Infections in Cancer Patients

Risk stratification, who needs prophylaxis

• Low risk: anticipated neutropenia <7 days, ANC nadir >100, no significant comorbidity. Most solid-tumor adjuvant chemo. Outpatient management acceptable.
• Intermediate risk: 7 to 10 days neutropenia. Autologous HSCT, induction lymphoma chemo. Often inpatient with empiric IV antibiotics for febrile neutropenia.
• High risk: ANC ≤100 for >7 days (anticipated prolonged profound neutropenia), mucositis, indwelling lines, comorbidities (renal, hepatic, hemodynamic instability). AML induction, allo-HSCT conditioning, CAR-T cytokine storm. Inpatient management mandatory; broadest empiric antibiotic coverage at first fever.
• Multinational Association for Supportive Care in Cancer (MASCC) score stratifies risk: ≥21 = low risk (outpatient candidates), <21 = high risk. Components include burden of illness, hypotension, COPD, solid tumor vs hematologic malignancy, dehydration, outpatient status, and age.

Bacterial prophylaxis

Fluoroquinolone prophylaxis

• Indication: anticipated profound neutropenia (ANC <100 for >7 days), primarily AML induction, allo-HSCT conditioning, and intensive lymphoma chemo. NOT for routine solid-tumor chemo.
• Agents: levofloxacin 500 mg PO daily (most common), ciprofloxacin 500 mg PO BID (alternative).
• Duration: start at the onset of neutropenia, stop at engraftment or first fever (switch to broad-spectrum IV).
• Evidence: Bucaneve G et al, NEJM 2005 (PMID 16148283) and Cullen M et al, NEJM 2005 (PMID 16148284), levofloxacin prophylaxis reduced febrile episodes and bacterial infections; meta-analyses showed a mortality benefit.
• Trade-offs: rising fluoroquinolone resistance, C. difficile risk, tendon and aortic AEs. Many centers have stopped routine FQ prophylaxis due to local resistance patterns.

Empiric therapy of febrile neutropenia

• First fever (≥38.3°C single or ≥38.0°C for ≥1 h) in a neutropenic patient (ANC <500): start empiric monotherapy within 60 minutes after blood cultures.
• Preferred regimens: cefepime 2 g IV q8h, piperacillin-tazobactam 4.5 g IV q6h, or meropenem 1 g IV q8h. Avoid ceftazidime for empiric monotherapy (worse Gram-positive coverage; rising resistance).
• Add vancomycin only for documented Gram-positive infection, suspected catheter infection, severe mucositis when on fluoroquinolone prophylaxis and ceftazidime empirically (cefepime, pip-tazo, and carbapenems already cover viridans strep), soft-tissue infection, or hemodynamic instability. Discontinue at 48 h if cultures are negative.
• Add antifungal coverage (voriconazole, isavuconazole, posaconazole, lipid amphotericin) if fever persists ≥4 to 7 days despite broad-spectrum antibiotics in patients expected to stay neutropenic >7 days (empiric strategy, no imaging required); alternatively a diagnostic-driven approach treats when HRCT shows nodules/halo sign or galactomannan/beta-D-glucan is positive.
• De-escalate based on culture/imaging at 48 to 72 h; switch to PO once afebrile plus ANC recovering.

Fungal prophylaxis

• High-risk populations for invasive fungal disease (IFD):
  • AML induction/re-induction
  • Allo-HSCT (especially with GVHD on high-dose steroids ≥0.5 mg/kg prednisone equivalent)
  • Prolonged neutropenia (ANC <100 for >14 days)
  • Acute leukemia in relapse
  • Anti-CD52 (alemtuzumab) or fludarabine-based regimens
  • CAR-T recipients with prolonged neutropenia and ICANS/CRS requiring high-dose steroids
• Recommended agents (yeast plus mold coverage):
  • Posaconazole DR tablet 300 mg PO BID on day 1 (loading), then 300 mg PO daily from day 2, first-line for AML induction and GVHD. Evidence: Cornely OA et al, NEJM 2007 (PMID 17251531) showed reduced invasive aspergillosis and all-cause mortality vs fluconazole/itraconazole.
  • Voriconazole 200 mg PO BID, alternative; therapeutic drug monitoring recommended (trough 1 to 5.5 mcg/mL).
  • Isavuconazole 372 mg PO/IV q24h after loading, covers mucormycosis (as does posaconazole; voriconazole does not), no QTc prolongation, fewer drug-drug interactions.
  • Fluconazole 400 mg PO daily, adequate for low-risk patients needing yeast-only coverage (post-autologous HSCT, low-intensity chemo). Does NOT cover molds.
  • Lipid amphotericin B, nebulized or IV; alternative when azoles are contraindicated.
• Duration: through neutropenia recovery (AML, HSCT pre-engraftment), or through the immunosuppression period (allo-HSCT with active GVHD on steroids ≥3 weeks).
• Drug-drug interactions: posaconazole, itraconazole, and voriconazole are strong CYP3A4 inhibitors; isavuconazole and fluconazole are moderate (interaction management is agent-specific), review vincristine (avoid co-administration with itraconazole/posaconazole due to severe neurotoxicity), tacrolimus, cyclosporine, statins, and many BTKi/TKIs.
• Reference: IDSA aspergillosis guideline, Patterson TF et al, Clin Infect Dis 2016 (PMID 27365388). ECIL-6 antifungal guidelines (Maertens JA et al, J Antimicrob Chemother 2018).

Pneumocystis jirovecii pneumonia (PJP) prophylaxis

• Indications:
  • Allo-HSCT recipients: start after engraftment (TMP-SMX held during neutropenia to avoid marrow toxicity), continue at least 6 months, longer with chronic GVHD on immunosuppression
  • PJP prophylaxis is risk-based (expected incidence >3.5%, prolonged steroids, marked T-cell depletion); anti-CD20 alone does not mandate it. Bendamustine-rituximab and dose-dense/steroid-heavy regimens are higher risk; routine prophylaxis for standard R-CHOP-21 is debated.
  • Anti-CD52 (alemtuzumab)
  • Fludarabine plus cyclophosphamide (FCR for CLL)
  • Chronic high-dose corticosteroids (≥20 mg prednisone for ≥4 weeks)
  • ALL induction/consolidation (especially pediatric protocols)
  • Idelalisib, copanlisib (PI3K inhibitors)
  • CAR-T recipients
  • Solid organ transplant recipients with cancer (different population)
• First-line: TMP-SMX (Bactrim) 1 SS daily, or 1 DS three times weekly. Bonus: also covers Toxoplasma, Nocardia, Listeria.
• Alternatives (sulfa allergy or marrow-suppression intolerance): dapsone 100 mg PO daily (check G6PD first), atovaquone 1500 mg PO daily with food, aerosolized pentamidine 300 mg q4 weeks.
• Duration: for 3 to 6 months after the last anti-CD20/anti-CD52 dose, or until lymphocyte recovery, or as long as immunosuppression continues.
• PJP treatment (not prophylaxis): TMP-SMX 15 to 20 mg/kg/day IV divided q6 to 8h ×21 days, in HIV-associated PJP add corticosteroids if room-air PaO2 <70 mmHg or A-a gradient ≥35 mmHg; in non-HIV (cancer) PJP benefit is unproven, so consider steroids individually, mainly in severe respiratory failure.

Antiviral prophylaxis

HSV / VZV reactivation prophylaxis

• Indications: seropositive patients receiving allo-HSCT, autologous HSCT, intensive AML chemo, lymphocyte-depleting therapy (alemtuzumab, fludarabine, anti-CD52), bortezomib (HSV/VZV risk), proteasome inhibitors, daratumumab, CAR-T.
• Agent: acyclovir 400 to 800 mg PO BID (or valacyclovir 500 mg PO daily). Continue at least 1 year post-allo-HSCT for VZV-seropositive recipients, longer with chronic GVHD or ongoing immunosuppression (HSV-only prophylaxis is shorter); longer (up to 12 months) for VZV-seropositive patients on bortezomib/daratumumab.

VZV biology and vaccination (source notes)

• VZV is a highly neurotropic and T-cell-tropic herpesvirus. Primary infection causes chickenpox; the virus then stays dormant in sensory dorsal root ganglia and can reactivate as zoster (shingles).
• Zostavax: live-attenuated, contraindicated in immunosuppressed patients (unavailable in the US since 2020); VZV-naive status is not a formal contraindication (susceptible immunocompetent adults should get varicella vaccine instead)
• Shingrix: recombinant (non-live) glycoprotein E subunit vaccine with an adjuvant system that enhances the immunologic response, non-live, so recommended for eligible immunocompromised adults; efficacy varies by population (~90% in immunocompetent older adults, ~68% after autologous HCT) (Correction: the source notes described Shingrix as "made from a live virus"; Shingrix is a recombinant subunit vaccine and is NOT live. Zostavax was the live-attenuated product.)

Cytomegalovirus (CMV), allo-HSCT specifically

• Letermovir 480 mg PO/IV daily (240 mg with cyclosporine), primary prophylaxis from day 0 to day 100 post-allo-HSCT in CMV-seropositive recipients. Evidence: Marty FM et al, NEJM 2017 (PMID 29211658), reduced clinically significant CMV infection 38% vs 61% at week 24, vs placebo, without the myelotoxicity of ganciclovir.
• Pre-emptive surveillance: weekly CMV PCR; start ganciclovir or valganciclovir at threshold (typically 1,000 IU/mL or per institutional protocol).
• Letermovir does NOT cover HHV-6, HSV, or VZV, which need separate agents.

CMV, expanded detail (source notes)

• Occurs most frequently in patients with allogeneic HCT or receiving alemtuzumab. Infection can result from viral reactivation (in immunocompromised CMV-seropositive patients ~50 to 60%, with CMV disease in ~10 to 30%) or primary infection (in CMV-seronegative patients).
• Preemptive treatment is antiviral therapy given to asymptomatic patients with laboratory markers of viremia to prevent CMV disease in high-risk patients. Duration is at least 2 weeks and until CMV is no longer detected.
• Valganciclovir (prodrug of ganciclovir) and ganciclovir (causes neutropenia/thrombocytopenia) are the agents of choice for first-line preemptive therapy; IV foscarnet or IV cidofovir if first-line cannot be tolerated.
• Maribavir is for post-transplant CMV infection/disease refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.
• CMV reactivation is common in lymphoproliferative disease (most commonly CLL) receiving alemtuzumab, occurring most frequently 3 to 6 weeks after initiation when T-cell counts reach a nadir. Do weekly CMV PCR while on alemtuzumab and for 2 months after completion. If CMV viremia is detected (PCR positivity in ≥2 consecutive samples 1 week apart), start preemptive oral valganciclovir or IV ganciclovir for 2 weeks and until CMV is no longer detectable.
• Letermovir as primary prophylaxis is recommended for CMV-seropositive allogeneic HCT recipients. Routine acyclovir or valacyclovir for primary CMV prophylaxis is not recommended.
• Toxicities: ganciclovir/valganciclovir cause marrow suppression (raising the risk of opportunistic infection); foscarnet causes nephrotoxicity and electrolyte abnormalities; cidofovir causes substantial nephrotoxicity and, less often, ocular toxicity; acyclovir/valacyclovir have excellent safety but are only weakly active against CMV (not recommended for CMV prophylaxis or treatment).

Hepatitis B reactivation prophylaxis

• Screen ALL patients starting cancer therapy: HBsAg, total anti-HBc, and anti-HBs. Per ASCO 2020 guideline (Hwang JP et al, J Clin Oncol 2020; PMID 32716741).
• High-risk regimens (≥10% reactivation): anti-CD20 (rituximab, obinutuzumab), allo-HSCT.
• Moderate-risk (1 to 10%): TKIs/BTK inhibitors, low-dose steroids. High-dose anthracyclines in HBsAg+ patients are HIGH risk (≥10%).
• Prophylaxis: entecavir 0.5 mg PO daily, or tenofovir disoproxil 300 mg / tenofovir alafenamide 25 mg PO daily. Start before chemo, continue for at least 12 months after the last anti-CD20 dose or end of cancer therapy (HBsAg+, or HBsAg-/anti-HBc+ on anti-CD20 or HSCT).
• Monitor HBV DNA plus LFTs q3 months.

Other viral considerations

• Influenza: annual inactivated vaccine for all cancer patients (avoid live vaccine in the actively immunosuppressed); oseltamivir prophylaxis during outbreaks or post-exposure.
• SARS-CoV-2: updated mRNA vaccines per CDC; consider monoclonal/antiviral therapy at infection in high-risk patients.
• RSV: RSV vaccine (Arexvy, Abrysvo, or mResvia) for older adults and at-risk adults per ACIP, including HSCT recipients; nirsevimab is an infant monoclonal antibody, not used in adults.

Vaccinations in cancer patients

• Live vaccines (MMR, varicella, live zoster, yellow fever, BCG, oral polio, oral typhoid, intranasal flu): contraindicated during active chemotherapy and for at least 3 months after (longer post-HSCT or with active immunosuppression).
• Inactivated vaccines: safe but reduced immunogenicity during chemo. Best timed for ≥2 weeks before chemo, or in the maintenance/post-treatment phase.
• Recombinant zoster vaccine (Shingrix): approved for immunocompromised adults ≥18 years; preferred over live zoster. Two doses 1 to 2 months apart. For HSCT: ~3 to 12 months after autologous HCT and 6 to 12 months after allogeneic HCT (the 50 to 70 day schedule is auto-HCT-specific, from ZOE-HSCT)
• Pneumococcal vaccines: PCV20 (or PCV15 followed by PPSV23 8 weeks later) for all cancer patients. Post-HSCT: 3 doses of PCV (PCV20 or PCV15) starting 3 to 6 months post-transplant; then a 4th PCV20, or PPSV23 at ≥12 months (PCV15 path) if no chronic GVHD. Chronic-GVHD patients get a 4th PCV instead of PPSV23.
• HSCT-specific revaccination schedule: inactivated vaccines are restarted as a full series from 3 to 6 months post-transplant (pneumococcal from 3 months); live vaccines (MMR, varicella) only at ≥24 months if off immunosuppression with no active GVHD.
• Reference: ASH/IDSA combined vaccination guidance; CDC Pink Book for immunocompromised hosts.

HSCT-specific infection prophylaxis

Allogeneic HSCT

• Pre-engraftment (day 0 to ~day 30): bacterial, fluoroquinolone if profound neutropenia; fungal, posaconazole or voriconazole; antiviral, acyclovir plus letermovir (CMV+); PJP, TMP-SMX (start after engraftment to avoid marrow toxicity, ~day 30).
• Early post-engraftment (day 30 to day 100): continue PJP, HSV/VZV, CMV letermovir; mold prophylaxis if GVHD on steroids.
• Late (day 100+): continue PJP/HSV/VZV until off immunosuppression; pneumococcal vaccine; address GVHD-driven immunodeficiency.
• Chronic GVHD on steroids: mold-active azole plus PJP prophylaxis plus acyclovir; give non-live (inactivated) vaccines on the standard post-HCT schedule despite chronic GVHD or immunosuppression; defer only live vaccines until off immunosuppression and GVHD resolved.

Autologous HSCT

• Lower infection risk than allo-HSCT, shorter prophylaxis duration.
• PJP prophylaxis ×6 months after autologous HSCT (or shorter if no lymphocyte deficit).
• HSV/VZV acyclovir prophylaxis ×6 months.
• Fluconazole during the neutropenic phase; no routine mold prophylaxis unless prolonged neutropenia/steroids.

CAR-T-specific infection considerations

• Acute phase (week 0 to 4): CRS managed with tocilizumab (add corticosteroids if needed); ICANS managed primarily with corticosteroids, tocilizumab only when ICANS coexists with CRS (not for isolated ICANS), bacterial plus fungal coverage during fever workup. Many centers continue a mold-active azole for high-dose steroid use.
• Sub-acute phase (month 1 to 6): CAR-T causes prolonged B-cell aplasia plus hypogammaglobulinemia. Monitor IgG and individualize IVIG replacement (especially IgG ≤400 mg/dL with severe or recurrent bacterial infections); B-cell aplasia alone does not mandate routine IVIG. Continue PJP plus HSV/VZV prophylaxis for ≥6 months post-infusion.
• HBV reactivation: screen all patients; provide prophylactic entecavir/tenofovir if HBsAg+ or HBcAb+ on anti-CD20 bridging chemo.

2024-2026 infection prophylaxis and treatment updates

• Rezafungin (Rezzayo): FDA Mar 2023, novel long-acting echinocandin, once-weekly IV (400 mg wk 1, 200 mg weekly); non-inferior to caspofungin for candidemia/invasive candidiasis (ReSTORE trial); outpatient-friendly for prolonged neutropenia.
• Ibrexafungerp (Brexafemme): first-in-class oral triterpenoid, approved for vulvovaginal candidiasis; oncology use for fluconazole-resistant Candida (especially C. auris, C. glabrata) emerging.
• Nirmatrelvir-ritonavir (Paxlovid) for COVID in cancer patients: preferred oral antiviral within 5 days of symptoms; MAJOR drug-drug interactions via CYP3A4 with ibrutinib, venetoclax, cyclosporine, tacrolimus, everolimus, palbociclib/ribociclib/abemaciclib, apixaban/rivaroxaban, see the Liverpool COVID DDI database. Remdesivir 3-day IV if PO unavailable or DDI-limited.
• COVID monoclonals: sotrovimab, tixagevimab-cilgavimab (Evusheld), and bebtelovimab all lost efficacy against Omicron subvariants; not authorized for US use from 2022 to January 2023; EUAs formally revoked December 2024. Pemivibart (Pemgarda) authorized Mar 2024 for PrEP in severely immunocompromised patients.
• Recombinant zoster vaccine (Shingrix) in HSCT: ZOE-HSCT trial (Bastidas A et al, JAMA 2019; PMID 31287523), 2-dose Shingrix starting 50 to 70 d post-autologous HSCT, efficacy ~68% vs placebo. Replaces live zoster vaccine (contraindicated).
• NCCN Prevention of Infections 2024 update: shorter empiric antibiotic courses (5 to 7 d) once afebrile plus ANC recovering; earlier de-escalation; vancomycin off at 48 h if cultures negative; question routine FQ prophylaxis in centers with ≥20% FQ resistance.
• Choose by resistance mechanism: ceftolozane-tazobactam for difficult-to-treat Pseudomonas (not CRE); ceftazidime-avibactam for KPC/OXA-48 CRE (not metallo-beta-lactamases alone); cefiderocol broad including metallo-beta-lactamases. For ESBL, carbapenems remain preferred; reserve these agents for carbapenem-resistant organisms.
• Prolonged PJP prophylaxis after CAR-T: continue TMP-SMX (or atovaquone/dapsone) ≥6 to 12 mo; longer if CD4 <200 or ongoing steroids; case reports of PJP >1 yr post-CAR-T (Rejeski Blood Adv 2024).
• Letermovir extended to day +200: allo-HSCT recipients with ongoing risk (T-cell-depleted grafts or T-cell-depleting therapy such as ATG/PTCy/alemtuzumab, cord blood, mismatched/haplo, GVHD on steroids), extended prophylaxis reduces late CMV reactivation (Russo D et al, Lancet Haematol 2024; PMID 38142695: clinically significant CMV 3% vs 19% through week 28; FDA label allows continuation through day 200).
• Isavuconazole prophylaxis in AML/MDS: growing off-label use, activity vs mucor, no QTc, cleaner DDIs than posaconazole.

Practical pearls

• Match prophylaxis to the regimen, not the diagnosis. A solid-tumor patient on a high-risk regimen (prednisone ≥20 mg for ≥4 weeks, purine analogs, alemtuzumab, PI3K inhibitors) needs PJP prophylaxis just like a lymphoma patient.
• TMP-SMX is the highest-yield single agent, covers PJP, Toxoplasma, Nocardia, Listeria; pleiotropic.
• Always rule out drug-induced fever and tumor fever, but never delay empiric antibiotics in a neutropenic patient.
• Cultures FIRST, antibiotics within 60 min. Do not let line placement or imaging delay empiric therapy.
• Bortezomib / daratumumab / CAR-T, zoster prophylaxis, VZV reactivation is common; acyclovir for 6 to 12 months.
• Idelalisib, copanlisib (PI3K inhibitors), PJP plus CMV monitoring, severe opportunistic infections drove the black-box warning for idelalisib (Lampson BL et al, Blood 2016).
• Anti-CD20 plus HBcAb+ patient: entecavir or TAF for at least 12 months after the last rituximab/obinutuzumab dose.
• Watch for opportunistic-infection presentations: aspergillus may present as fever plus pleuritic chest pain plus halo sign on CT; PJP as dyspnea plus hypoxia disproportionate to CXR findings; CMV as fevers plus cytopenias plus colitis plus retinitis.
• De-escalate aggressively: 48 to 72 h after starting empiric antibiotics, narrow based on cultures plus clinical course. Vancomycin off at 48 h unless clinical or microbiologic evidence of Gram-positive infection (e.g. cellulitis with negative cultures still warrants continuation).