Pocket Medicine (Pocket Notebook Series)

PNEUMONIA

Definitions and clinical manifestations

• Pneumonia: s/s (fever, cough, purulent sputum, dyspnea) + new infiltrate on chest imaging

• Community-acquired pneumonia (CAP): pneumonia acquired outside of hospital setting

• Hospital-acquired pneumonia (HAP): pneumonia acquired ≥48 hrs after hospitalization

• Ventilator-associated pneumonia (VAP): pneumonia acquired ≥48 hrs after intubation

• Lung empyema: accumulation of pus in pleural space

• Lung abscess: parenchymal necrosis with confined cavitation

• Aspiration pneumonitis: acute lung injury after inhalation of gastric contents without infection, though bacterial infection can occur within 24–72 hrs of injury

Microbiology of Pneumonia
Clinical Setting	Etiologies
CAP (AJRCC 2019;200:7)	No pathogen identified in 50–60%, virus alone in ~25%, bacteria alone in ~10%, virus-bacteria coinfection in <5% Viruses: influenza, RSV, hMPV, parainfluenza, rhinovirus, coronavirus S. pneumoniae (most common bacterial cause) S. aureus (espec. post-influenza) Mycoplasma, Chlamydia (espec. in young & healthy) H. influenzae, M. catarrhalis (espec. in COPD) Legionella (espec. in elderly, smokers, ↓ immunity, TNF inhibitors) Klebsiella & other GNR (espec. in alcoholics & aspiration)
HAP/VAP	S. aureus, Pseudomonas, Klebsiella, E. coli, Enterobacter, Acinetobacter, Steno. IV abx w/in 90 d risk factor for MDR. Viral ~20% cases.
Empyema	S. pneumo, S. aureus, E. coli, Klebsiella, H. influenzae, anaerobes
Lung abscess	Often polymicrobial, incl. oral flora. S. aureus, anaerobes, Strep (anginosus, GAS), GNR (Klebsiella, E. coli, Pseudomonas), Nocardia, Actinomyces, fungi, mycobacteria, Echinococcus
Immunosupp.	Above + Pneumocystis, Cryptococcus, Nocardia, non-TB myco- bacteria (NTM), CMV, invasive molds

Diagnostic studies (AJRCC 2019;200:e45)

• Sputum Gram stain/Cx: reliable if high quality (ie, sputum not saliva; <10 squam cells/lpf). If bacterial PNA should be purulent (>25 PMN/lpf). Yield ↓ >10 h after abx (CID 2014;58:1782).

• Procalcitonin: ↑ in acute bacterial (not viral) PNA. Consider stopping abx if levels <0.25 ng/ml (<0.5 ng/mL in ICU Pts) or ↓ ≥80% from peak. ↓ abx exposure by 2–3 d (Lancet ID 2016;16:819 & 2018;18:95). Not validated in immunosuppressed hosts. Levels harder to interpret in CKD. False ⊕ in cardiac arrest, shock, burns, surgery.

• CXR (PA & lateral; see Radiology inserts)

• HIV test (if unknown); MRSA nares swab in HAP/VAP (if ⊖ 96% NPV for MRSA PNA)

• Consider in severe disease (otherwise not recommended):

Legionella urinary Ag (detects L. pneumophila L1 serotype, 60–70% of clinical disease)

S. pneumoniae urinary Ag (Se 70%, Sp >90%)

Blood cultures (before antibiotics!): ⊕ in ~10% of inPts, depending on pathogen

• If clinical suspicion for mTB: (induced) sputum AFB stain ×3 q ≥8h (w/ ≥1 early morning). Mycobact. cx (empiric respiratory isolation while pending); MTb DNA PCR if smear ⊕.

• Viral testing (DFA or PCR) on nasopharyngeal swab or sputum

• Bronchoscopy: immunosupp., critically ill, failure to respond, suspected PCP, inadequate/ ⊖ sputum cx (send Gram stain/cx, Legionella cx, fungal cx/wet prep, mycobacterial cx/smear, modified AFB stain, galactomannan)

• Reasons for failure to improve on initial treatment:

Insufficient time: may take ≥72 h to see improvement (fever persists >4 d in ~20%)

Insufficient drug levels for lung penetration (eg, vanco trough <15–20 μg/mL)

Resistant organisms or superinfxn: eg, MRSA, Pseudo.; consider bronchoscopy

Wrong dx: fungal/viral, chemical pneumonitis, PE, CHF, ARDS, DAH, ILD; consider CT

Parapneumonic effusion/empyema/abscess: if CXR ⊖, consider bedside US or CT. If effusion >1 cm, drain & send fluid pH, gluc, Gram stain & Cx.

Metastatic infection (eg, endocarditis, septic arthritis)

Triage

• qSOFA predicts poor outcomes, prolonged ICU stay, and in-hospital mortality if >2 of 3: RR>22, AMS, SBP<100 (JAMA 2016; 315:801)

Treatment (NEJM 2019;380:651; AJRCC 2019;200:e45)
Scenario	Regimen
CAP (outPt)	Amoxicillin, azithro, or doxy (avoid latter two if >25% resistance locally)
CAP (ward)	[3rd-gen ceph + azithro] or levoflox; omadacycline ≈ FQ (NEJM 2019;380:517)
CAP (ICU)	3rd-gen ceph + azithro. Only cover MRSA or Pseudomonas if risk factors (prior PsA PNA, MRSA infection, recent hospitalization, IV abx)
HAP/VAP	[Pip-tazo or cefepime or carbapen.] + [vanc or linezolid]. May add resp FQ or azithro if concerned for atypicals. Daptomycin not active in lungs.
Empyema/ abscess	[3rd-gen ceph + MNZ] or amp-sulbactam. Only cover Pseudomonas or MRSA if risk factors. Empyema: drain if >1 cm ± chest tube. Abscess: drainage not required. De-escalate to PO abx based on clinical improvement & micro.

• Avoid quinolones if suspect TB. When possible, de-escalate abx based on sensitivities.

• Steroids: not unless indicated for shock or COPD exacerbation; may ↓ mortality, mech vent, & ARDS in severe CAP (Cochrane 2017;12:CD007720). Avoid in influenza.

• Duration: CAP: 5–7 days, can de-escalate IV abx to PO after clinical improvement. HAP/VAP: 7 days. Empyema/abscess: 2–6 wks based on complexity, drainage.

Prevention

• All persons >65 or age 19–64 w/ CHF, lung disease, cirrhosis, DM, EtOH, smoker, immunosupp. (eg, ESRD, organ transplant, HIV, leukemia, lymphoma, asplenia)

• PCV20 vaccine or PCV15 + PPSV23 1 yr later

VIRAL RESPIRATORY INFECTIONS

URI, bronchitis, bronchiolitis, pneumonia (Lancet 2011;377:1264)

Microbiology & epidemiology (http://www.cdc.gov/flu/weekly)

• Typical pathogens: Short, mild = rhinovirus, other non-SARS-CoV-2 coronavirus.

Longer, more severe or complicated = influenza, parainfluenza, RSV, adenovirus, metapneumovirus, COVID-19 (vide infra). Can be esp. severe in immunosupp.

Diagnosis

• Sx: fever, cough, myalgias, SOB, wheezing, sore throat, rhinorrhea, malaise, confusion

• Respiratory viral panel on nasal swab or sputum/BAL; rapid flu nasopharyngeal swab preferred to nasal swab (Se 50–70%, Sp >90%); RT-PCR for flu A/B (>95% Se & Sp)

Treatment (NEJM 2017;390:697)

• Influenza (A & B):

• Neuraminidase inhib. (eg, oseltamivir); must start w/in 48 h of sx for low-risk; for critically ill or immunosupp., start ASAP even if >48 h. Peramivir IV if unable to tolerate PO.

• Endonuclease inhib. (baloxavir), superior to oseltamivir in ↓ sx & viral load on 1^st day of Rx, but resistance emerging; no data in severe influenza (NEJM 2018; 379:913)

• RSV: can consider inhaled ribavirin in immunosupp, but very expensive & rarely used

Prevention

• Inactivated influenza vaccine: rec for all >6 mo of age.

• Isolation, droplet precautions for inpatients strongly recommended

• Ppx for high-risk contacts of confirmed influenza: oseltamivir × 7 d or baloxavir single dose

CORONAVIRUS (COVID-19) / SARS-COV-2 INFECTION

Microbiology & epidemiology

• Person-to-person transmission via respiratory particles; asx & pre-sx transmission can occur

• Incubation period: up to 14 days, median time of 4–5 days from exposure to sx onset

Presentation

• Ranges from asx to severe illness. Of those with sx, 81% mild-to-moderate, 14% severe (hypoxia), 5% critical (ARDS, shock, multiorgan failure) (JAMA 2020:323;13)

• Common sx: fever, chills, cough, dyspnea, myalgias, HA, N/V, diarrhea, loss of smell/taste

• Risk factors for severe illness: age ≥65, CVD, DM, stroke, lung dx, CKD, obesity

Diagnosis

• RT-PCR testing of nasopharynx, lower respiratory tract, or anterior nares

• Rapid antigen testing of anterior nares (less Se than PCR)

• CXR: typically bilateral opacities (esp peripheral), can be nl early; consider CT if dx ?

Treatment (https://www.covid19treatmentguidelines.nih.gov/)

• Non-hospitalized: mAb, paxlovid and molnupiravir if risk factors for severe disease

• Hospitalized w/ suppl O₂: dexamethasone ± remdesivir (inhibits vRNA polymerase)

• Hospitalized w/ mechanical ventilation or ECMO: dexamethasone + anti IL6 (tocilizumab/ sarilumab) or anti JAK (baricitinib/tofacitinib) if rapidly ↑ O₂ requirement but not intubated

• Anticoag. due to high rate of thrombosis; Ppx vs. Rx dosing based on severity and risk

Prevention

• Vaccines against spike protein highly effective. Infxn may occur but severity much lower.

• See CDC website for quarantine guidelines (https://www.cdc.gov/coronavirus/2019-ncov/your-health/quarantine-isolation.html)

FUNGAL INFECTIONS

Fungal diagnostics

• Antigen detection

1,3-β-D glucan (Se 75%, Sp 85%): Candida, Aspergillus, Histo, Coccidio, PCP, for invasive infxn in immunocomp host. Cannot detect Mucor, Rhizopus, Blasto, Crypto.

Galactomannan (Se 71%, Sp 89%): Aspergillus. BAL preferred. Test serum only if heme malig or HSCT. Not for screening or Rx monitoring in solid organ Tx, chronic granulomatous disease (false ⊕ w/ colonization).

Histo urine/serum Ag: Se of urine Ag 90% (serum 80%) if dissem; Sp limited by X-react

Crypto Ag (serum, CSF): sAg >90% Se & Sp in invasive, less for pulm. only unless HIV+

Blastomyces: urine >serum Ag, high Se but modest Sp given X-react w/ other fungi

• Culture: Candida grows in blood/urine Cx, but ↓ Se of BCx in deep tissue infection; others (eg, Crypto, Histo) ↓↓ Se of BCx; if suspect Coccidio alert lab (biohazard)

• Antibody detection: useful for Coccidio (serum IgG and IgM 7–21 days post exposure)

• Biopsy: no grinding of tissue if Zygomycetes suspected

Candida species

• Microbiology: normal GI flora; C. albicans & nonalbicans spp.

• Epidemiology: neutropenia, immunosupp., broad-spectrum abx, intravascular catheters (esp. if TPN), IVDU, abd surgery, DM, renal failure, age >65

• Clinical manifestations:

Mucocutaneous: cutaneous (eg, red, macerated lesions in intertriginous zones); oral thrush (exudative, erythematous or atrophic; if unexplained, r/o HIV); esophageal (odynophagia; ± oral thrush); vulvovaginal, balanitis

Candiduria: typically colonization due to broad-spectrum abx and/or indwelling catheter

Candidemia: ⊕ blood cx are never a contaminant! R/o retinal involvement (ophtho consult) & endocarditis w/ TTE ± TEE (esp. w/ prosthetic valve) as req ↑ Rx duration. May present w/ erythematous papules or pustules in immunosupp.

Candida in sputum: usually not a clinically significant pathogen

Hepatosplenic: typically, after prolonged neutropenia as cell counts are recovering

Treatment (CID 2016;62:409)
Mucocutaneous	Clotrimazole, nystatin, fluconazole, itraconazole
Candiduria (if pyuria or sx of infxn)	Fluconazole or intravesical ampho if severe infxn, immunosupp. or planned GU procedure.
Candidemia w/o neutropenia	Echinocandin (mica 1st line) if stable w/o prior azole exposure can consider fluc; remove CVC; test for azole-resist.
Candidemia w/ neutropenia	Echinocandin or ampho; remove CVC; test for azole-resist.

Aspergillosis (Lancet 2021;397:499)

• ABPA: airway hypersensitivity secondary to aspergillus colonization

• Chronic pulmonary aspergillosis: includes aspergilloma (fungus ball), pulm. nodules, chronic cavitary and chronic fibrotic pulmonary aspergillosis that can present with subacute cough, dyspnea, hemoptysis; aspergilloma/nodules can be asymptomatic

• Invasive aspergillosis: seen in immunosupp., esp prolonged neutropenia. Primarily pulmonary, ie, PNA w/ chest pain, cough, hemoptysis; CT: solid/cavitary nodules, halo sign. Non-pulm. manifestations: rhinosinusitis (like Zygomycetes), CNS (brain abscesses, mycotic aneurysm), endophthalmitis (eye pain, visual changes), cutaneous, GI (typhlitis)

Rx: voriconazole or posaconazole preferred over ampho. For aspergilloma, ± resection.

Zygomycetes (eg, Mucor, Rhizopus)

• Epidemiology: diabetes (espec. those w/ prior DKA), heme malignancy, neutropenia, transplant, chronic steroids, iron overload, trauma, h/o voriconazole Rx or Ppx

• Clinical: rhinocerebral = severe periorbital/facial pain, swelling, vision changes, sinusitis, opthalmoplegia, nasal ulcerations/ necrosis, HA. Other: pulm. (PNA w/ infarct & necrosis); cutaneous (indurated painful cellulitis ± eschar); GI (necrotic ulcers); renal (flank pain, fever).

• Treatment (high mortality): 1st line is debridement + ampho. Can deescalate to posaconazole or isavuconazole if improving after debridement.

ENDEMIC FUNGI

Cryptococcus (CID 2010;50:291)

• Epidemiology: immunosupp. most susceptible (espec. AIDS, transplant recipients, and cirrhosis); can occur in healthy hosts (esp C. gattii)

• Clinical manifestations

CNS (meningoencephalitis): subacute HA, fever, meningismus, CN abnl, ± stupor

Other sites: pulm., GU, cutaneous, CNS cryptococcoma. With any crypto dx, LP all Pts.

• Dx: CSF cell counts vary in HIV vs. non-HIV; serum/CSF CrAg (Se 99%, Sp 86–100%); cx

• Treatment

CNS Rx has induction (ampho ± flucytosine × 2 wks), consolidation and maintenance (fluconazole) phases (NEJM 2013;368:1291); if ↑ ICP, may need repeat LP/VP shunt

Non-CNS disease (pulm., skin, bone, blood) in HIV ⊖ Pts: consider fluconazole

Histoplasmosis (CID 2007;45:807)

• Epidemiology: endemic to central & SE U.S., but sporadic cases throughout U.S.

• Clinical manifestations

Acute: PNA ± hilar LAN, often subacute, but high inoculum can cause acute severe PNA

Chronic lung disease: cough + B sx ± cavitary lesions (Ddx TB, blasto)

Disseminated (seen in immunosupp.): fever, fatigue, wt loss, mucocutaneous lesions, ΔMS, arthritis, pericarditis, interstitial infiltrates HSN, LAN, cytopenias

• Treatment: mild to mod: itraconazole; disseminated/severe: ampho → itraconazole

Coccidioidomycosis (CID 2016;63:112)

• Epidemiology: endemic to SW U.S., Central and South America

• Clinical manifestations

Acute: subclinical PNA, arthralgias, rash (erythema nodosum)

Chronic lung disease (seen in immunosupp): dyspnea, chest pain, hemoptysis, “B” sx

Disseminated (immunosupp, pregnant): meningitis, osteo, monoarthritis, cutaneous

• Treatment: no Rx for mild PNA in immunosupp.; ampho for severe/CNS involvement; azoles for extrathoracic w/o CNS involvement; some cases require debridement

Blastomycosis (CID 2008;46:1801)

• Epidemiology endemic to the eastern ½ of U.S.

• Clinical manifestations

Acute: PNA w/o hilar LAN that can progress to ARDS

Chronic: cough + “B” sx, fibronodular infiltrates, masses ± cavitary lesions (Ddx TB, histo)

Disseminated (seen in immunosupp.): rash (verrucous, ulcerated lesions), subcutaneous nodules, osteo, GU (prostatitis, epididymoorchitis), CNS involvement uncommon

• Treatment: mild to mod: itraconazole; disseminated/severe/CNS: ampho → itraconazole

INFXNS IN IMMUNOSUPPRESSED HOSTS

Overview

• Many Pts have ≥1 risk (eg, DM, ESRD, transplant, extremes of age)

• Accurate dx of opportunistic infections and targeted Rx key in this population

• The following is not an exhaustive list, but a delineation of common or classic etiologies

Predisposition	Classic Infectious Etiologies
Humoral immune dysfunction (eg, CVID, myeloma) and asplenia	Encapsulated bacteria: S. pneumo, H. flu, N. meningitidis (vaccinate against these 3, ideally prior to splenectomy) Other bacteria: E. coli and other GNRs, Capnocytophaga Parasites: Babesia, Giardia; Viruses: VZV, echovirus, enterovirus
Granulocytopenia or neutropenia (includes DM, ESRD → functional impairment)	Bacteria: Gram positive: coag ⊖ staph, S. aureus, viridans strep, S. pneumo, other strep; Corynebacterium spp., Bacillus spp. Gram negative: E. coli, Klebsiella, Pseudomonas Fungi: Yeast: Candida albicans and other Candida spp. Molds: Aspergillus, Mucor spp., endemic fungi and others Viruses: VZV, HSV1 and 2, CMV
Impaired cell-mediated immunity (CMI) (eg, HIV/AIDS, chronic steroids, posttransplant, DM, ESRD, autoimmune dis.)	Bacteria: Salmonella spp., Campylobacter, Listeria, Yersinia, Legionella (Lancet 2016;387:376), Rhodococcus, Nocardia, TB, non-TB mycobacteria Fungi: Candida, Crypto, Histo, Coccidio, Aspergillus, Pneumocystis, Zygomycetes spp. and other molds Viruses: HSV, VZV, CMV, EBV, JC virus, BK virus Parasites: Toxoplasma, Cryptosporidium, Isospora, Microsporidia Babesia; Strongyloides
Organ dysfunction	Liver (esp. cirrhosis): Vibrio spp., encapsulated bacteria ESRD: impaired granulocyte fxn and CMI as above Iron overload (or deferoxamine Rx): Yersinia, Zygomycetes
Biologics (eg, TNF inhibitors, anti-B- cell Rx; ✓ for TB before starting)	Bacteria: sepsis, septic arthritis, TB, NTM, Listeria, Legionella Fungi: Pneumocystis, Histo, Coccidio, Aspergillus, endemic fungi Viruses: JC virus (PML), EBV, HSV, VZV, HBV Parasites: Strongyloides reactivation

(NEJM 2007;357:2601; Am J Med 2007;120:764; CID 2011;53:798)

URINARY TRACT INFECTIONS

Definitions

• Asymptomatic bacteriuria: presence of bacteria in urine without signs or sx of infection

• Uncomplicated: confined to bladder. No upper tract or systemic infection signs.

• Complicated: extends beyond bladder (pyelonephritis, renal/perinephric abscess, prostatitis) with symptoms of fever, rigors, malaise, flank pain, CVA tenderness or pelvic/perineal pain. More likely to develop bacteremia or sepsis. Men, those w/ nephrolithiasis, strictures, stents, urinary diversions, immunosupp, DM, are not automatically complicated. Pregnant & renal Tx are considered complicated.

Microbiology

• Uncomplicated: E. coli (80%), Proteus, Klebsiella, S. saprophyticus (CID 2004;39:75). In healthy, nonpregnant women, lactobacilli, enterococci, Group B strep, and coag-neg staph (except S. saprophyticus) are likely contaminants (Annals 2012;156:ITC3).

• Complicated: as above + PsA, enterococci, staph (uncommon 1º urinary pathogen w/o catheter or recent instrumentation; ? bacteremia w/ hematogenous spread). ↑ MDR.

• Catheter-associated: E. coli most prevalent, candida, Enterococcus, PsA, other GNR

• Urethritis: Chlamydia trachomatis, Neisseria gonorrhoeae, Ureaplasma urealyticum, Trichomonas vaginalis, Mycoplasma genitalium, HSV

Clinical manifestations

• Cystitis: dysuria, urgency, frequency, hematuria, suprapubic pain; fever absent. R/o vaginitis if symptoms of cystitis & urethritis. Neurogenic bladder Pts may have atypical sx (↑ spasticity, autonomic dysreflexia, malaise).

• Urethritis: dysuria, urethral discharge (see “STI”)

• Prostatitis

Chronic: similar to cystitis + symptoms of obstruction (hesitancy, weak stream)

Acute: perineal pain, fever, tenderness on prostate exam

• Pyelonephritis: fever, chills, flank or back pain, nausea, vomiting, diarrhea

• Renal abscess: pyelonephritis sx + persistent fever on appropriate antibiotics

Diagnostic studies (NEJM 2016;374:562)

• Urinalysis: pyuria + bacteriuria ± hematuria ± nitrites

• Urine Cx (clean-catch midstream or straight-cath)

Obtain cx only if symptoms (although in ill Pts, can include ∆MS, autonomic instability)

⊕ if: ≥10⁵ CFU/mL, though <10⁵ but ^{≥102/mL may still indicate UTI in some scenarios}

Pyuria & ⊖ UCx=sterile pyuria. Ddx: prior abx, nephrolithiasis, interstitial nephritis, tumor, TB, urethritis (see “STI”)

• Catheter-associated: requires (1) s/s (incl atypical) + (2) urine Cx w/ 1 species ≥10³ colonies from clean urine sample (after replacing Foley). Pyuria alone not sufficient to dx

• Blood cultures: obtain in febrile Pts; consider in complicated UTIs

• For all men w/ UTI, consider prostatitis: ✓ prostate exam

• CT A/P: consider in severely ill, obstruction, persistent sx after 48–72 hours of approp abx

Treatment of UTIs (CID 2011;52:e103; JAMA 2014;312:1677)
Scenario	Empiric Treatment Guidelines (narrow based on UCx)
Asymptomatic bacteruria	Do not treat. Exceptions: pregnant women, renal transplant, prophylaxis prior to invasive urologic procedures (CID 2019;68:1611).
Cystitis (JAMA 2014;16:1677)	Uncomp: nitrofurantoin (Macrobid 100 mg PO q12h or Macrodantin 100 mg PO q6h) × 5 d or TMP-SMX DS × 3 d or fosfomycin (3 g × 1). Refer to dosing guidelines for ↑ Cr. Complicated: outPt FQ or TMP-SMX PO × 7–14 d FQ or TMP-SMX superior to β-lactams (NEJM 2012;366:1028) InPt: CTX or FQ; PO if improving, if growing GPC add vancomycin If catheterized remove or exchange catheter.
Prostatitis	FQ or TMP-SMX PO × 14–28 d (acute) or 6–12 wk (chronic)
Pyelonephritis	OutPt: FQ × 7 d or TMP-SMX PO × 14 d (Lancet 2012;380:452) InPt: CTX × 14 d; if at risk for MDR pathogen cefepime, pip-tazo, carbapenem, or plazomicin (NEJM 2019;380:729) (Δ IV → PO when clinically improved & afebrile 24–48 h, tailor to Cx)
Renal abscess	Drainage + antibiotics as for pyelonephritis

SEXUALLY TRANSMITTED INFECTIONS

Risk Factors and Screening (MMWR 2021;70:1)

• High risk: >10 lifetime sexual partners, prior STI, MSM, sex workers

• Screening recommendations: differ based on sexual practices and risk. All adults should have one-time HIV Ag/Ab, HCV Ab. Consider q3mo testing for STIs if high risk.

Genital Lesions (MMWR 2021; 70:1)
	Disease	Symptoms
Painless	Syphilis (T. pallidum)	1°: chancre = firm, indurated, clean base 2°: fever, LAN, rash palms/soles, uveitis, condylomata lata 3°: aortitis/aneurysm, gumma, CN palsies (7/8), tabes dorsalis, aseptic meningitis Latent = asx; early latent <1yr; late >1yr/unknown
	LGV (C. trachomatis, L1–L3)	1°: transient papule 2°: 2–6 wks later, painful inguinal LN (buboes) 3°: Anorectal syndrome w/ proctitis, ulcers
	Donovanosis/GI (K. granulomatis)	Multiple beefy, firm, irregular ulcers (“granuloma inguinale”), no LAN; in tropics
Painful	Genital herpes (HSV 2>1)	Prodrome: multiple painful vesicles 1° outbreak: more severe ± LAN/fever
	Chancroid (H. ducreyi)	Multiple ulcers ± LAN, in tropics

Diagnosis (MMWR 2021;70:1; JAMA 2022;327:161)

• Syphilis: 1^st step is treponemal test: IgG to T. pallidum. ⊕ for life.

2^nd step: confirm w/ non-treponemal test (VDRL/RPR titer). Should ↓ 4-fold w/ Rx.

Neurosyphilis: LP not needed if only ocular or otic sx. CSF VDRL may be ⊖.

• LGV: clinical dx + ⊕ rectal C. trachomatis NAAT + r/o other causes of proctitis

• Donovanosis: bx w/ Donovan bodies (encapsuled GNR) in monocytes/macrophages

• Genital herpes: clinical dx; confirm w/ PCR, viral cx from lesion

• Chancroid: clinical dx; r/o syphilis & HSV

Treatment (MMWR 2021;70:1; JAMA 2022;327:161)

• Syphilis

1°/2°/early latent: PCN G benzathine 2.4 mil U IM × 1

3°/late latent: PCN G 2.4 mil U IM × 3

Neuro: IV PCN G 4 mil U q4h 10–14 d (CID 2011; 53:S110)

• LGV: doxy 100 mg BID × 21 d + aspiration of buboes

• Donovanosis: azithro 1g qwk × 3 wks, until healed (MMWR 2015;64)

• Genital herpes: valacyclovir 1g bid × 7–10 d. Consider suppression if >6 outbreaks/yr.

• Chancroid: azithro 1g × 1 PO or cipro 500 mg bid × 3 d

Genital Discharge (MMWR 2021;70:1)
Disease	Symptoms
Gonorrhea (N. gonorrhoeae) & Chlamydia (C. trachomatis)	♀: Mucopurulent cervicitis, dysuria, PID; can be asx ♂: Urethritis, infxn of epididymis/prostate All: pharyngitis
Mycoplasma genitalium	Suspect in Pts w/ urethritis/cervicitis after Rx for GC/CT
Trichomoniasis (T. vaginalis)	♀: Malodorous purulent discharge, dysuria, dyspareunia ♂: Asymptomatic
Bacterial vaginosis (Gardnerella vaginalis)	♀: Malodorous grey/white discharge, no dyspareunia

♀ denotes all persons with a vagina. ♂ denotes all persons with a penis.

Diagnosis (MMWR 2021;70:1; JAMA 2022;327:161)

• NAAT (vaginal/cervical/urine ♀; urine ♂), mycoplasma testing not widely available

• For GC/CT, strongly suggest urine + rectal/pharyngeal swab if history of oral or anal sex

• Trichomoniasis: motile trichomonads on wet mount

• Bacterial vaginosis: clue cells on wet mount; ⊕ whiff test; vaginal culture

Treatment (MMWR 2021;70:1; JAMA 2022;327:161)

• GC: CTX 500 mg IM × 1 (if wt >150 kg, 1 g). CT: doxy 100 mg PO bid × 7 d (preferred) or azithro 1 g PO × 1. Do not need to treat both if neg NAAT. Retest at 3 mos.

• M. gen.: doxy 100 mg PO bid × 7 d, then: moxifloxacin 400 mg PO qd × 7 d

• Trich: ♀ → MNZ 500 mg PO bid or tinidazole 2 g PO qd × 7 d. ♂ → MNZ 2 g PO × 1.

• Bacterial vaginosis: MNZ 500 mg PO bid × 7 d or vaginal Rx w/ MNZ gel daily × 5 d

SKIN AND SOFT TISSUE INFECTIONS

Definitions

• Cellulitis: infection of dermis and subcutaneous tissue characterized by erythema, warmth, tenderness, and swelling; often occurs as a result of skin breaches (JAMA 2016;315:3)

• Skin abscess: subcutaneous collection of pus

• Staph toxic shock syndrome: rapid onset fever, rash, hypotension, and multiorgan injury. Staph aureus cx are not necessary for dx. Often associated with packing (tampon, nasal packing). Management may require surgical debridement + abx.

Risk Factors

• Trauma, edema, preceding skin inflammation or infection, obesity, DM, other immunosupp.

Microbiology (CID 2014;59:e10)

• Purulent: MRSA (NEJM 2006;355:666) causes up to 75% of purulent skin/soft tissue infections, followed by MSSA and strep

• Non-purulent: Strep, MSSA, aerobic GNRs. MRSA less commonly unless significant risk factors (prior MRSA infection, IVDU, HD, recent abx or hospitalization).

• Bites: skin (Strep, Staph [MRSA only if risk factors]) and oral flora (including anaerobes) + special exposures:

Feature	Microbiology	Clinical	Treatment
Cat bite*	Pasturella spp	Rapid onset erythema, swelling, lymphangitis, fever	Amox/clav
Dog bite	Pasturella & Capnocytophaga spp	Can cause severe sepsis w/ DIC & gangrene in asplenic/cirrhotics and other immunosupp.	Amox/clav If Capno. suspected: pip/tazo or carbapenem
Penetrating injury	Pseudomonas	Can be a/w deep tissue abscess	Directed based on suscept.
Gardening	Sporothrix	Ulcerating nodules, lymphatic spread	Itraconazole
Salt H2O or raw oysters/fish	V. vulnificus	Hemorrhagic bullae & sepsis (esp. in cirrhotics)	Doxy + Ceftaz/CTX
	Mycobacterium marinum	Indolent, nodules on extremities/ superficial lymphadenitis	Macrolide + rifampin/ ethambutol
Fresh H2O	Aeromonas	Myonecrosis/rhabdo can occur.	FQ, TMP-SMX, or CTX

^*Cat scratch disease caused by Bartonella acquired via cat scratch or bite. Results in lymphadenitis.

Diagnosis

• Clinical diagnosis based on physical examination

• Cultures from intact skin are not helpful and should not be performed (CID 2014;59:e10)

• BCx are typically low yield (~5–10%)

• Ultrasound can be used to identify deep abscesses and facilitate drainage. If abscess is found, incision/drainage is key to treatment.

• Aspirate from an abscess may provide microbiologic dx

Cellulitis Treatment (NEJM 2014;370:2238; CID 2014;59:e10; JAMA 2016;316:325 & 2017;317:2088)
Purulent	Usual Micro	Severity	Treatment
No	β-hemolytic Strep >S. aureus	Mild	Oral: PCN VK, cephalosporin
		Mod	IV: PCN, ceftriaxone, cefazolin
		Severe	IV: vanc + pip/tazo (± clinda for toxic shock syndrome)
Yes	S. aureus (incl. MRSA) >> β-hemolytic Strep	Mild	Consider I&D only vs. I&D + clinda or TMP-SMX (NEJM 2017;376:2545)
		Mod	I&D + TMP-SMX or doxycycline
		Severe	I&D + IV vanc, daptomycin or linezolid (± clinda for toxic shock syndrome)

Mild: abscess <2 cm, no systemic signs of infection, immunocompetent, no indwelling hardware; moderate: systemic signs; severe: SIRS or immunosuppressed

• Limb elevation; erythema may worsen after starting abx b/c bacterial killing → inflam.

• In obese Pts, adequate drug dosing important to avoid treatment failure (J Infect 2012;2:128)

• Duration: 5 to up to 14 d based on severity and response to treatment. Take pictures & draw margins to track progress.

NECROTIZING SOFT-TISSUE INFECTIONS (NEJM 2017;377:2253)

Definition

• Fulminant tissue destruction, systemic toxicity & high mortality. Surgical emergency.

• May include cellulitis, fasciitis, myositis, myonecrosis (gas gangrene).

Risk factors

• Can affect healthy individuals via skin/mucosal breach or traumatic wound, but ↑ risk w/ DM, PVD, EtOH abuse, IVDU, cirrhosis, or other immunosupp.

Microbiology

• Necrotizing fasciitis

• Type I: polymicrobial (mixed aerobes & anaerobes), typically in older Pts w/ above RFs. Fournier’s gangrene involves genitalia and/or perineum

Head and neck NSTI evolve from oral flora including anaerobes

• Type II: monomicrobial, usually group A strep, less likely Staph, Vibrio, Aero.; a/w TSS

• Clostridial myonecrosis (gas gangrene): C. perfringens; C. septicum (large Gram ⊕ rods w/ blunt ends on Gram stain). A/w traumatic wounds that create an anaerobic environment ideal for Clostridia.

Clinical manifestations

• Erythema, edema, warmth + systemic illness ± crepitus, bullae, necrosis

• Rapid progression of clinical signs

• Pain out of proportion to apparent cellulitis; skin hyperesthetic and later anesthetic

Diagnosis

• Clinical dx is sufficient to initiate urgent surgical exploration

• Aspiration of necrotic center; BCx; Gram stain; lactate, AST, & CK for deep tissue necrosis

• Imaging: noncontrast CT, but do not delay Rx/surgery (Arch Surg 2010;145:452)

• Microbiologic dx from Gram stain and culture of surgical specimens

Treatment (CID 2014;60:169)

• Urgent surgical exploration with debridement of necrotic tissue and ID consultation

• Empiric antibiotics: [pip/tazo or ceftriaxone + metronidazole or carbapenem] + [vanco or linezolid]. For Group A Strep: penicillin + clindamycin + consideration of IVIG for toxic shock.

DIABETIC FOOT INFECTIONS

Microbiology and severity (CID 2004;39:885)

• Mild (superficial ulcer, no involvement of deeper structures, surrounding erythema <2 cm, and no systemic illness): usually S. aureus or aerobic streptococci

• Moderate (ulcer with involvement of deeper structures, surrounding erythema >2 cm, or lymphangitic streaking and no systemic illness): more likely to be chronic and polymicrobial (PsA, enterococci, enteric GNR, anaerobes)

• Severe (moderate + systemic illness or metabolic instability): anaerobic streptococci, enteric GNR, PsA, Bacteroides, Clostridium

Initial evaluation

• Cleanse, debride, probe, and obtain deep anaerobic + aerobic cultures

• Assess for PVD: sensation, pulses, ABIs

Diagnosis

• Deep tissue wound cx at time of debridement (ideally prior to antibiotics). Superficial swabs are typically of limited utility due to colonization.

• For mod/severe: obtain blood cx, ESR, CRP

• Osteomyelitis should always be ruled out. At ↑ risk if: grossly visible bone or able to probe to bone, ulcer >2 cm, ulcer duration >1–2 wk, ESR >70. If suspicious for osteo, obtain plain films ± MRI (see osteomyelitis below).

Treatment (CID 2012;54:e132)

• Mild infxn: oral abx. Target GPCs (diclox, cephalexin, or amox/clav); use TMP-SMX or doxy for MRSA.

• Mod/severe infxn: IV abx. Target GPCs (vanco, linezolid,dapto) + GNRs (CTX, levo, or amp/sulb) ± anaerobes (metronidazole or clinda). Add PsA coverage (cefepime or pip- tazo) if: macerated wound, significant water exposure, warm climate

• Elevation, non–weight-bearing status, wound care, glycemic control, Rx for venous insufficiency and arterial ischemia

• Many require surgery: early, aggressive, and repeated debridement; revascularization or amputation may be necessary

OSTEOMYELITIS

Infection of bone due to hematogenous seeding or direct spread from contiguous focus

Etiology (Lancet 2004;364:369)

• Hematogenous: S. aureus; mycobacterial infection of vertebral body = Pott’s disease

• Contiguous focus (may be acute or chronic)

Open fracture, orthopedic surgery, etc.: S. aureus and S. epi

Skin breakdown + vasc. insuffic. (eg, diabetic foot, pressure ulcer): polymicrobial

GU source (GNR, Enterococcus)

Clinical manifestations

• Surrounding soft-tissue compromise ± fistula to superficial skin

• ± Fever, malaise, and night sweats (more common in hematogenous than contiguous)

• Vertebral osteomyelitis (esp. IVDU): unremitting, focal back pain, ± fever (NEJM 2010;362:1022)

Diagnosis (JAMA 2008;299:806)

• Crucial to obtain cx data of causative organism to avoid long-term empiric abx

• Bone biopsy or tissue cx obtained surgically or via percutaneous biopsy (send aerobic, anaerobic, mycobacterial, and fungal cultures + pathology) unless ⊕ blood cx. Do not rely on swabs of ulcers or fistulae drainage.

• Physical exam: high suspicion in diabetic foot (see above) if can probe ulcer to bone or ulcer >2 cm² (Sp 83%, 90% PPV)

• Blood cultures before antibiotics (more often ⊕ w/ acute hematogenous osteomyelitis)

• CBC, CRP, ESR (>70 greatly ↑ likelihood of osteo)

• Imaging

Plain radiographs: normal early in disease; lytic lesions seen after 2–6 wk

MRI: preferred imaging study (overall Se 90%, Sp 82%; Archives 2007;167:125)

CT: can demonstrate periosteal reaction and cortical and medullary destruction

CT & MRI very Se but ↓ Sp; false ⊕ if contig focus w/ periosteal reaction, Charcot Δs

Radionuclide imaging: very Se but non-Sp (false ⊕ if soft-tissue inflammation)

Treatment

• Antibiotics: based on cx data. If clinically stable, consider holding antibiotics until bone bx obtained. Duration depends on Rx strategy/goals of Rx management (eg, 6 wks for vertebral osteo; Lancet 2015;385:875). After ≥7 days from either start of IV abx or surgery, if doing well consider (in consultation with ID!) ∆’ing IV to PO (if good bioavailability and bone penetration) (NEJM 2019;380:425).

• Surgery should be considered for any of the following: acute osteo that fails to respond to medical Rx, chronic osteo, complications of pyogenic vertebral osteo (eg, neurologic compromise, spinal instability, epidural abscess) or infected prosthesis

EPIDURAL ABSCESS

Etiology

• Hematogenous spread (⅔): skin infection, soft tissue (dental abscess), or endocarditis

• Direct extension (⅓): vertebral osteo, sacral ulcer, spinal anesthesia or surgery, LP

• Risk factors: IVDU diabetes, renal failure, alcoholism, immunosuppression

• S. aureus most common pathogen; in immunosuppressed, consider fungal, TB, and Nocardia

Clinical manifestations

• Back pain with spinal or paraspinal tenderness + fever ± followed by radiculopathy. Sx of cord compression or cauda equina is a surgical emergency.

Diagnostic studies

• MRI with contrast

• Aspiration of abscess fluid for Gram stain & cx or operative Gram stain & cx

• Blood cx (frequently ⊖)

Treatment

• Antibiotics (typically MRSA and gram-negative coverage initially then narrowed based on culture data) ± surgery (decompressive laminectomy and debridement) for failure to improve on medical Rx. Emergent surgery for early s/s of cord compression (w/ vertebral osteo and epidural abscess).

INFECTIONS OF THE NERVOUS SYSTEM

ACUTE BACTERIAL MENINGITIS

Definition

• Inflammation of tissue around the brain/spinal cord

• Usually arising from nasopharynx (hematogenous spread), bacteremia, or direct inoculation (surgery, contiguous infection, trauma, foreign body [eg, CSF shunt])

Microbiology in Bacterial Meningitis (NEJM 2011;364:2016)
S. pneumoniae (30–60%)	Look for preceding infection (bacteremia, pneumonia, endocarditis) Drug-resistant S. pneumoniae: ~40% PCN-resistant (even intermediate resistance problematic) ~<10% 3rd-gen. cephalosporin-resistant See “Pneumonia” for S. pneumoniae vaccination recs
N. meningitidis (10–35%)	Primarily in age <30 y; associated petechiae or purpura ↑ risk in asplenia, complement defic., HIV, SCT, unvaccinated Vaccine rec for all age 11–18 y, HIV infection, asplenia, C5-9 deficiency
H. influenzae (<5%)	↑ risk in asplenia, complement defic., HIV, SCT, unvaccinated, CSF leak, trauma/surgery, mastoiditis Vaccine rec for all children; markedly ↓ incidence
L. monocytogenes (5–10%)	↑ in immunosupp (glucocorticoids, transplant), elderly, malignancy, pregnant, cirrhosis. Outbreaks a/w contaminated dairy & raw veg.
GNRs (1–10%)	More common in health care associated meningitis (E. coli, Klebsiella sp., Pseudomonas aeruginosa)
Staphylococci (5%)	Preceding infection (endocarditis, bacteremia), post CNS surgery, foreign bodies (CSF shunt, intrathecal pump)
Mixed infection	Suspect parameningeal focus or CSF leak, post CNS surgery

Clinical manifestations (Lancet 2016;339:16)

• Headache (84%), fever (74%), stiff neck (74%), photosensitivity, GCS <14 (71%), nausea (62%), seizure (23%); 95% have 2 of 4: HA, fever, stiff neck, ΔMS

• Presentation may be atypical (eg, lethargy w/o fever) in elderly and immunosupp.

Physical exam (CID 2002;35:46; Am J Emerg Med 2013;31:1601)

• Nuchal rigidity (Se 30%, Sp 68%), Kernig’s sign (Se 5%, Sp 95%), Brudzinski’s sign (Se 5%, Sp 95%), jolt sign (HA worsens w/ horizontal rotation) (Se 64%, Sp 43%)

• ± Focal neuro findings (~30%; hemiparesis, aphasia, visual field cuts, CN palsies)

• ± HEENT findings: sinus tenderness, clear rhinorrhea (CSF leak)

• ± Skin and joint findings: petechial rash (N. meningitidis), genital or oral ulcers (HSV), arthritis with joint effusion (N. meningitidis)

Sequential management of bacterial meningitis

1. Blood cx, initiate empiric antibiotics, consider corticosteroids (vide infra)

2. CT head if indicated (see below)

3. LP ASAP (if not contraindicated); yield of CSF cx unlikely to be changed if obtained w/in ~4 h of initiation of abx

Diagnostic studies (NEJM 2017;388:3036)

• Blood cultures ×2 before abx

• WBC count: >10,000 in >90% of bacterial meningitis in healthy hosts

• Head CT to r/o mass effect before LP if ≥1 high-risk feature: immunosupp., h/o CNS disease, new-onset seizure, focal neuro findings, papilledema, GCS <15 (CID 2004;39:1267)

• Lumbar puncture with opening pressure (NEJM 2006;355:e12)

Send CSF for cell count and differential, glucose, protein, Gram stain, bacterial cx

Additional CSF studies based on clinical suspicion: AFB smear/cx (or MTb PCR), cryptococcal Ag, fungal cx, VDRL, PCR (HSV, VZV, enteroviral), cytology

CSF Gram stain has 30–90% Se; cx 80–90% Se if LP done prior to abx though abx should not be delayed for LP if there is concern for bacterial meningitis

Rule of 2s: CSF WBC >2k, gluc <20, TP >200 has >98% Sp for bacterial meningitis

Repeat LP only if no clinical response after 48 h of appropriate abx or CSF shunt

Metagenomic next-generation sequencing ↑ dx yield (NEJM 2019;380:2327)

Empiric Treatment of Bacterial Meningitis (Lancet 2012;380:1693)
Adults <50 y	Ceftriaxone + vancomycin (trough 15–20), consider acyclovir IV
Adults >50 y	Ceftriaxone + vancomycin + ampicillin, consider acyclovir IV
Immunosuppressed	[Cefepime or meropenem] + vanc ± amp (not nec. if on meropenem), consider acyclovir IV & fungal coverage
Healthcare assoc. infection (eg, surgery, CSF shunt)	[Cefepime or meropenem or ceftazidime] + vancomycin
When possible, organism-directed Rx, guided by sensitivities or local patterns of drug resistance should be used
Confirm appropriate dosing as higher doses are often needed in meningitis (though may need to be adjusted for renal function)
Corticosteroids: If causative organism is unknown, dexamethasone 10 mg IV q6h × 4 d recommended prior to or with initiation of abx. Greatest benefit in S. pneumoniae and GCS 8-11 (↓ neuro disability & mortality by ~50%). Avoid in crypto (NEJM 2016;374:542).
Prophylaxis: for close contacts of Pt w/ N. meningitidis; rifampin (600 mg PO bid × 2 d) or ciprofloxacin (500 mg PO × 1) or ceftriaxone (250 mg IM × 1). See Microbiology in Bacterial Meningitis Table for available vaccinations.
Precautions: droplet precautions until N. meningitidis is ruled out

ASEPTIC MENINGITIS

Definition

• Clinical/lab evidence of meningeal inflammation with negative bacterial cx (CSF & blood)

Etiologies (Neurology 2006;66:75)

• Viral: enteroviruses are most common cause (summer/fall; rash, GI, URI sx), HIV, HSV, VZV, mumps (parotitis), lymphocytic choriomeningitis virus (rodent exposure), encephalitis viruses, adenovirus, polio, CMV, EBV, WNV

• Focal bacterial infection: brain/epidural/subdural abscess, CNS septic thrombophlebitis

• Partially treated bacterial meningitis

• Other infectious: TB, fungal (cryptococcus, coccidiodes), Lyme, syphilis, leptospirosis

• Neoplasm: intracranial tumors (or cysts), lymphomatous or carcinomatous meningitis

• Drug-induced meningitis: NSAIDs, IVIG, antibiotics (TMP-SMX, PCN), anti-epileptics

• Systemic autoimmune illness: SLE, sarcoidosis, Behçet’s, Sjögren’s syndrome, RA

• Mollaret’s: recurrent lymphocytic meningitis, spontaneously resolving (often HSV-2)

Diagnosis

• Obtain LP for CSF analysis: lymphocytic pleocytosis common in viral etiologies (see Typical CSF Findings in Meningitis table above)

• Consider CSF cytology and MRI brain/spine to evaluate for malignancy

• Consider serum autoimmune and serum viral testing in appropriate settings if CSF is unrevealing and there is no improvement with empiric treatment

Empiric treatment

• Suspected bacterial meningitis: see empiric treatment of bacterial meningitis above

• Suspected viral meningitis: if concern for HSV meningoencephalitis → IV acyclovir

• Unclear etiology: consider initiation of empiric bacterial meningitis treatment while observing and awaiting CSF studies

ENCEPHALITIS (NEJM 2018;379:557)

Definition

• Inflammation of brain parenchyma characterized by impaired cerebral function (AMS, neurologic deficits) often due to primary viral infection or post-viral inflammation

Etiologies (specific etiology found in <20% of cases; Neurology 2006;66:75; CID 2008;47:303)

• HSV-1 all ages/seasons. If sxs recur after Rx, consider viral relapse vs. autoimmune encephalitis b/c high rates of autoimmune disease wks later (Lancet Neurol 2018;17:760).

• VZV 1° or reactivation; ± vesicular rash; all ages (favors elderly), all seasons

• Arboviruses: evaluate for exposure to vector/geography. Mosquitoes: West Nile, Eastern/Western equine, St. Louis, La Crosse; Ixodes tick: Powassan.

• Enteroviruses (coxsackie, echo): preceding URI/ GI sx; peaks in late summer/early fall

• Other infectious: CMV, EBV, HIV, JC, measles, mumps, rabies, adeno, influenza, Lyme

• Non-infectious: autoimmune/paraneoplastic (anti-NMDAR, anti-Hu, anti-Ma2, anti-CRMP5, anti-mGluR5), post-infxn demyelination (eg, ADEM)

Clinical manifestations

• Fever + ΔMS (subtle to severe), seizure, focal neuro deficit, HA in meningoencephalitis

Diagnostic studies (CID 2013;57:1114)

• CSF analysis: lymphocytic pleocytosis; PCR for HSV (95% Se & Sp), VZV; consider other PCR based on risk factors (CMV/EBV, HIV, JC, adeno/enterovirus, WNV)

• Consider testing for autoimmune etiologies and serologic viral testing in appropriate settings if CSF is unrevealing and there is no improvement with empiric HSV/VZV Rx

• MRI (CT if unavailable); HSV temporal lobe; W. Nile & Powassan thalamic hyperintensity

• EEG to r/o seizure; findings in encephalitis are nonspecific (temporal lobe focus in HSV)

Treatment

• HSV/VZV: IV acyclovir 10 mg/kg IV q8h; consider empiric treatment given frequency

BELL’S PALSY

Definition & clinical manifestations

• Acute idiopathic unilat. facial nerve palsy (CN VII), often presumed HSV reactivation

• P/w unilateral facial muscle weakness, hyperacusis, ↓ taste, lacrimation, & salivation

• Risk factors: pregnancy (preeclampsia), obesity, HTN, diabetes, preceding URI

Diagnosis (Otol Head Neck Surg 2013;149:656)

• Labs, imaging, EMG not needed in routine cases

• Ddx: Bilateral: Lyme, GBS, sarcoid. Additional neuro sx: stroke, tumor. Rash: herpes zoster. Other: otitis media, HIV, Sjögren.

Treatment and Prognosis (CMAJ 2014;186:917)

• 70% recover spontaneously w/in 6 mos, >80% recover with glucocorticoid treatment

• Oral corticosteroids started w/in 72 hrs of sx onset improve odds of recovery; dose varies based on severity (House-Brackmann grading). No conclusive data on antivirals.

• If eyelid closure is compromised, eye protection is crucial to prevent trauma

HERPES ZOSTER (SHINGLES)

Definition & etiology

• Painful vesicular rash in a peripheral nerve distribution due to reactivation of VZV

• Spread by contact with active lesion (prior to crusting) in uncomplicated zoster or via airborne transmission in disseminated zoster

Clinical manifestations & complications

• Uncomplicated: pain in a dermatomal distribution → dermatomal eruption of erythematous papules → vesicles → crusted plaques in varying stages of evolution

• Disseminated: vesicles across multiple dermatomes, visceral organ involvement (pneumonia, hepatitis, CNS) seen in immunosupp. (eg, transplant, malignancy)

• Zoster opthalmicus: ocular involvement (V1 of CN V) requires urgent ophtho eval

• Post-herpetic neuralgia: neuropathic pain lasting >90 d after dx

Diagnosis

• Clinical diagnosis if uncomplicated. Confirm with PCR (most sensitive), DFA, and viral culture (allows for resistance testing) of vesicular fluid (scrape from unroofed vesicle).

Treatment & prevention

• Uncomplicated: acyclovir, valacyclovir, or famciclovir x 7 d; initiate w/in 72 h of onset for greatest benefit; consider after 72 h if new lesions present; minimal benefit after crusting

• Superimposed bacterial cellulitis is common; if suspected, treat with appropriate antibiotics

• Disseminated/immunosupp.: IV acyclovir, eval for visceral spread, droplet precautions

• Prevention: Shingrix (2 doses) for all Pts >50; consider in younger if immunosupp.

BACTEREMIA & ENDOCARDITIS

BACTEREMIA

Definitions

• 1° bacteremia: bloodstream infection due to direct inoculation of the blood

• Central line associated bloodstream infection (CLABSI): bacteremia in which the same organism is growing from peripheral and catheter cultures (CID 2009;49:1)

• 2° bacteremia: infection of another site (eg, UTI, PNA, colitis, etc.) spreading to blood

• Contaminant: bacteria growing in a blood culture that does not represent a true infection

Risk factors for bloodstream infections (JAMA 2012;308:502; CID;2020;71)

• Syndromes with high likelihood of bacteremia:

Sepsis

Endovascular infxns: endocarditis, infection of pacemaker, vascular graft or IV catheter

Vertebral osteomyelitis, epidural abscess, septic arthritis

• Risk factors: indwelling lines, IVDU, immunosupp. (neutropenic, transplant)

• Organisms

More likely pathogenic: S. aureus, β-hemolytic strep, enterococci, GNR, S. pneumo, Neisseria, Candida

Less likely pathogenic: coag-neg staph, diphtheroids, Cutibacterium

• Time to growth: <24 h → higher risk, >72 h → lower risk (except slow-growing, eg, HACEK)

• Factors increasing likelihood of endocarditis: high-grade bacteremia w/o source, persisting after line removal or drainage of focal source, in hosts at risk for endocarditis or w/ organisms known to cause IE; emboli

Diagnosis

• ≥2 sets BCx prior to abx (set = aerobic + aneaerobic cx) at separate puncture sites

• If proven bacteremia, daily surveillance cxs until 48 hrs of ⊖ cxs. May not need for GNRs (ClD 2017;65:1776).

• TTE/TEE if concern for endocarditis (see IE section)

• TTE and urgent ophthalmology evaluation if yeast is growing in BCx

Treatment (CID 2009;49:1; JAMA 2020;323:2160)

• Empiric abx based on Gram stain, cx, & clinical syndrome, then tailor based on sensi

Short-Term Central Venous Catheter-Related Bloodstream Infxns
S. aureus	Risk of endocarditis in bacteremia: ~25% (JACC 1997;30:1072). ID consult a/w ↓ mortality (ClD 2015;60:1451). Remove CVC, evaluate for endocarditis, osteo, hardware infections. Preferred abx: MSSA → nafcillin, oxacillin, or cefazolin. MRSA → vancomycin. Duration: 2 wks if normal host, no implants, no e/o endocarditis or metastatic complications. Otherwise 4–6 wks.
Coag-neg staphylococci	CVC retention does not ↓ rate of resolution, but a/w ↑ rate of recurrence (CID 2009;49:1187). If CVC left, treat 10–14 d; if removed 5–7d.
Enterococcus	Remove CVC & treat for 7–14 d
GNR	Remove CVC esp if Pseudomonas. Rx for 14 d (7 if uncomplicated).
Yeast	Remove CVC & treat for 14 from first ⊖ BCx. ID consult a/w ↓ mortality.

• Persistently ⊕ BCx: remove CVCs, look for metastatic infxn (endocarditis, septic arthritis, osteo), infected thrombosis, or prosthetic material (vascular graft, PPM)

BACTERIAL ENDOCARDITIS

Definition

• Infection of endothelium of heart (including but not limited to the valves) including both prosthetic valve endocarditis (PVE) and native valve endocarditis (NVE)

Risk Factors

• Abnormal valve (JAMA 1997;277:1794; JACC 2018;72:2443)

High risk: prior endocarditis, prosthetic valve or ring, some congenital heart disease (unrepaired cyanotic; shunt/conduit; prosthesis in past 6 mos), transplant heart, valvulopathy, VAD

Medium risk: previous rheumatic fever, non-rheumatic valve disease (including MVP w/ MR or thickened leaflet), HCM, bicuspid AoV

• Risk of bacteremia: IVDU, indwelling venous catheters, hemodialysis, prosthetic material in heart (eg, pacemaker, ICD, graft), poor dentition

^a↑ risk w/ DM, indwelling lines, immunosupp. ^bCx ⊖ = abiotrophic strep, HACEK (Haemophilus para-influenzae & aphrophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), T. whipplei, Bartonella, Coxiella, Chlamydia, Legionella, Brucella (JAMA 2007;297:1354; Annals 2007;147:829; J Clin Microbiol 2012;50:216)

Clinical manifestation (Lancet 2016;387:882)

• Persistent bacteremia → fever (80–90%), rigors, night sweats, anorexia, myalgias

• Valvular or perivalvular infection → HF, conduction abnormalities (eg, AVB)

• Septic emboli: stroke, embolic MI, renal/splenic/pulmonary infarcts, septic arthritis, osteo

• Immune complex phenomena: arthritis, glomerulonephritis

• Subacute endocarditis can present with subacute progressive “B” sx (fatigue, wt loss)

Physical exam

• Cardiac murmur (85%), s/s of new HF (pulmonary edema, JVP elevation, edema)

• Skin/ocular changes (uncommon but highly specific)

Janeway lesions (painless hemorrhagic macules on palms/ soles due to septic emboli)

Osler’s nodes (painful nodules on pads of digits due to immune complex deposition)

Splinter hemorrhages in fingernails or toenails

Roth spots (retinal hemorrhages)

• MSK: point tenderness along spine, red/hot joints

• Neurologic deficits c/f embolic stroke; vertebral tenderness c/f osteo or epidural abscess

• Devices: evaluate CVCs, PM/ICD pocket, and sites of other hardware/ prosthetics

Diagnosis (CID 2010;51:131; EHJ 2015;36:3075; Circ 2015;132:1435)

• Blood cultures (before abx): 3 sets (aerobic & anaerobic bottles) from different sites, ideally spaced ≥1 h apart. ✓ BCx (at least 2 sets) after appropriate abx have been initiated to document clearance; repeat q24–48h until ⊖.

• Serial ECGs to assess for conduction disease and ↑ PR interval (c/f perivalvular abscess)

• Echocardiogram: TTE in all Pts. TEE if (i) TTE abnl but nondx, (ii) TTE ⊖ but high suspicion, (iii) complications suspected or present (eg, AVB), (iv) high-risk (prosthetic valve, CIED, prior IE, congenital heart dis.), (v) S. aureus, enterococcus, or fungus, (vi) Δ in signs or sx (eg, new conduction abnl, regurgitation, etc.) (vii) if considering a shortened course (10–14 d) of abx (vide infra)

	Sensitivity
	NVE	PVE	Abscess
Transthoracic (TTE)	39–58%	33%	18–63%
Transesophageal (TEE)	>90%	86%	76–100%

(Mayo Clin Proc 2014;89:799; Circ 2015;132:1435; Eur Radiol 2015; 25:2125; J Am Soc Echo 2016;29:315)

• Gated cardiac CT useful if TTE/TEE equivocal or suspected paravalvular abscess

• PET/CT using FDG useful for suspected PVE or CIED infxn if TTE/TEE equivocal

• Brain/spine imaging if concern for CNS spread (mycotic aneurysms, embolic stroke) or spinal involvement (vertebral osteo, epidural abscess)

• Cx ⊖ endocarditis: may be due to abx prior to BCx. PCR, bacterial 16S ribosomal RNA, serol. may be helpful. Detailed hx: animal exposure, travel, unpast. dairy, etc. ID eval. Consider organisms listed in Cx ⊖ footnote in microbiology table (vide supra).

Modified Duke Criteria
Definitive: 2 major or 1 major+3 minor or 5 minor; Possible: 1 major+1 minor or 3 minor
Major	Minor
• BCx with common endocarditis pathogen (grown in 2 separate cx) • Coxiella serology ≥1:800 • Endocardial involvement: vegetation, abscess, prosthetic dehiscence or new valvular regurgitation	• Predisposing condition (see risk factors) • Fever • Vascular phenomena: septic arterial or pulmonary emboli, mycotic aneurysms, ICH, Janeway lesions • Immune phenomena: ⊕ RF, GN, Osler’s nodes, Roth spots • ⊕ BCx not meeting major criteria

Se ~90%, Sp >95%, NPV ≥92% (CID 2000;30:633).

Treatment (ID consult is strongly recommended)

Treatment (Circ 2015;132:1435)
Empiric	NVE or PVE >12 mos post-op: vanc + CTX PVE <12 mos post op: vanc + CTX ± gentamicin (if OK renal fxn)
Strep	Penicillin, ampicillin, cftx; if PVE consider gentamicin in discussion w/ ID
Staph (S. aureus and lugdunensis)	MRSA: vanc or dapto MSSA: nafcillin, oxacillin, or cefazolin (avoid if CNS involvement due to poor penetration); vanc inferior to β-lactam for MSSA For PCN allergy w/ MSSA consider desensitization Consider rifampin / gentamicin in PVE in discussion w/ ID
Enterococci	Ampicillin + [CTX or gent]; if VRE: linezolid, dapto, ampicillin if sensitive
Gram negatives	HACEK: CTX, ampicillin or FQ. Pseudomonas: 2 anti-Pseudomonal agents [eg, β-lactam + (aminoglycoside or FQ)]
Fungi (candida, aspergillus)	Candida: amphotericin B ± flucytosine or micafungin Aspergillus: amphotericin B or voriconazole Ophtho consult for fungemia to rule out endophthalmitis

• De-escalate abx to organism-directed therapy based on speciation and sensitivities

• If on anticoagulation or antiplatelet, typically can continue unless concern for stroke, intracranial hemorrhage, or need for emergent surgery

• Monitor for complications of endocarditis (CHF, conduction block, osteomyelitis, new embolic phenomenon) which can occur even on abx

• Duration is usually 4–6 wks

After ≥10d IV abx can consider ∆’ing to PO if clinically appropriate and available PO abx in consultation with ID (NEJM 2019;380:415)

Uncomplicated right-sided NVE or PCN-S Strep spp → 2 wks may be adequate

• IVDU-associated best managed by multidisciplinary teams including Addiction Medicine

Indications for surgery (consult early; JTCS 2017;153:1241; Circ 2021;143:e72)

• Emergent if refractory cardiogenic shock

• Urgent (during initial hospitalization):

Sx HF

Penetrating infection: periannular abscess, heart block, fistula, worsening conduction

Persistent infection: ⊕ BCx after >5 d of appropriate abx, ↑ or ? large vegetation

Emboli: recurrent or w/ residual large (>10 mm) vegetation & severe AR/MR. Cerebral emboli not contraindic. unless severe stroke or hemorrhage (Stroke 2006;37:2094).

S. aureus, fungal or multiRx-resistant organisms

PVE (emergent if dysfunction or dehiscence)

Endocarditis Prophylaxis (Circ 2007;116:1736)
Cardiac conditions*	Prosthetic valve; previous endocarditis; congenital heart disease (CHD) including unrepaired or incompletely repaired cyanotic CHD (palliative shunts or conduits), 1st 6 mo after completely repaired CHD using prosthetic material; cardiac transplant recipients w/ valvulopathy. (Prophylaxis no longer rec. in acquired valvular dysfxn, bicuspid AoV, MVP with leaflet thickening or regurgitation, HCM.)
Procedures*	Dental: manipulation of gingival tissue or periapical region of teeth or perf oral mucosa (eg, extraction, periodontal, implant, root canal, cleaning)
Regimens	Oral: amoxicillin 2 g 30–60 min before Unable to take PO: amp 2 g IM/IV or cefazolin or CTX 1 g IM/IV PCN-allergic: cephalexin or azithro or claritho or doxy

^*Pts should meet both indications (high-risk condition & high-risk procedure) to qualify for Ppx

TUBERCULOSIS

Definitions

• Primary: new Mycobacterium tuberculosis (TB) in a naïve host; symptomatic or asymptomatic; 90% of infected normal hosts will never develop clinically evident disease

• Latent: well-controlled infection without clinical or radiographic evidence of active disease; can persist for years to decades

• Reactivated: activation of latent; more likely in the setting of immunosuppression.

• Milliary: disseminated lympho-hematogenous spread due to primary or reactivated TB

• Multidrug-resistant (MDR): resistant to isoniazid (INH) & rifampin. Can occur as 1° infxn.

• Extensively drug-resistant (XDR): resistant to INH, rifampin (RIF), fluoroquinolones (FQ), and at least one of amikacin, kanamycin, or capreomycin

Epidemiology (NEJM 2016;375:1081)

• Transmission via aerosols; untreated active dx requires airborne isolation in healthcare facilities and community isolation measures; must involve local public health authorities

• Acquisition: residents/travel in TB-endemic area, IVDU, resident/worker in correctional facility or homeless shelter, close contact w/ active TB

• Reactivation: risk is 5% in first 2 yr, 5–10% overall; ↑ if HIV ⊕, immunosupp. (anti-TNF, steroids), ESRD, DM, cancer, transplant, malnourished, smoker, substance use disorder

Screening for latent TB

• Whom to screen: high likelihood of exposure and/or high risk of progression to active disease including HIV ⊕ and prior to immunosuppression (pre-transplant or anti-TNF)

• Relies on host immune system, so limited Se in immunosuppressed individuals

• Nb, testing for host exposure & immune response to TB, not whether TB active (vide infra)

• Screening tests

IFN-γ release assays (IGRA): preferred test; Ag-stimulated IFN-γ release from Pt’s T-cells. ↑ Sp over TST/PPD in BCG vaccinated Pts.

Tuberculin skin test (TST/ PPD): inject purified protein intradermally, examine for wheal 48–72 hrs later. Interpret based on max diameter of induration, not erythema.

Size of Reaction	Persons Considered to Have ⊕ Test (NEJM 2002;347:1860)
>5 mm	HIV ⊕ or immunosupp. (eg, prednisone 15 mg/d × >1 mo) Close contacts of Pt w/ active TB; CXR c/w prior active TB
>10 mm	All other populations with ↑ prevalance/risk. Healthcare workers, recent conversion (↑ induration by >10 mm in 2 y).
>15 mm	No risk factors
False ⊖	Faulty application, anergy (including from active TB), acute TB (2–10 wk to convert), acute non-TB mycobacteria (NTM), malignancy
False ⊕	Improper reading, cross-reaction with NTM, BCG vaccination (although usually <10 mm by adulthood)
Booster effect	↑ in duration b/c immunologic boost by prior skin test in prev sensitized individual (by TB, NTM, or BCG). Test ⊖ → ⊕ but not true conversion due to recent infxn. 2nd test true baseline. Can be 1 y after initial test.

Clinical manifestations (Lancet 2016;387:1211)

• Constitutional symptoms are common in all manifestations, but may be absent

• Primary TB pneumonia: middle or lower lobe consolidation, ± effusion, ± cavitation

• TB pleurisy: pulmonary effusion ± pericardial and peritoneal effusions secondary to granuloma breakdown and local inflammation; can occur in primary or reactivation

• Reactivation TB pulmonary disease: upper lobe infiltrate ± volume loss ± cavitation

• Milliary TB: diffuse millet seed-sized lesions, more common in immunosupp.

• Extrapulmonary TB: lymphadenitis, pericarditis, peritonitis, CNS disease including meningitis, GU tract disease ± sterile pyuria, osteoarticular disease (vertebral = Pott’s disease), granulomatous hepatitis, splenitis, cutaneous disease

• TB and HIV: HIV ⊕ at ↑ risk infxn, reactivation (8–10%/yr without ART, higher w/ ↓ CD4), and progressive 1° infxn. CXR can be atypical espec. if CD4 ≤200 (JAMA 2005;293:2740).

Diagnostics for active TB (CID 2017;64:11)

• Pulmonary TB: common CXR findings discussed above; induced sputum AFB smear & culture (3 samples at least 8 h apart) ± NAAT/ PCR (GeneXpert); consider bronchoscopy + BAL ± transbronchial biopsy. GeneXpert can also detect RIF resistance (non-bloody sputum only). Sp 98%/Se 74%, independent of HIV status.

• Extrapulmonary TB

Pleural/pericardial effusions or ascites: fluid sampling for AFB cx/smear, NAAT/ PCR, cell counts. Adenosine deaminase (ADA) can be ↑, best validated in ascites. Free INFγ can be elevated in pleural/ascitic fluid (not validated in pericardial effusions). Higher diagnostic yield with pleural/pericardial biopsies for disease at these sites.

CSF: fluid sampling for AFB cx/smear (submit at least 10 mL), NAAT/PCR, cell count (lymphocyte predominanace), glucose (low), protein (high), ADA (high)

Soft tissue: tissue biopsy with AFB staining, pathology w/ granulomas

Treatment of latent TB

• If screening test ⊕ and no risk factors, confirm prior to treatment; if ⊕ w/ risk factors, proceed to treatment (CID 2017;64:11).

• Prior to treatment of latent TB, active TB must be ruled out with, at a minimum, ROS for symptoms (cough, fever, night sweats, weight loss), physical exam, and CXR (though may be normal in immunosupp.)

Scenario	Prophylaxis Regimen
PPD/IGRA ⊕ (regardless of HIV status)	1st line: Rifampin × 4 mo or INH/rifampin daily x 3 mos or INH/rifapentine weekly × 12 wks) (MMWR 2020; 69:1) Alternative: INH + vitamin B6 × 6–9 mos
Contact case known or suspected to have MDR TB	No proven regimen: ? PZA + EMB, ? PZA + FQ

• ✓ LFTs monthly if receiving INH (risk ↑ w/ age; Chest 2005;128:116): if AST/ALT ↑ 5× ULN or sx (nausea, vomiting, abd pain) → stop TB meds & re-eval

Patient isolation

• Decision based on likelihood of active disease. Consider when cough, dyspnea, hemoptysis, ≥1 risk factor (HIV ⊕, foreign born, substance use disorder, homeless, recent incarceration, prior TB or exposure).

• Discontinue if alternative dx and AFB smear neg ×3, or TB treated for 2 wk & AFB neg ×3

Treatment of active tuberculosis (NEJM 2015;373:2149; Lancet 2016;387:1211)

• Prior to treatment, consult ID, check LFTs, Cr, HIV & hepatitis A/B/C screen, DM screen, pregnancy screen, vision testing for acuity and color, EtOH use history

• Treatment requires several drugs to prevent resistance (see below)

• Suspect MDR TB if prior TB Rx (esp. if poor adherence), travel to area w/ ↑ rates of MDR (India, China, Eastern Europe including Russia, South Africa), exposure to person w/ likely MDR-TB (NEJM 2008;359:636)

• “Paradoxical worsening” of sx can occur after starting Rx. More common w/ extrapulm. TB & more frequent/severe w/ concurrent immune reconstitution (eg, HIV ⊕ Pts started on ART, Pts taken off immunosuppression). Must r/o Rx failure (repeat Cx, imaging), consider checking drug levels.

• Duration of treatment varies based on host, clinical manifestation, and improvement/ progression on treatment

Antituberculous Medications
Drug	Adverse Effects*
Isoniazid (INH)	Hepatitis (avoid EtOH), periph neuropathy (↓ risk by suppl. vit B6), drug-induced lupus
Rifampin (RIF)	Orange tint of body fluids, GI upset, hepatitis (avoid EtOH), hypersensitivity, fever, drug interactions
Pyrazinamide (PZA)	Hepatitis (avoid EtOH), hyperuricemia, arthritis
Ethambutol (EMB)	Optic neuritis
Streptomycin (SM)	Ototoxicity, nephrotoxicity
Amikacin (AMK)	Ototoxicity, nephrotoxicity
Quinolone (moxifloxacin, levofloxacin)	GI upset, tendinopathy, ↑ QTc

^*Risk of hepatitis ↑ w/ pre-existing liver disease. Consult ID, consider holding/replacing PZA or INH.

Scenario	Antituberculous Treatment Regimens
Pulmonary TB ≥4% INH-resist. in community (incl. most of U.S.)	INH + RIF + PZA + EMB until suscept. known If sensitive to INH & RIF → INH + RIF + PZA × 2 mo, then → INH + RIF × at least 4 mo If resistant, see next row
Drug-resistant TB (INH-R, RIF-R, or MDR/XDR)	Consult ID specialist (NEJM 2008;359:636)
Extrapulmonary TB	Consult ID specialist
TB in HIV ⊕ patient	Consult ID specialist

HIV/AIDS

Definition & Clinical Manifestations

• Acute HIV: rash, lymphadenopathy, fever, oral ulcers, pharyngitis, myalgias, diarrhea Presents ~2–6 wk after exposure; not all HIV infections result in symptoms of acute HIV

• AIDS: HIV + CD4 <200/mm³ or AIDS-defining opportunistic infection (OI) or malignancy

Epidemiology

• ~1.2 million Americans living w/ HIV (13% unaware); ~37 million worldwide

• High risk groups: MSM, transgender women, IVDU, sex worker, partners of high-risk Pts

• Transmission: sexual (risk 0.1–1% per sex act w/o ARV), needlesticks (occupational or IVDU), vertical (15–40% w/o ARV), transfusions, organ transplant (uncommon in U.S.)

Prophylaxis (NEJM 2015;373:2237; Lancet 2016;387:53; J Infect Dis 2018;218:16; CDC 2021)

• Pre-exposure (PrEP): TDF/FTC daily, ↓ transmission >90% if adherent. Consider for serodiscordant partners, condomless sex in high-risk groups, STI w/in 6 mo, IVDU w/ equipment sharing. Rule out HIV prior to initiation, ✓ renal fxn, STIs, & HIV q3 mo.

• Post-exposure (PEP): start ASAP (within 72 hr) after high-risk exposure from HIV ⊕ source (case-by-case decision if HIV status ?). Test baseline HIV, STIs, HBV, HCV. Rx: 2 NRTIs (usually TDF/FTC) + RAL or DTG × 4 wks. Consider initiating PrEP afterwards.

Screening and Diagnosis (JAMA 2018;320:379)

• Screen all 13–64 yo at least once, every preg, if new STI dx; screen high risk annually

• HIV Ab/p24Ag (ELISA assay): ⊕ 1–12 wk after acute infxn; >99% Se; 1° screening test

• If ⊕, Ab differentiation assay confirms and differentiates HIV-1 vs. -2 (MMWR 2013;62:489)

• HIV RNA PCR viral load (VL) in plasma; assay range is 20–10 million copies/mL; false ⊕ can occur, but usually low # copies; in contrast, VL should be high (>750 k) in 1° infxn

• CD4 count: not a dx test, b/c can be HIV ⊕ w/ normal CD4 or be HIV ⊖ w/ low CD4

Approach to newly diagnosed HIV ⊕ Pt (CID 2020;73:e3572)

• Counsel re: excellent prognosis w/adherence to treatment, treatment options, & disclosure

• Lab evaluation: CD4 count, HIV VL & genotype, CBC w/ diff., BMP, LFTs, HbA1c, lipids, UA, PPD/ IGRA, syphilis Ab, Chlamydia & gonorrhea (3 site), Hep A/B/C, G6PD (if high-risk ethnicity), preg screen, HLA-B*5701 if Rx w/ abacavir. If AIDS: CMV IgG, Toxo IgG.

• Confirm all vaccinations (including annual flu) are up to date, avoid live vax if CD4 ≤200

• Initiate ARV early (same day, preferably after labs/genotype and w/ guidance from HIV specialist) regardless of CD4 level because ↓ mortality (NEJM 2015;373:795)

• Treatment prevents transmission to partners. Risk of transmission w/ unprotected sex w/ undetectable VL >6 months is ~0% (JAMA 2016;316:171; Lancet HIV 2018;5:e438).

• Regimens include: 2 NRTI (eg, TAF + FTC) + either INSTI or boosted PI (eg, DRV/r)

Common Antiretrovirals (ARVs)		Common Side Effects
NRTI	abacavir (ABC; Ziagen) emtricitabine (FTC; Emtriva) lamivudine (3TC; Epivir) tenofovir (TAF or TDF) zidovudine (AZT; Retrovir)	Class: GI intol, lipoatrophy, lactic acidosis ABC: hypersensitivity (3%), ✓ HLA-B*5701 AZT: BM suppression (esp. macrocytic anemia) TDF: renal toxicity, bone density loss TAF: minimal renal toxicity
NNRTI	efavirenz (EFV; Sustiva) etravirine (ETR; Intelence) nevirapine (NVP; Viramune) rilpivirine (RPV; Edurant)	Class: rash, hepatitis, mixed CYP450 inducer/inhib EFV: CNS effects (incl depression) NVP: rash and hypersensitivity [risk factors are female, CD4 >250, pregnancy (∴ avoid)]
PI	atazanavir (ATV; Reyataz) darunavir (DRV; Prezista) lopinavir (LPV; Kaletra) PIs given w/boosters ritonavir or cobicistat for ↑ PK	Class: GI intol; hepatotoxicity; inhibit CYP450 (many DDIs, eg statins, steroids, DOACs); ↑ glc; hyperlipid (less w/ ATV); MI (NEJM 2007;356:1723) ATV: crystalluria → nephrolithiasis DRV: rash (10%); possible sulfa cross-reactivity
EI	maraviroc (MVC; Selzentry)	Dizziness, hepatotoxicity; ✓ CCR5 tropism assay
INSTI	bictegravir (BIC; Biktarvy) dolutegravir (DTG; Tivicay) elvitegravir (EVG; Vitekta) raltegravir (RAL; Isentress) cabotegravir (CAB; Vocabria)	Class: diarrhea; weight gain; ↑ CPK DTG/BIC ↑ metformin levels; monitor glc DTG a/w 0.003% risk of neural tube defects (NEJM 2019;381:827) CAB/RPV: injection site rxn

NRTI, nucleoside/tide reverse transcriptase inhib; NNRTI, nonnucleoside RTI; PI, protease inhib; EI, entry inhib (CCR5 antagonist); INSTI, integrase inhib; several multiclass combo pills exist

• Initiation of ARVs may transiently worsen existing OIs (TB, MAC, CMV, others) due to immune reconstitution inflammatory syndrome (IRIS). Prednisone during 1^st 4 wks of ARVs ↓ risk for TB-associated IRIS, but not routinely given (NEJM 2018;379:1915).

• Do not start ARVs immediately if c/f cryptococcal or TB meningitis

• After ARV initiation, check VL q4 wks until undetectable, then monitor q3–4 mos

Approach to previously established HIV ⊕ Pt

• H&P (mucocutaneous, neurocognitive, OIs, malignancies, STDs); meds and adherence

• Review ARVs (past and current); if hospitalized typically continue ARVs, if any must be held, stop all to ↓ risk of resistance

• Regimen failure: cannot achieve undetectable VL after months on ARVs, viral rebound (VL >200 copies/mL ×2 after prior suppression), ↓ CD4 count or clinical worsening

OI Prophylaxis (https://aidsinfo.nih.gov/guidelines & JAMA 2018;320:379, HIV.gov:2020)
OI	Indication	1° Prophylaxis
Tuberculosis	⊕ PPD (≥5 mm), IGRA, or high-risk exposure	See treatment for latent TB
Pneumocystis jiroveci (PCP)	CD4 <200/mm or CD4 <14% or thrush	TMP-SMX DS qd (first line) or dapsone qd or atovaquone qd or pentamidine inhaled q4wk
Histoplasmosis	CD4 <150/mm + endemic/ exposure	Itraconazole qd
Toxoplasmosis	CD4 <100/mm3 and ⊕ Toxo IgG	TMP-SMX DS qd or dapsone 50 mg qd + pyrimeth. qwk + leucovorin 25 qwk
MAC	Ppx no longer rec. if effective ARVs initiated
When to stop Ppx: PCP and toxo if CD4 >200 × 3 mos; Histo if CD4 >150 × 6 mos

COMPLICATIONS OF HIV/AIDS

CD4 Count	Complications
Any	S. pneumo, TB, VZV, HPV complications, Kaposi’s sarcoma, lymphoma, ↑ CVD risk, ↓ bone density.
<500	Constitutional sx. Mucocutaneous: seborrheic dermatitis; psoriasis; oral hairy leukoplakia; HSV. Recurrent bacterial infxns.
<200	PCP, Toxo, PML, Crypto, candida, Histo/Coccidio (endemic areas)
<50–100	CMV, MAC, CNS lymphoma, invasive aspergillosis, bacillary angiomatosis (dissem. Bartonella), death (<50 is medical emergency)

Fever workup in patient with HIV/AIDS

• Etiologies (Infect Dis Clin North Am 2007;21:1013)

infxn (82–90%): MAC, TB, CMV, early PCP, Histo, Crypto, Coccidio, Toxo, endocarditis

noninfectious: lymphoma, drug reaction. Non 1° HIV itself rarely (<5%) cause of fever.

• Workup: guided by CD4 count, s/s, epi, & exposures

CBC, BMP, LFTs, BCx, CXR, UA, mycobact. & fungal cx, ✓ meds, ? ✓ chest & abd CT

CD4 <100–200 → serum crypto Ag, urinary Histo Ag, CMV PCR

pulmonary s/s → CXR; ABG; sputum for bacterial cx, PJ stain, AFB; bronchoscopy

diarrhea → stool cx, O&P, AFB; direct visualization with bx on colonoscopy

cytopenias → BM bx for path & cx of aspirate including for mycobacteria & fungi

headache/visual Δs→ LP; send CSF for bacterial/fungal cx, CrAg, ? MTb PCR; send CMV PCR from serum; dilated eye exam with Ophtho

Cutaneous

• Eosinophilic folliculitis; warts (HPV); HSV & VZV; MRSA SSTI; scabies; candidiasis; eczema; prurigo nodularis; psoriasis; drug eruption; subungual onychomycosis

• Molluscum contagiosum (poxvirus): 2–5 mm pearly papules w/ central umbilication

• Kaposi’s sarcoma (KSHV or HHV8): red-purple nonblanching nodular lesions

• Bacillary angiomatosis (disseminated Bartonella): friable violaceous vascular papules

Oral

• Aphthous ulcers; KS; thrush/oral candidiasis (curd-like patches, often painless)

• Oral hairy leukoplakia: painless proliferation of papillae w/ adherent white coating usually on lateral tongue, caused by EBV but not precancerous

Ophthalmologic

• CMV retinitis (CD4 usu <50); Rx: ganciclovir or valganciclovir, foscarnet, or cidofovir

• HZV, VZV, syphilis (any CD4 count, treat as neurosyphilis) or Toxo (CD4 usually <100)

Endocrine/metabolic

• Hypogonadism; adrenal insufficiency (CMV, MAC, TB, HIV, or med-related); sarcopenia; osteopenia/porosis/fragility fractures (at all CD4 counts)

• Lipodystrophy: central obesity, peripheral lipoatrophy, dyslipidemia, hyperglycemia

Cardiovascular (JACC 2013;61:511)

• Higher rates of CAD, stroke, VTE, dilated CMP; pulm. HTN; pericarditis/effusion

Pulmonary

Radiographic Pattern	Common Causes
Normal	Early PCP
Diffuse interstitial infiltrates	PCP, TB, viral, or disseminated fungal
Focal consolidation or masses	Bacterial or fungal, TB, KS
Cavitary lesions	TB, NTM, aspergillus, other fungal, bacterial (incl. Staph aureus, Nocardia, Rhodococcus)
Pleural effusion	TB, bacterial or fungal, KS, lymphoma

• Pneumocystis jiroveci (PCP) pneumonia (CD4 <200) (NEJM 1990;323:1444)

fever, night sweats, dyspnea on exertion, dry (“doorstop”) cough

CXR w/ interstitial pattern, ↓ P_aO₂, ↑ A-a ∇, ↑ LDH, ⊕ PCP sputum stain, ⊕ β-glucan

Rx if P_aO₂ >70: TMP-SMX 15–20 mg of TMP/kg divided tid, avg dose = DS 2 tabs PO tid

Rx if P_aO₂ <70 or A-a gradient >35: prednisone before abx (40 mg PO bid; ↓ after 5 d)

HIV ⊕ smokers much more likely to die from lung cancer than OI (JAMA 2017;177:1613)

Gastrointestinal & hepatobiliary

• Esophagitis: Candida, CMV (solitary, lg serpiginous), HSV (multiple, small shallow), giant aphthous ulcers, pills; EGD if no thrush or no response to empiric antifungals

• Enterocolitis: bacterial (esp. if acute: Shigella, Salmonella, C. diff); protozoal (esp. if chronic: Giardia, Isospora, Cryptosporidium, Cyclospora, Microsporidium, Entamoeba); viral (CMV, adeno); fungal (histo); MAC; AIDS enteropathy; TB enteritis

• GI bleeding: CMV, KS, lymphoma, histo; proctitis: HSV, CMV, LGV, N. gonorrhoeae

• Hepatitis: HBV, HCV, CMV, MAC, TB, histo, drug-induced

• AIDS cholangiopathy: often a/w CMV or Cryptosporidium or Microsporidium (at ↓ CD4)

Renal

• HIV-assoc. nephropathy (collapsing FSGS); nephrotoxic drugs (eg, TDF → prox tub dysfxn)

Hematologic/oncologic (NEJM 2018;378:1029)

• Cytopenia: ACD, BM infiltration by tumor/infxn (eg, MAC/TB), drug toxicity, hemolysis, ITP

• Non-Hodgkin lymphoma: ↑ frequency with any CD4 count, but incidence ↑ with ↓ CD4

• Hodgkin lymphoma (any CD4; impact of ART unclear)

• CNS lymphoma: CD4 count <50, EBV-associated

• Kaposi’s sarcoma (HHV-8): at any CD4 count, incidence ↑ b/c CD4 ↓, usu. MSM

Mucocut. (violacious lesions); pulmonary (nodules, infiltrates, LAN); GI (bleed, obstruct.)

• Cervical/anal CA (HPV high risk in MSM)

• ↑ rates of liver CA (a/w HBV/HCV), gastric CA

Neurologic/Psychologic

• Meningitis: Crypto (dx w/ CSF; serum CrAg 90% Se), bacterial (inc. Listeria), viral (HSV, CMV, 1° HIV), TB, histo, Coccidio, lymphoma; neurosyphilis (cranial nerve palsies)

• Space-occupying lesions: may present as HA, focal deficits or Δ MS. Workup: MRI, brain bx only if suspect non-Toxo etiology (Toxo sero ⊖) or no response to 2 wk of empiric anti-Toxo Rx (if Toxo, 50% respond by d3, 91% by d14; NEJM 1993;329:995)

Etiology	Imaging Appearance	Diagnostic Studies
Toxoplasmosis	Enhancing lesions, typically in basal ganglia (can be multiple)	⊕ Toxo serology (Se ~85%)
CNS lymphoma	Enhancing ring lesion (single 60% of the time)	⊕ CSF PCR for EBV ⊕ SPECT or PET scan
Progressive multifocal leukoencephalopathy (PML)	Multiple nonenhancing lesions in white matter	⊕ CSF PCR for JC virus
Other: abscess, nocardiosis, crypto, TB, CMV, HIV	Variable	Biopsy

• HIV-assoc. dementia: depressive sx, impaired attention/concentration, psychomotor slowing

• Depression: ↑ rates of suicide/depression

• Myelopathy: infxn (CMV, HSV), cord compression (epidural abscess, lymphoma)

• Peripheral neuropathy: meds (esp 1^st gen NRTIs), CMV, diabetes

Disseminated Mycobacterium avium complex (DMAC)

• Fever, night sweats, wt loss, abd pain, diarrhea, pancytopenia. Can cause localized lymphadenitis. Rx: clarithro/azithro + ethambutol ± rifampin/rifabutin.

Cytomegalovirus (CMV)

• Retinitis, esophagitis, colitis, hepatitis, neuropathies, encephalitis. CMV VL may be ⊖. Consider tissue biopsy. Rx: ganciclovir, valganciclovir, foscarnet, or cidofovir.

TICK-BORNE DISEASES

–: <15%, +: 15–25%, ++: 25–50%, +++: 50–75%, ++++: >75%

Tick prophylaxis: protective clothing, tick ✓ q24h, DEET/picardin, if bitten remove ASAP

LYME DISEASE

Microbiology & epidemiology

• Spirochete B. burgdorferi transmitted by Ixodes scapularis (deer tick)

• Humans contact ticks in low brush near wooded areas

• Infection usually requires tick attached >36–48 h

• Most common vector-borne illness in U.S.; peak in summer in NE/Mid-Atlantic/Midwest

• Consider coinfection w/ Anaplasma, Babesia, B. miyamotoi

Clinical Manifestations
Stage	Manifestations
Early localized (w/in 1 month)	General: flu-like illness. Derm (~80%): erythema migrans (EM) = erythematous patch ± central clearing, ~6–38 cm.
Early disseminated (wks to mos)	General: fatigue, malaise, LAN, HA Derm: multiple EM lesions Rheum (~10%): migratory arthralgias & myalgias Neurologic (~15%): cranial neuropathies (esp. CN VII), aseptic meningitis, mononeuritis multiplex (± pain), transverse myelitis Cardiac (~8%): heart block, myopericarditis
Late disseminated (mos to yrs)	Derm (rare in U.S.): acrodermatitis chronica atrophicans, panniculitis Rheum (~60%, espec. if not Rx’d): recurrent mono- or oligoarthritis of large joints (classically knee), synovitis Neurologic (rare!): subacute encephalomyelitis, polyneuropathy

(NEJM 2014;370:1724; CID 2020; 72:e1)

Diagnostic studies (CID 2020; 72:e1)

• Avoid testing without signs/symptoms

• Early localized: clinical dx if EM + possible exposure; no need for testing (often sero ⊖)

• Early or late disseminated: 2-step testing

1^st step: ELISA screen (some false ⊕, false ⊖ w/ early abx or <6 wk after tick bite)

2^nd step: if ⊕ ELISA, confirm with IgM/IgG Western blot (↑ Sp) or 2^nd ELISA

• Serum testing is sufficient for diagnosis of Lyme CNS infection or Lyme arthritis, though consider CSF (Ab testing in parallel with serum) or joint fluid sampling (PCR) to rule out other causes and provide a more definitive diagnosis

Treatment (CID 2020; 72:e1; IDSA 2021)

• Prophylaxis: doxycycline × 1 only if all of the following:

1) Ixodes scapularis tick attached ≥36 h

2) Local Lyme carriage in ticks ≥20%

3) Abx can be given w/in ≤72 h of tick bite

4) No contraindication to doxycycline (eg, preg, allergy, age <8 y)

Regardless of Ppx, monitor for fever, flu-like sx, rash (erythema migrans) × 30 d

• Treatment

Isolated EM: doxy × 10 d (alternative: cefurox or amox × 14 d or azithro × 7 d)

Arthritis: doxy × 28 d (alternative: cefurox or amox × 28 d)

Carditis/meningitis: CTX IV or doxy PO (based on severity/response) × 14–21 d

• Consider coinfection if severe/refractory sx, persistent fever, cytopenias

• Recurrent sx after abx are likely re-infection, not relapse (NEJM 2012;367:1883)

BABESIOSIS

Microbiology & epidemiology (MMWR 2012;61:505)

• Babesia microti (U.S.) transmitted by Ixodes ticks; also risk from blood transfusion

• Peak incidence summer in NE U.S. (esp. near coast, “Nantucket fever”), north-central MW

Clinical manifestations

• Typically 1–4 wks after tick exposure; <9 wks if transfusion

• Range: asx/mild flu-like sx to severe DAT ⊖ hemolytic anemia/DIC, multiorgan failure

• Risk factors for severe dx: asplenia, ↓ cellular immunity, TNF inhib, ↑ age, pregnancy

Diagnosis (CID 2021;72:e49)

• Symptoms + blood smear w/ intraerythrocytic parasites (ring forms)

• Degree of parasitemia = % infected RBC on smear (correlates roughly w/ severity)

• Repeat smears (q12–24h) if sx persist despite negative initial smear

• PCR serum if smear ⊖ (or unavailable) and clinical suspicion

Treatment (CID 2021;72:e49)

• Atovaquone & azithro preferred; clinda/quinine (more adverse events); call ID if severe

• Duration depends on host; immunosupp often need longer Rx

• Consider exchange transfusion if parasitemia >10%, severe hemolysis/ end-organ failure

EHRLICHIOSIS/ANAPLASMOSIS

Microbiology & epidemiology

• Gram ⊖ obligate intracellular bacterium; human monocytic ehrlichiosis (E. chaffeensis, HME); human granulocytic anaplasmosis (A. phagocytophilum, HGA)

• Transmission: HME by Amblyomma americanum (lone star tick), Dermacentor variabilis (dog tick); HGA by Ixodes; HGA in NE, mid-Atl, MN; HME in SE and south-central U.S.

• Peak incidence spring and early summer; can be transmitted by blood transfusion

Clinical manifestations (typically w/in 3 wks of tick exposure)

• Asx or nonspecific: fever, myalgias, malaise, HA, delirium; onset often acute

• Laboratory: leukopenia, thrombocytopenia, ↑ aminotransferases, ↑ LDH, ↑ CK

• Severe disease can be complicated by bacterial superinfection

Diagnosis

• Intraleukocytic morulae on peripheral smear in acute infection; serum PCR ⊕ in acute infection and convalescence

Treatment (JAMA 2016;315:1767)

• Start Rx based on clinical suspicion; definitive dx requires PCR (but not 100% Se)

• Doxycycline × 10 d; if Pt does not defervesce in ≤48 h, consider co-infection/alt dx

ROCKY MOUNTAIN SPOTTED FEVER (RMSF)

Microbiology & epidemiology

• Infection with Rickettsia rickettsii (Gram ⊖ obligate intracellular bacterium)

• Transmitted by D. variabilis, D. andersoni (wood tick); peak in spring/early summer

• Occurs in mid-Atl, SE/south central U.S., mountain west, Mexico, Central & S. America

Clinical manifestations (typically w/in 1–2 wks of tick exposure)

• Nonspecific: fever, HA, ΔMS, myalgias, N/V, occasionally abdominal pain

• Rash (2–5 d after onset of fever) = centripetal: starts on ankles and wrists → trunk, palms, & soles; progresses from macular to maculopapular to petechial

• Severe cases → vasculitis, multi-organ failure, meningoencephalitis; more likely in elderly

Diagnosis (MMWR 2016;65:1)

• Clinical dx (often w/o rash initially); requires high suspicion given risk of delayed Rx

• Acute illness: skin bx for rickettsiae (Se 70–90%), consider ✓serologies (may be ⊖)

• Confirm dx: re-check serology 14–21 d later, ⊕ if 4-fold ↑

Treatment (MMWR 2016;65:1)

• Doxy × 7–10 d, empiric Rx if suspicion; if does not defervesce in ≤48 h ? co-infection/alt dx

TULAREMIA

Microbiology

• Infxn w/ Francisella tularensis bacteria via arthropod bites, animal contact (bite, scratch, lick), contaminated food or water, aresolized materials

Clinical manifestations (typically w/in 2–10 d of exposure)

• Fever, chills, malaise, HA, nausea, myalgias; ulcer w/ black eschar at site of entry; LAN; conjunctivitis; pharyngitis; PNA

Diagnosis & treatment

• Serology should be collected at presentation and 2 wks later, bacteria difficult to culture

• FLQ for mild infection, aminoglycoside for severe infection in consultation with ID

FEVER SYNDROMES

Temperature ≥100.4°F or ≥38°C

Diagnostic approach

• Thorough history including ROS, PMH/PSH, immunizations, including from childhood

• Fever curve (holding antipyretics); look at trend/pattern. Less likely to mount fever if: ESRD/ESLD, extremes of age, protein calorie malnutrition, immunosupp., steroid use.

• Exposures: travel, occupation/hobbies, animals, sexual contacts, TB. Consider geography, season, and incubation time in relation to exposures.

• Physical exam: look for thrush, dental caries; full eye exam; cardiac murmurs; HSM; abd tenderness; rash/skin lesions; LAN; synovitis; complete neuro exam

FEVER OF UNKNOWN ORIGIN (FUO)

Definition & etiologies (NEJM 2022;386:463)

• Fever (as per above def) on >1 occasion during ≥3 wk & no dx despite 1 wk of evaluation

• More likely to be unusual manifestation of common disease than an uncommon disease

• In Pts with HIV: >75% causes are infectious, but rarely due to HIV itself

• Frequent reassessment needed to identify focal signs and progression of disease

Category	Etiologies of Classic FUO (Medicine 2007;86:26; AJM 2015;128:1138)
Infection ~30%	Tuberculosis: disseminated or extrapulm. disease can have normal CXR, PPD/IGRA, sputum AFB; bx (lung, liver, bone marrow) for granulomas has 80–90% yield in milliary disease Endocarditis: if blood cxs neg consider Bartonella, Coxiella, et al. Abscess: dental, paraspinal, hepatic, splenic, subphrenic, pancreatic, -perinephric, pelvic, prostatic abscess or prostatitis, appendicitis Osteomyelitis, sinusitis, typhoid, 1° CMV or EBV, malaria, Babesia
Connective tissue disease ~30%	Giant cell arteritis/PMR: headache, scalp pain, jaw claudication, visual disturbances, myalgias, arthralgias, ↑ ESR Adult-onset Still’s: evanescent truncal rash, LAN, pharyngitis, ↑↑ ferritin PAN, ANCA ⊕, other vascul.; SLE, RA, psoriatic or reactive arthritis
Neoplasm ~20%	Lymphoma: LAN, HSM, ↓ Hct or plt, ↑ LDH; leukemia; myelodysplasia Renal cell carcinoma: microscopic hematuria, ↑ Hct HCC, pancreatic and colon cancers, sarcomas, mastocytosis Atrial myxomas: obstruction, embolism, constitutional symptoms
Misc ~20%	Drug fever, factitious, DVT/PE, hematoma Thyroiditis or thyroid storm, adrenal insufficiency, pheochromocytoma Granulomatous hepatitis (many causes), sarcoidosis, Kikuchi’s, Behçet’s Familial Mediterranean fever (peritonitis, episodic fever, pleuritis; ↑ WBC & ESR during attacks); other defects in innate immunity

More common causes boldfaced

Workup (Archives 2009;169:2018; AJM 2015;128:1138)

• Initial: CBC w/ diff, CMP, ESR, CRP, 3 sets BCx (off abx), U/A, UCx, CXR

• Additional workup based on sx: ANA, RF, cryoglobulin, LDH, CK/aldolase, SPEP, TFTs, PPD or IGRA, HIV Ag/Ab ± PCR, RPR, EBV serologies, CMV PCR, HBV/HCV serologies

• Consider imaging: chest & abd CT, tagged WBC scan, FDG-PET, TTE, LE duplex US

• Tissue dx: consider bx of LN (excisional preferred), liver (especially if ↑ Aϕ), TA (for GCA), BM, kidney (RPGN)

Treatment

• Empiric abx not indicated (unless Pt neutropenic or critically ill)

• Empiric glucocorticoids not indicated unless strong suspicion for specific rheumatologic dx

• Stop unnecessary meds (only 20% with a med cause have eos or rash)

• Up to 30% of cases remain undiagnosed, most spontaneously defervesce (wks to mos)

FEVER AND RASH

Approach to diagnostic workup

• Meningococcemia, endocarditis, RMSF, sepsis, & toxic shock need urgent dx & Rx

• Workup: CBC w/diff, BMP, LFTs, LDH, CK, U/A, HIV Ag/Ab ± PCR, BCx (off abx)

• To narrow Ddx: characterize time course of rash, progression, & morphology

• Erythema multiforme: symmetric “target” lesions often of palms, soles, & mucous memb

Infxn etiol: HSV, Mycoplasma, syphilis, VZV, EBV, CMV, adenovirus, etc.

Non-infxn etiol: most likely meds (eg, NSAIDs, sulfa, AEDs), autoimmune disease

• Erythema nodosum: tender erythematous or violaceous nodules usually symmetric on LE

Infxn etiol: Strep, TB, EBV, Bartonella, HBV, psittacosis, fungal, L. venereum, etc.

Non-infxn etiol: sarcoidosis, IBD, Behçet’s, other rheum, pregnancy/OCP use

• Pursue specific dx based on exposure hx & exam, including serologies, viral PCRs, possibly skin biopsy ± exam of vesicular or bullae fluid if present

• Immunosupp. Pts need broad w/u; higher risk of disseminated/rapidly progressive infxns

Variable	Possible Etiology
Summer/fall > other seasons	Enterovirus
Winter	Parvovirus, Meningococcemia
Spring/summer	Lyme, RMSF, Ehrlichiosis, Anaplasmosis
Year-round	Adenovirus, Mycoplasma
Cat and dog exposure	Bartonella, Pasteurella, Toxoplasma, Capnocytophaga
Tick exposure	Lyme, RMSF, Ehrlichiosis, Anaplasmosis
Adult <30 y	Mononucleosis (EBV or CMV)
Inadequate immunization	Measles, Rubella, VZV, influenza
Sexually active	HIV, syphilis, disseminated gonococcal infection, HSV
Consider noninfectious causes: allergy/DRESS, DVT, phlebitis, vasculitides, neutrophilic dermatoses, gout, connective tissues dis., malignancy, foreign body rxn

Treatment

• Empiric abx not indicated (unless Pt neutropenic or critically ill)

• Consider important empiric isolation precautions (ie, varicella → airborne/contact; measles → airborne; meningococcus → droplet) while workup pending

FEVER IN A RETURNED TRAVELER

See CDC.gov/travel for up to date information on regional risks and recommendations

Region or Exposure	Common Etiologies (NEJM 2017;376:548)
Sub-Saharan Africa	Malaria >> dengue and other arboviruses, rickettsial disease, enteric fever
South/Southeast Asia	Dengue > malaria, enteric fever (S. typhi/paratyphi), Chikungunya and other arboviruses
Central & S. America	Dengue, enteric fever, malaria
Caribbean & Mexico	Dengue >> Chikungunya and other arbovirsuses > enteric fever, malaria
Middle East	Middle East Respiratory Syndrome, brucellosis
Freshwater swimming	Schistosomiasis, leptospirosis
Unpurified drinking water	Enteric disease (E. coli >> S. typhi, Campylobacter, hepatitis E > Vibrio cholerae), amoebic liver abscess
Lacking immunizations	HAV/HBV, S. typhi, influenza, measles, rubella, yellow fever

• Pts visiting friends and relatives abroad are most likely to contract illness during travel

• Also consider domestic infxns, influenza, STIs, & non-infxn causes

Select clinical manifestations

• Ebola: fever in traveler from area with active transmission of Ebola w/in 21 d

• Malaria: nonspecific sx including diarrhea, headache, myalgias, cough, Δ MS

• Dengue: nonspecific sx including headache, severe myalgias, rash/petechiae

• Chikungunya: nonspecific sx including joint pain, moderate myalgias

• Typhoid (Lancet 2015;385:1136): diarrhea/constipation, abd pain, ± rash, relative bradycardia

• Rickettsial disease: headache, myalgias, lymphadenopathy, ± rash/eschar

• Zika: rash, arthralgia, headache, conjunctivitis; often less severe than dengue, Chikungunya

Workup

• Routine testing: CBC w/ diff, BMP, LFTs, BCx, UA, rapid malaria test

• Fever in a traveler from a malaria zone is malaria until proven otherwise; consider a medical emergency → hospitalization & empiric Rx. One ⊖ smear does not r/o.

• Other tests based on s/s, labs, exposure, incubation period, geography, and seasonality. O&P exam, CXR, blood smears for filaria/Babesiosis/Borrelia, serologies, STI & HIV, PPD or IGRA, bone marrow aspirate, bx of lymph nodes or skin lesions, CSF studies.