/mm 3 or any AIDS-defining diseases

bacterial —MAC, TB, recurrent Salmonella sepsis

viral —CMV retinitis, chronic HSV, PML

fungal —esophageal candidiasis, extrapulmonary coccidioidomycosis, histoplasmosis or cryptococcosis

parasitic — Pneumocystis jiroveci pneumonia (PJP), toxoplasmosis, chronic Cryptosporidiosis or isosporiasis

hiv —HIV encephalopathy, wasting syndrome

neoplasms —Kaposi's sarcoma, CNS lymphoma, non-Hodgkin’s lymphoma, cervical carcinoma

MAJOR CAUSES OF DEATH IN HIV PATIENTS ON HAART —AIDS (30%), liver disease (14%), cardiovascular disease (9%), non-AIDS cancers (8%)

CNS Lesions in HIV Patients

Differential Diagnosis

brain abscess —toxoplasma (CD4 <100/mm 3 , usually multiple ring-enhancing lesions), tuberculosis (any CD4), Cryptococcus (CD4 <100/mm 3 ), Histoplasma (CD4 <500/mm 3 ), aspergillosis

CNS lymphoma (CD4 <100/mm 3 )

progressive mult-ifocal leukoencephalopathy (PML, CD4 <100/mm 3 )—reactivation of JC virus, hypodense white matter lesion

DIAGNOSIS —CBCD, lytes, urea, Cr, blood C&S, toxoplasma IgG antibodies, EBV PCR, JC virus PCR, CT/MR head, PET scan (CNS lymphoma has higher activity than abscess), brain biopsy (if suspect CNS lymphoma). The combination of (1) multiple ring enhancing lesions, (2) positive antitoxoplasmosis antibodies, and (3) lack of toxoplasma prophylaxis in a HIV patient with CD4 count <100/mm 3 has 90% PPV for diagnosing toxoplasma

TREATMENT OF TOXOPLASMOSIS —pyrimethamine plus either sulfadiazine or clindamycin

Chronic Meningitis in HIV Patients

Differential Diagnosis

cryptococcus (CD4 <100/mm 3 )—ubiquitous fungus. High opening pressure (>200 cmH 2 O)

bacterial meningitis (any CD4)— N. meningitis , S. pneumoniae, Listeria , Gram-negative bacilli

viral meningitis (any CD4)—HSV encephalitis

DIAGNOSIS —CBCD, lytes, urea, Cr, blood C&S, serum CRAG (sens 95% for Cryptococcus), CT head, lumbar puncture (for Cryptococcus and cryptoantigen)

TREATMENT OF CRYPTOCOCCUS —induction with amphotericin B 0.7 mg/kg IV daily plus flucytosine 25 mg/kg PO QID, switch to fluconazole 400 mg PO daily ×2 months for consolidation, followed by fluconazole 200 mg PO daily as maintenance. Management of increased intracranial pressure may be needed

Respiratory Infections in HIV Patients

Differential Diagnosis

community-acquired pneumonia (any CD4)—most common cause is S. pneumoniae . Others include Moraxella, H. influenzae

tuberculosis (any CD4)—170× increased risk in HIV patients. May be extrapulmonary

non- TB mycobacterium —MAC (CD4 <100/mm 3 , pulmonary involvement alone is rare, usually disseminated)

fungal (CD4 <500/mm 3 )— Histoplasma , Coccidioides , Cryptococcus

pneumocystis jirovecii pneumonia (PJP, CD4 <200/mm 3 )

DIAGNOSIS —CBCD, lytes, urea, Cr, LDH (↑ in PJP but non-specific), blood C&S and mycobacterial culture, sputum C&S and AFB, ABG, urine C&S, CXR, bronchoscopy (lavage, biopsy)

TREATMENT OF PJP — trimethoprim–sulfamethoxazole 15 mg of TMP/kg PO/IV divided q8h daily ×21 days. If severe disease (PaO 2 <70 mmHg), add prednisone 40 mg PO BID ×5 days, then 40 mg PO daily ×5 days, then 20 mg PO daily ×11 days. Alternatives to trimethoprim–sulfamethoxazole include dapsone plus trimethoprim, or clindamycin plus primaquine, pentamidine IV. Use atovaquone if G6PD deficiency

Esophagitis in HIV Patients

Differential Diagnosis

infections candida (CD4 <500/mm 3 )—50–70% HSV (any CD4)—5–10% CMV (CD4 <100/mm 3 )—5–15%

non-infectious —GERD, pill esophagitis, neoplasms

idiopathic (any CD4)—10–30%

diagnosis —empiric therapy (fluconazole), endoscopy with cultures for fungus, virus, and biopsy

Hepatitis/Cholangitis/Pancreatitis in HIV Patients

Differential Diagnosis

infections TB (any CD4) mycobacterium avium complex (MAC, CD4 <100/mm 3 )— M. avium, M. intracellulare viruses —HBV, HCV, CMV parasites —Cryptosporidium, Microsporidium, Cyclospora

alcohol

drugs —antiretrovirals, antibiotics (sulfa, isoniazid, rifampin, ketoconazole, fluconazole)

diagnosis —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, lipase, INR, cultures and serologies, U/S abd, CT abd, ERCP

Colitis/Diarrhea in HIV Patients

Differential Diagnosis

infections bacterial — Salmonella, Shigella, Campylobacter, Yersinia, EHEC, EIEC, C. difficile TB (any CD4) mycobacterium avium complex (MAC, CD4 <100/mm 3 )— M. avium , M. intracellulare CMV (CD4 <100/mm 3 ) parasitic ★ MAGIC ★— M icrosporidium, Ent A moeba, G iardia, I sospora, C ryptosporidium

medications —antiretrovirals, antibiotics

AIDS enteropathy —diagnosis of exclusion

DIAGNOSIS —CBCD, lytes, urea, Cr, stool C&S, stool O&P with acid fast staining, stool MAC, C. diff toxin, fecal WBC, Cryptosporidium

TREATMENT OF MAC — clarithromycin 500 mg PO BID or azithromycin 600 mg PO daily, plus ethambutol 15 mg/kg PO daily, plus rifabutin 600 mg PO daily for at least 12 months and at least 6 months of immune reconstitution (CD4 >100–200/mm 3 )

Aids-Associated Malignancies

Aids-Defining Malignancies

K aposi's sarcoma (any CD4)—strongly associated with HHV8. Lesions may involve skin, oral mucosa, lungs, and GI tract. Treat with liposomal doxorubicin

non- H odgkin's lymphoma (CD4 <100/mm 3 )—diffuse large B-cell lymphoma, primary effusion lymphoma (associated with HHV8 and EBV), and plasmablastic lymphomas. Treat with combination chemotherapy (CHOPR)

primary CNS lymphoma (CD4 <100/mm 3 )—strongly associated with EBV. Treat with radiation and/or high-dose methotrexate or intrathecal chemotherapy

cervical carcinoma (any CD4)—strongly associated with HPV. Treat with surgery, radiation, and/or chemotherapy (cisplatin)

NON- AIDS -DEFINING MALIGNANCIES —increased incidence of Hodgkin’s lymphoma, multiple myeloma, anogenital cancer, testicular cancer (seminoma), and basal cell carcinoma in HIV patients. Lung cancer, colorectal cancer, melanoma, squamous cell carcinoma of skin, and head and neck cancer may also be increased

Education, Prophylaxis, and Immunization for HIV Patients

EDUCATION AND COUNSELING —patient MUST be told to reveal HIV status to sexual partners and other supportive individuals. Advise regarding condom use and safer sex practices. Risk reduction strategies should be explored for substance abuse (e.g. avoid alcohol use that may cause disinhibition), tobacco use, and other social issues. HIV is a chronic disease that can be successfully treated

PJP PROPHYLAXIS —for patients with CD4 <200/mm 3 . Trimethoprim–sulfamethoxazole SS 1 tab PO daily, or trimethoprim–sulfamethoxazole DS 1 tab PO daily, or trimethoprim–sulfamethoxazole DS 1 tab PO three times a week. If allergic, desensitize or use dapsone

TOXOPLASMOSIS PROPHYLAXIS —for patients with positive Toxoplasma serology and CD4 <100/mm 3 . Trimethoprim–sulfamethoxazole DS 1 tab PO daily. If allergic, dapsone plus pyrimethamine plus folinic acid are alternatives

MAC PROPHYLAXIS —for patients with CD4 <50/mm 3 . Azithromycin 1200 mg PO once weekly

HISTOPLASMOSIS PROPHYLAXIS —for patients with CD4 <150/mm 3 and living in endemic area. Itraconazole 200 mg PO daily

TB PROPHYLAXIS —for patients with positive tuberculin skin test reaction (induration ≥5 mm) and not treated for TB previously. Isoniazid 5 mg/kg/day PO daily to max 300 mg/day, or 900 mg TIW ×9 months. Rifampin 600 mg PO daily ×4 month restricted to exposures to INH-resistant, RIF-susceptible isolates. Should be followed by a TB specialist

vaccinations

give —pneumococcal vaccine every 5 years, hepatitis B vaccine (if non-immune), hepatitis A vaccine (if non-immune and especially if homosexual), influenza vaccine annually

generally avoid —live vaccines (oral polio, varicella, measles-mumps-rubella, or yellow fever immunizations)

Related Topics

Hepatitis B (p. 130)

Hepatitis C (p. 131)

HIV in Pregnancy (p. 413)

Needle Stick Injury (p. 269)

Tuberculosis (p. 250)

Antiretroviral Therapy for HIV Patients

NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) —zidovudine (ZDV, AZT), stavudine (d4T), didanosine (ddI), lamivudine (3TC), abacavir (ABC), tenofovir (TDF), and emtricitabine (FTC). Major side effects include hepatic steatosis, lactic acidosis, neuropathy, anemia, pancreatitis, and renal disease

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) —efavirenz (EFV), nevirapine (NVP), etravirine (ETR). Major side effects include rash, Stevens–Johnson syndrome, hepatitis, and CNS complications

PROTEASE INHIBITORS (PI) —saquinavir (SQV), indinavir (IDV), nelfinavir (NFV), lopinavir–ritonavir (LPV/RTV), fosamprenavir (FPV), atazanavir (ATV), tipranavir (TPV), and darunavir (DRV). Major side effects include hyperglycemia, fat redistribution syndrome, insulin resistance, and GI intolerance

INTEGRASE INHIBITORS —raltegravir

FUSION INHIBITOR (FI) —enfuvirtide (T-20)

CCR5 ANTAGONIST —maraviroc

EXAMPLES OF PREFERRED HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) REGIMENS

NRTI (tenofovir plus emtricitabine) plus NNRTI (efavirenz)

NRTI (tenofovir plus emtricitabine) plus PI (atazanavir/ritonavir or darunavir/ritonavir)

NRTI (tenofovir plus emtricitabine) plus integrase inhibitor (raltegravir)

Therapeutic Decisions in HIV

GOALS OF HIV THERAPY —durable suppression of HIV viral load to undetectable levels, reduction in HIV-related morbidity, improvement in quality of life, prolongation of survival, restoration of immune function, and prevention of HIV transmission

APPROACH —start treatment in all symptomatic patients and in asymptomatic patients if CD4 <350/mm 3 . Treatment should be considered for CD4 between 350 and 500/mm 3 and is optional for those >500/mm 3 . Rapidly declining CD4 counts (>100/mm 3 /year) or baseline viral loads >100,000 copies/mL increase the urgency of treatment. Initiate HIV treatment regardless of CD4 in pregnancy, HIV nephropathy, and in those with HBV when therapy for HBV is indicated. A commitment to lifelong treatment and adherence is essential prior to initiating therapy. HIV therapy is increasingly complex and should only be undertaken by those with expertise in HIV management

RESPONSE —successful if viral load ↓ by 2 logs after 8 weeks and ↓ to <50 copies/mL after 6 months of therapy. Need to continue therapy or may develop viral load rebound/drug resistance. If failure, consider non-adherence and/or resistance. Resistance testing should be performed, and the regimen should be changed based on resistance profile

Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV Patients

PATHOPHYSIOLOGY —delayed (1 week to several months) inflammatory response as the immune system is restored by antiretrovirals, leading to acute, paradoxical deterioration of pre-existing infections (TB, MAC, PJP, histoplasma, HCV, HBV). Clinical features highly variable. IRIS is a diagnosis of exclusion after considering drug reactions, non-adherence, new onset, or progression of opportunistic infection. May occur in up to 25% of patients with opportunistic infections started on HAART (e.g. lymphadenopathy after starting antiretrovirals in patients with disseminated MAC or worsening CXR and fever in patients with TB). In general, treat opportunistic infections for 2 weeks prior to initiating antiretroviral therapy

TREATMENTS —supportive, continue antiretrovirals, give corticosteroids

Viral Hepatitis in HIV Co-infected Patients

Hepatitis B

pathophysiology —HIV/HBV co-infection rate is up to 20–30% in Asia/sub-Saharan Africa where transmission is mostly vertical or between young children and 5–10% in the USA and Europe where transmission is mostly via IDU and sexual contact. Co-infection is associated with increased risk of progression to end-stage liver disease

diagnosis —for patients with isolated HBcAb, 10–45% have occult HBV infection with detectable levels of HBV DNA

prevention —hepatitis B vaccination of family and sexual partners

treatment —long-term combination therapy with a nucleoside analogue and nucleotide analogue (e.g. tenofovir plus either emtricitabine or lamivudine) is recommended in co-infected patients

Hepatitis C

pathophysiology —HIV/HCV co-infection rate up to 70–95% for patients with IDU and hemophilia and 1–12% for men who have sex with men. Co-infection results in more aggressive HCV, with more rapid progression to liver failure and hepatocellular carcinoma, particularly if concurrent alcohol use

diagnosis —rarely may be HCV seronegative requiring PCR testing. Histologic injury as defined by liver biopsy is a much better predictor of clinical outcomes than liver enzymes or HCV viral load and may be useful in selected patients to guide therapy

prevention —risk reduction and safer needle use

treatment —pegylated interferon α plus ribavirin at standard doses. Response rate is about 50% lower than for HCV monoinfection. ddI is contraindicated and AZT use is discouraged in those on ribavirin

NEJM 2007 356:14

Influenza

NEJM 2008 359:24

Differential Diagnosis

VIRAL —influenza A, B, C, parainfluenza, RSV, metapneumovirus, adenovirus, rhinovirus

BACTERIAL PNEUMONIA — Streptococcus pneumoniae , Staphylococcus aureus , Haemophilus , Moraxella

ATYPICAL — Mycoplasma , Chlamydia , Legionella , TB, community-acquired MRSA

Pathophysiology

CLASSIFICATION —the three types of influenza are A, B, and C. Influenza A can be classified into various subtypes based on the combination of two surface glycoproteins: neuraminidase (1 of 9 subtypes) and hemagglutinin (1 of 16 subtypes), e.g. H1N1, H1N2, and H3N2. Influenza A subtypes and influenza B can be further classified into various strains that arise due to antigenic drift

HOSTS —influenza B and influenza C viruses mainly affect humans. In contrast, influenza A can infect both humans and animals, including wild birds, poultry, pigs, dogs, and horses. Some influenza A strains are highly pathogenic and can cause severe disease in specific hosts, while others are associated with low pathogenicity. The process whereby at least two different viral strains combine to form a new subtype with a mixture of surface antigens of the original strains is termed antigenic shift and is the source of pandemic influenza virus

ANTIGENIC DRIFT —a gradual change in viral RNA sequence that occurs in both influenza A and B. This process is due to random point mutations in the genes encoding neuraminidase or hemagglutinin, creating strains of virus with new surface glycoproteins. Thus, antibodies against previous strains are ineffective. Can result in seasonal epidemics

ANTIGENIC SHIFT —an abrupt and significant emergence of novel viral strains. Only happens in influenza A. Antigenic shift occurs through mixing of human influenza A and animal (e.g. pig, bird) influenza A virus genes to create a new human influenza A subtype through a process called genetic reassortment (e.g. swine flu, avian flu). Rarely, avian strains of influenza may directly infect humans. Antigenic shift generates new virus and triggers pandemics as the majority of the population have no immunity against this new virus

PANDEMIC (worldwide outbreak)—based on the following criteria: (1) emergence of a new subtype of influenza A virus, (2) this virus is able to infect humans, (3) this virus can spread easily from person to person in a sustained manner

Clinical Features

SYMPTOMS —acute onset of systemic symptoms, such as fever, headache, myalgia, arthralgia, fatigue, and respiratory symptoms such as cough, dyspnea, and sore throat

COMPLICATIONS — respiratory (bacterial pneumonia), muscular (rhabdomyolysis, myositis), neurologic (encephalitis, aseptic meningitis, transverse myelitis, Guillain–Barre syndrome)

Investigations

Basic

labs —CBCD, lytes, urea, Cr, AST, ALT, ALP, bilirubin, urinalysis

microbiology —nasopharyngeal swab for rapid assays (variable sensitivity/specificity), RT-PCR (preferred), or DFA (Direct Fluorescent Antigen detection). Blood C&S, sputum Gram stain/AFB/C&S, urine C&S

imaging —CXR

Special

lumbar puncture —if neurologic symptoms

ABG

Management

PREVENTION IS KEY —annual vaccination for the following individuals: 50 or older, children 6–24 months or taking long-term salicylates, any chronic medical condition, pregnant women, healthcare workers, household contacts of those at risk, and residents of chronic care facilities. In some jurisdictions, universal vaccination for influenza is recommended. Depending on the match between vaccine and circulating virus, the efficacy can range from 70 to 90% for a good match and 0 to 50% for poor matches

TREATMENT —neuraminidase inhibitors ( oseltamivir 75 mg PO BID ×5 days, or zanamivir 10 mg inhaled BID ×5 days) are active against influenza A and B. Antiviral treatment is most effective when started within 48 h of symptom onset. Treatment decreases the duration of symptoms by 1 day, reduces viral shedding, and may reduce complications in those at risk. Inhaled zanamivir is relatively contraindicated in patients with asthma or chronic respiratory conditions. Household contacts of infected individuals should be vaccinated and may be given prophylaxis with oseltamivir 75 mg PO daily or zanamivir 10 mg inhaled daily ×10 days. Resistance to oseltamivir is a problem in some strains of influenza A, and amantadine or rimantidine may have a role. Treatment of pneumonia with antibiotics

Treatment Issues

NEURAMINIDASE INHIBITORS —neuraminidase plays an important role for viral release from the host cell. Oral oseltamivir and inhaled zanamivir are active against both influenza A and influenza B

ADAMANTANES —block replication of influenza A RNA through inhibition of M2 protein ion channels. Amantadine and rimantadine are inactive against influenza B and C and resistance is now widspread in influenza A

VACCINE PRODUCTION —every February/March, the World Health Organization makes recommendations regarding the three strains (two A and one B) of influenza viruses that are most likely to cause outbreaks in the fall/winter in the upcoming season. Vaccines are then produced based on this decision

Antiviral Agents

Fungal Infections

General Approach

CLASSIFICATION —fungal infections can be classified into three main categories: yeasts, molds (“filamentous fungi”), and dimorphic fungi

yeasts —grow as single cells (via budding) and include Candida, Malassezia, Rodotorula, Trichosporon

molds —these filamentous fungi grow as hyphae (via sexual and asexual reproduction) and include Aspergillus , zygomycetes, Fusarium , and dematiaceous (pigmented) fungi. Ubiquitous in the environment (e.g. soil, decaying vegetation, water, air). Infection may cause blood vessel invasion, thrombosis, and obstruction. Clinical syndromes include cerebral parenchymal infections, pulmonary parenchymal infections, hepatosplenic abscesses, and otitis externa

dimorphic fungi —exist as both molds and yeasts and include Coccidioides , Histoplasma , Blastomyces, and Cryptococcus . At low temperatures, found as multicellular molds (which release spores that are inhaled). In warm temperatures (e.g. inside the body), inhaled spores germinate into yeasts, which are infectious to the patient, but no longer contagious (i.e. these patients do not require isolation)

Candidiasis

PATHOPHYSIOLOGY — Candida albicans (“Germ-tube positive” with pseudohyphae) or non-albicans species (“Germ-tube negative,” e.g. C. glabrata, C. tropicalis, C. parapsilosis, C. krusei ), mostly in patients with hematological malignancy, neutropenia, on immunosuppressants, IDU, or those in the intensive care unit with hemodialysis, broad-spectrum antibiotics, surgery, central venous catheters, and parenteral nutrition

CLINICAL FEATURES —localized mucocutaneous infections (thrush and vaginitis), serious focal infections (endophthalmitis, meningitis, osteomyelitis), or disseminated infection (candidemia) with pustular skin lesions, retinal lesions. Candiduria is common in ICU patients, but represents colonization only unless patient is symptomatic

treatments

oropharyngeal — clotrimazole troche 10 mg 5× daily, nystatin suspension (500,000 U) or nystatin pastilles (200,000 U) 4× daily, fluconazole 100 mg PO/IV daily ×1–2 weeks

esophagitis — fluconazole 200 mg PO/IV daily ×2–3 weeks

candiduria —remove catheter, indications for treatment include kidney transplant recipients, prior to cystoscopy or invasive GU procedure, neonates, severe illness, and possibly neutropenia (controversial). Fluconazole 200 mg PO/IV daily ×2 weeks

acute disseminated candidemia —remove all intravascular devices. Fluconazole 800 mg then 400 mg PO/IV daily ×2 weeks (minimum), or one of the echinocandins, including caspofungin 70 mg then 50 mg IV daily, micafungin 100 mg IV daily, or anidulafungin 200 mg then 100 mg IV daily ×2 weeks (minimum) after last positive culture for C. albicans . Echinocandin and lipid formulation of amphotericin B are preferred for initial therapy in neutropenic patients. Almost all (>95%) C. albicans are sensitive to fluconazole. Some laboratories report C. albicans as “ C. albicans complex ” because of structural resemblance between albicans and dubliniensis . This is of no clinical significance because albicans and dubliniensis have same susceptibility patterns. Susceptibility patterns for other non-albicans infections may significantly differ. Consider echinocandin for non-albicans

CID 2009 48:5

Aspergillosis

MICROBIOLOGY —genus contains >185 species including A. fumigatus (80% of clinical infections), A. flavus, A. niger, and A. terreus

PATHOPHYSIOLOGY —mostly in patients with neutropenia, organ or stem cell transplants, advanced AIDS, or on corticosteroids. Invasive aspergillosis has mortality of >50%

CLINICAL FEATURES —spectrum of pulmonary involvement includes colonization, pulmonary aspergilloma (“fungal ball”), allergic bronchopulmonary aspergillosis (ABPA), chronic necrotizing aspergillus pneumonia (CNPA), and invasive aspergillosis. Second most common cause of fungal endocarditis (after Candida ). Cutaneous involvement may follow trauma or dissemination from respiratory tract

DIAGNOSIS —often difficult and may require biopsy with culture and histology. Check quantitative immunoglobulin, aspergillus IgG and IgE, galactomannan levels (suggestive of invasive aspergillosis). CT chest may show multiple nodular lesions (halo sign=nodule with surrounding hemorrhage, air-crescent sign=necrosis and cavitation). Sputum fungal culture and eosinophils, bronchoalveolar lavage, or lung biopsy

TREATMENTS — voriconazole 6 mg/kg q12h ×24 h then 4 mg/kg IV q12h or 200 mg PO BID until resolved. Alternatives include caspofungin 70 mg then 50 mg IV q24h, lipid-formulation amphotericin B 3–5 mg/kg IV daily, micafungin 100–150 mg IV daily, posaconazole 200 mg PO QID then 400 mg BID after clinical stabilization. Some species, especially A. terreus , are resistant to amphotericin. Aspergillus is the only filamentous fungus that can be treated with echinocandins

CID 2008 46:3

Zygomycetes (Mucormycosis)

MICROBIOLOGY —large group of filamentous fungi including Rhizopus, Absidia, Rhizomucor, Mucor, and Cunninghamella

PATHOPHYSIOLOGY —mostly affecting immunocompromised patients and those with diabetes. Prognosis extremely poor

CLINICAL FEATURES —CNS, pulmonary, GI, and cutaneous involvement. Infection can cause devastating rhino-orbital-cerebral and pulmonary infections

TREATMENTS —antifungal therapy frequently needs to be combined with surgical debridement. Empiric treatment options include lipid formulations of amphotericin B and pozaconazole. Note that susceptibility testing of Zygomycetes is not always reliable, and that caspofungin and “azoles” (apart from pozaconazole) are not generally effective

Histoplasmosis

PATHOPHYSIOLOGY — H. capsulatum endemic along St. Lawrence seaway and in Midwestern states located along the Ohio and Mississippi River valleys. Symptoms typically occur in patients who are immunocompromised or exposed to a large inoculum

CLINICAL FEATURES —usually asymptomatic. Pulmonary manifestations may mimic sarcoidosis and include pneumonia (localized or diffuse), granuloma/cavitary lung lesions, and hilar and mediastinal lymphadenopathy. Pericarditis, arthritis, arthralgia and erythema nodosum may also occur without pulmonary symptoms. Disseminated disease may present with hepatosplenomegaly, pancytopenia, oropharyngeal ulcers, skin, and CNS involvement

DIAGNOSIS —fungal culture of blood and tissue, urine antigen, Histoplasma serology, and histopathology. Histoplasma is predominantly an intracellular pathogen; therefore cultures need to be placed in “isolator tube” (containing cell lysis product)

TREATMENTS — itraconazole 200 mg PO TID ×3 days, then 200 mg PO daily–BID, lipid formulation of amphotericin B (preferred for ill patients)

CID 2007 45:7

Cryptococcosis

MICROBIOLOGY —formerly believed to be unicellular yeast, although now confirmed to be dimorphic. Unlike other dimorphic fungi (e.g. Histoplasma, Blastomyces, and Coccidioides ), Cryptococcus is ubiquitous and not geographically isolated. Cryptococcus neoformans has two varieties: C. neoformans var. neoformans and var. gattii

Pathophysiology

C. neoformans —almost invariably in immunocompromised patients including HIV with CD4 <100/mm 3 , transplantation, hematologic malignancies, chronic kidney diseases, diabetes mellitus, cirrhosis, or corticosteroid use. This pathogen is inhaled, then disseminates with predilection for CNS with meningitis more common than focal parenchymal infections

C. gattii —seen more commonly in immunocompetent hosts and paradoxically uncommon in immunosuppressed hosts. Symptomatic infection is usually pulmonary ± focal parenchymal brain infection

CLINICAL FEATURES —CNS, pulmonary, and cutaneous involvement (but may involve any organ)

TREATMENTS — CNS infection (lumbar puncture to lower intracranial pressure, amphotericin B plus flucytosine, followed by fluconazole), pulmonary or cutaneous infection (fluconazole or itraconazole)

CID 2010 50:3

Coccidioidomycosis

PATHOPHYSIOLOGY —endemic to lower deserts of southern Arizona, central California, southwestern New Mexico, and west Texas in USA. Also Mexico, Central and South America. Peak incidence from May–July and October–December. Affects mostly patients with immunosuppression

CLINICAL FEATURES —an acute pulmonary infection that is often asymptomatic, but can cause a flu-like illness or pneumonia. Pulmonary symptoms include chest pain, cough, fever, and hemoptysis if cavitary lesions. Radiologically, unilateral infiltrate and hilar adenopathy are common. Cutaneous symptoms include erythema nodosum and erythema multiforme. Most common sites of dissemination are skin, bone, and meninges

DIAGNOSIS —fungal culture and serology. Note that Cocciodioides is a level 3 pathogen. Therefore, cultures should be processed in high-level isolation unit and labeled carefully. There have been numerous reports of iatrogenic infection of laboratory personnel when adequate precautions not taken

TREATMENTS —usually resolves spontaneously if uncomplicated disease. Antifungal therapy may need to be combined with surgery for certain pulmonary infections. Fluconazole 400 mg PO daily, itraconazole 200 mg PO daily (duration dependent on site of infection and may last months to years). Coccidioides meningitis should be treated with amphotericin B

CID 2005 41:9

Blastomyces

PATHOPHYSIOLOGY —mostly found in northwest Ontario, the Great Lakes, and some Eastern states (e.g. Ohio, Mississippi River valley). Infection occurs by inhalation of aerosolized spores from soil

CLINICAL FEATURES —asymptomatic infection is common. Pulmonary symptoms of acute or chronic pneumonia (incubation time 45–100 days). Extrapulmonary dissemination to skin, bone/joint, GU tract, usually associated with pulmonary disease

DIAGNOSIS —fungal culture. Presence of “broad-based budding yeast” in clinical specimens strongly suggests Blastomyces

TREATMENTS —amphotericin B or lipid formulation for moderate to severe disease or CNS involvement. Itraconazole for mild disease or step-down but has poor blood–brain barrier penetration; alternatives are voriconazole or fluconazole

CID 2008 46:12

Antifungal Agents

Indications for Voriconazole

INVASIVE ASPERGILLOSIS —first line treatment for invasive and CNS

INVASIVE CANDIDIASIS —second or third line treatment for patients who are refractory or intolerant of fluconazole (first line for some) or amphotericin B (first line for others)

FUNGEMIA —empiric treatment for fungi not yet speciated where neither amphotericin B nor fluconazole can be used

FEBRILE NEUTROPENIA —empiric antifungal treatment for patients intolerant of amphotericin B

Indications for Caspofungin

INVASIVE ASPERGILLOSIS —third line treatment for patients who are refractory or intolerant of voriconazole (first line) or amphotericin B (second line)

INVASIVE CANDIDIASIS —second or third line treatment for patients who are refractory or intolerant of fluconazole (first line for some) or amphotericin B (first line for others)

FUNGEMIA —empiric treatment for fungi not yet speciated where neither amphotericin B nor fluconazole can be used

FEBRILE NEUTROPENIA —empiric antifungal treatment for patients intolerant of amphotericin B

Treatment Definitions

REFRACTORY —persistence of positive cultures OR lack of clinical response despite ≥5 days of therapy and removal of catheter if applicable

INTOLERANCE —doubling from baseline and serum Cr ≥450 μmol/L [≥5.1 mg/dL], creatinine clearance ≤40 mL/min or concomitant administration of nephrotoxins, tripling of serum creatinine from baseline, documented allergy, or intolerable infusion reactions

Infection Control

Nosocomial Infections

DEFINITION —infections acquired in hospital that occur between 72 h after admission and 72 h after discharge (up to 30 days for surgical procedures)

URINARY TRACT INFECTIONS —secondary to urinary catheters. Infection rates are 1–5%, up to 100% for long-term catheterization. Complications include cystitis, prostatitis, pyelonephritis, and urosepsis

VENTILATOR-ASSOCIATED PNEUMONIAS —secondary to endotracheal tube insertion (>48 h, p. 94)

BACTEREMIA —secondary to central venous catheters. Infection rates are 3–7%

SURGICAL SITE INFECTIONS —secondary to incisions

PREVENTION STRATEGIES —hand washing, hand washing, and hand washing. Education, isolation, and surveillance are important. Practice routine/standard/universal precautions with the use of gloves when handling all body fluids except sweat. Always use sterile technique when inserting urinary and central venous catheters. Minimize NG tube insertion and keep patient erect if intubated

Isolation

airborne (negative pressure room with high-efficiency particulate aerator filter, certified N95 respirator for personal protection)—varicella, tuberculosis. Negative pressure room required

droplet (mask within 3–6 feet; eye protection)— H. influenzae , N. meningitidis , influenza, RSV, pertussis

contact (glove, gown, wash hands)— C. difficile , VRE, MRSA

N. MENINGITIDIS prophylaxis

chemoprophylaxis —for exposures in last 7 days with ciprofloxacin 500 mg PO ×1 dose or rifampin 600 mg PO BID ×2 days can be used to reduce the risk of N. meningitidis in “close contacts.” Vaccines are not recommended for primary prophylaxis post-exposure, but may be useful for epidemic control on a population basis

close contacts —defined as healthcare workers with direct exposure to respiratory secretions (e.g. mouth-to-mouth resuscitation or intubation), household members, intimate contacts, children in school environments, coworkers in the same office, young adults in dormitories, and recruits in training centers. Not recommended for most medical personnel (i.e. those without direct exposure to patient’s oral secretions) or for casual or indirect contacts (e.g. school or workmates)

Needle Stick Injury

PREVENTION —routine/standard/universal precautions (gloves, gowns, masks if risk of exposure of body fluids), never recap needles, education

PRE-EXPOSURE PROPHYLAXIS —immunization (hepatitis B vaccine at 0, 1, 6 months, influenza)

RISK OF TRANSMISSION —depends on the mechanism of exposure, source patient characteristics, pre- and post-exposure prophylaxis

HBV —6–30% if source positive. Transmission via urine, feces, and saliva unlikely

HCV —1.8% if source positive. Transmission via urine and feces unlikely

HIV —0.3% if source positive. Transmission via urine, feces, and saliva unlikely

Post-Exposure Procedure

source patient testing —HBV, HCV, HIV

exposed person baseline testing —HBV, HCV, HIV (ELISA, Western), CBCD, lytes, urea, Cr, AST, ALT, ALP, bili

HBV prophylaxis —HB Ig (only if source patient is HBsAg positive or unknown and the exposed person is unvaccinated) and start vaccination for HBV

HIV prophylaxis —antiretroviral (if source patient HIV positive). Therapy may include zidovudine and lamivudine ± protease inhibitor such as lopinavir/ritonavir (if source patient had been treated and drug resistance possible). Treatment should be started within 4 h

counseling —protective sexual intercourse, hold blood donation and breastfeeding, side effects of prophylactic medication(s), follow-up in 2 weeks

MMWR 2005 54:RR-9

prophylaxis for other infectious agents —diphtheria (penicillin or erythromycin), meningococcal (rifampin, ciprofloxacin, ceftriaxone), pertussis (trimethoprim–sulfa, erythromycin), rabies (rabies immune globulin, vaccine), varicella zoster (varicella-zoster immune globulin, vaccine), hepatitis A (immune globulin, vaccine)

Immunization for Adults

Ann Intern Med 2009 150:1

Principles

Risk Factors for Specific Organisms

HBV —household contacts/sexual partners of hepatitis patients, IDU, homosexual, multiple sexual partners, tattoo, piercing, transfusions, healthcare workers (prior to vaccine era), residents/workers of institutions for mentally ill or criminals, birth in endemic country

HCV —sexual partners (controversial), IDU, tattoo, piercing, transfusions, residents/workers of institutions for mentally ill or criminals

pneumococcal, meningococcal, haemophilus influenzae —splenectomy

Contraindications

all vaccines —anaphylaxis, severe illness

live vaccines —pregnancy, immunocompromised (steroids, AIDS but not HIV, malignancies)

SIDE EFFECTS —local erythema, fever

Notes