3.3 Infectious Diseases: Specialty Infections

Specialty Infections

Human Immunodeficiency Virus (HIV)

The Department of Health and Human Services (DHHS) guidelines strongly recommend initiating antiretroviral therapy (ART) immediately (or as soon as possible) after HIV diagnosis for all individuals. Early initiation preserves immune function, significantly reduces morbidity, and prevents onward transmission (Undetectable = Untransmittable, or U=U). Modern regimens are highly efficacious, well-tolerated, and present a very high genetic barrier to resistance.

Initial Recommended Regimens for Most People with HIV

The standard of care involves an Integrase Strand Transfer Inhibitor (INSTI) combined with a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone. INSTIs function by blocking the HIV integrase enzyme, thereby preventing the covalent insertion of viral DNA into the host genome.

Preferred INSTI-based Regimens:

• Biktarvy (Bictegravir / Tenofovir alafenamide / Emtricitabine): A highly preferred single-tablet regimen (STR). Tenofovir alafenamide (TAF) is favored over older Tenofovir disoproxil fumarate (TDF) due to significantly lower rates of bone mineral density loss and a dramatically reduced risk of renal toxicity (proximal renal tubulopathy/Fanconi syndrome).
• Triumeq (Dolutegravir / Abacavir / Lamivudine): A widely used STR. Critical safety point: Abacavir can cause a severe, potentially fatal multi-organ hypersensitivity reaction. Patients must undergo pharmacogenomic testing for the HLA-B*5701 allele prior to initiation. If the test returns positive, abacavir is strictly contraindicated, and the patient's chart must reflect an abacavir allergy.
• Tivicay (Dolutegravir) + Descovy (TAF / Emtricitabine) OR Truvada (TDF / Emtricitabine): A flexible two-pill regimen option.
• Dovato (Dolutegravir / Lamivudine): A paradigm-shifting two-drug STR that avoids tenofovir and abacavir entirely. It is highly effective but has strict baseline exclusion criteria. It should not be initiated if the patient has a baseline HIV RNA > 500,000 copies/mL, has active Hepatitis B (HBV) co-infection (as lamivudine alone is insufficient to treat HBV), or if genotypic resistance testing results are unavailable prior to starting.

Opportunistic Infections and Prophylaxis

When CD4 cell counts fall precipitously, patients become highly susceptible to opportunistic infections. Primary prophylaxis is vital:

• CD4 < 200 cells/mm$^3$: Risk of Pneumocystis jirovecii pneumonia (PCP). Prophylaxis with TMP-SMX (Bactrim) DS once daily or SS once daily is recommended. Dapsone or atovaquone are alternatives for sulfa-allergic patients.
• CD4 < 100 cells/mm$^3$: Risk of Toxoplasma gondii encephalitis (if Toxoplasma IgG positive). TMP-SMX DS once daily serves as dual prophylaxis for both PCP and Toxo.
• CD4 < 50 cells/mm$^3$: Risk of Mycobacterium avium complex (MAC). While azithromycin was historically used, updated guidelines no longer recommend primary MAC prophylaxis if the patient is initiating ART immediately and is expected to achieve immune reconstitution.

Clostridioides difficile Infection (CDI)

CDI is a devastating, toxin-mediated (Toxins A and B) disease characterized by profuse, watery diarrhea, typically triggered by recent antibiotic exposure (clindamycin, fluoroquinolones, and broad-spectrum beta-lactams are highest risk). Accurate diagnosis involves a multi-step algorithm using Enzyme Immunoassay (EIA) for Glutamate Dehydrogenase (GDH) antigen, Toxin A/B EIA, and Nucleic Acid Amplification Testing (NAAT/PCR).

The 2021 IDSA/SHEA focused update shifted the paradigm for first-line therapies, favoring fidaxomicin to aggressively reduce recurrence rates.

Classification and Treatment of an Initial Episode

1. Non-Severe and Severe CDI:

• Non-Severe Definition: WBC $\le$ 15,000 cells/mm$^3$ AND Serum Creatinine (SCr) < 1.5 mg/dL.
• Severe Definition: WBC > 15,000 cells/mm$^3$ OR SCr $\ge$ 1.5 mg/dL.
• Preferred Regimen: Fidaxomicin 200 mg PO BID for 10 days. Fidaxomicin is a narrow-spectrum macrocyclic antibiotic that is bactericidal against C. difficile and profoundly spares the normal gut microbiota (Bacteroides species), leading to significantly lower clinical recurrence rates compared to vancomycin.
• Alternative First-line: Vancomycin 125 mg PO QID for 10 days. (Note: Metronidazole is no longer recommended as first-line therapy for adults unless both fidaxomicin and vancomycin are entirely unavailable due to inferior cure rates and high recurrence).

2. Fulminant CDI:

• Definition: CDI accompanied by systemic toxicity, hypotension, shock, ileus, or toxic megacolon. This is a life-threatening surgical emergency.
• Treatment Regimen:
  • Vancomycin 500 mg PO (or via nasogastric tube) QID PLUS Metronidazole 500 mg IV q8h.
  • Clinical Pearl: If the patient has a paralytic ileus, oral vancomycin will fail to transit to the colon. In this critical scenario, Vancomycin retention enemas (e.g., 500 mg mixed in 100 mL of normal saline per rectum q6h) must be added. Metronidazole is given intravenously because it uniquely achieves therapeutic concentrations in the inflamed colonic wall via the systemic circulation.

Management of Recurrent CDI

Recurrence occurs in roughly 25% of patients following a first episode.

• First Recurrence: If vancomycin was used initially, use a prolonged tapered and pulsed vancomycin regimen (e.g., QID x10-14 days, then BID x7 days, then daily x7 days, then every 2-3 days for 2-8 weeks) or a standard 10-day course of fidaxomicin. If fidaxomicin was used first, use standard vancomycin or a tapered/pulsed vancomycin regimen.
• Multiple Recurrences: Patients with multiple recurrences may qualify for Fecal Microbiota Transplantation (FMT) to restore gut flora diversity, or the administration of bezlotoxumab (a monoclonal antibody directed against C. difficile toxin B). Bezlotoxumab should be used with extreme caution in patients with a history of congestive heart failure due to exacerbation risks.

Infective Endocarditis (IE)

Infective endocarditis is an aggressive infection of the endocardial surface of the heart, most frequently seeding the heart valves (mitral and aortic are most common).

Diagnosis: Modified Duke Criteria

Definitive diagnosis rigorously requires 2 Major criteria, 1 Major + 3 Minor criteria, or 5 Minor criteria.

• Major Criteria:
  • Two separate positive blood cultures drawn >12 hours apart with typical microorganisms (e.g., S. aureus, Viridans group streptococci, Enterococcus species, HACEK organisms).
  • Distinct evidence of endocardial involvement (e.g., oscillating vegetation, paravalvular abscess, or new partial dehiscence of a prosthetic valve noted on Transesophageal Echocardiogram [TEE]).
• Minor Criteria: Predisposing heart condition or IV drug use, fever > 38.0°C, vascular phenomena (Janeway lesions, major arterial emboli, mycotic aneurysms), immunologic phenomena (Osler nodes, Roth spots, glomerulonephritis with hematuria), or microbiologic evidence falling short of major criteria.

Antimicrobial Synergy Principles

Therapy for IE strictly mandates prolonged (4-6 weeks) intravenous bactericidal antibiotics. The density of bacteria within the valvular vegetation and the relative absence of host immune defenses necessitate high-dose therapy. For certain pathogens, combination therapy is utilized to achieve pharmacologic synergy—where the combined bactericidal effect is substantially greater than the sum of the individual effects.

Enterococcal Endocarditis: Enterococcus faecalis and E. faecium are inherently tolerant to beta-lactams. Achieving a bactericidal effect requires the combination of a cell wall-active agent (ampicillin or aqueous crystalline penicillin G) plus an aminoglycoside (gentamicin) or a complementary secondary beta-lactam (ceftriaxone).

• Aminoglycoside Synergy TDM (Therapeutic Drug Monitoring): When continuous or multiple daily dosing gentamicin is utilized for synergy in gram-positive IE, the target serum concentrations are markedly lower than those used for gram-negative sepsis.
  • Target Peak: 3 to 4 mcg/mL (This low concentration is sufficient to facilitate the intracellular entry of the aminoglycoside through the thick peptidoglycan cell wall, which has been damaged/permeabilized by the beta-lactam).
  • Target Trough: < 1 mcg/mL (Essential to minimize catastrophic nephrotoxicity and ototoxicity during a grueling 4-6 week course).
• Clinical Shift: Due to the significant, cumulative nephrotoxicity associated with weeks of gentamicin, the combination of Ampicillin + Ceftriaxone (which saturates complementary Penicillin Binding Proteins) is now widely preferred as first-line for E. faecalis IE. It achieves equivalent clinical cure rates with a vastly superior safety profile, especially in elderly patients or those with pre-existing chronic kidney disease.

Prosthetic Valve Endocarditis (Staphylococcal): Infections involving prosthetic valves require the addition of Rifampin to the core beta-lactam/vancomycin regimen. Rifampin possesses unique ability to penetrate the bacterial biofilm that aggressively coats the prosthetic material. Gentamicin is also added for the first 2 weeks to rapidly clear bacteremia.