Opportunistic Infections in

Immunocompromised Host
July 22nd, 2023

Assist.Prof. Nattawat Teerawattanapong, PharmD, BCP

Faculty of Pharmacy, Mahasarakham University
 Assess the advantages and disadvantages of pharmacotherapies for OIs
in immunocompromised hosts (ICH), including antimicrobial spectrum
of activity, PK/PD.
 Select the most appropriate pharmacotherapeutic plan and monitoring
based on patient- and disease-specific information and best available
evidence.
 Interpret S/Sx, and laboratory and other relevant diagnostic test
results.
 Recommend modifications of patient-specific treatment plans based on
efficacy, immunologic response, and adverse effects.
 Identify preventative therapies in ICH.
 May be congenital or acquired
 Alteration of the phagocytic, cellular or humoral immunity that
increases the risk of infectious complications or an opportunistic
process
 Alteration or breaks in the skin or mucosal barriers that permits
microorganisms to cause local or systemic infection
 Microbial infection: HIV, hepatitis viruses, herpes, bacterial, parasitic
 Malignancy
• Disease (e.g. lymphomas, leukemias, myeloma, solid tumors)
• Chemotherapy
 Disorders of biochemical homeostasis: DM, CKD, chronic liver disease,
malnutrition
 Autoimmune diseases (e.g. SLE, rheumatoid arthritis)
 Immunosuppressive therapy
 Transplant: HSCT, SOT, treatment for rejection
 Trauma
 Others: pregnancy, aging, stress, splenectomy or functional asplenia
 Approach to an ICH suspected to have an infection
• Causes
• Predisposing factors
• Underlying diseases
• Therapeutic interventions
• Anti-infective strategy
 Challenges
• Associated signs and symptoms are often muted
• Microbiologic confirmation in < 50%
• Difficult to treat organisms or unusual pathogens
 Diagnostic evaluation
• Careful history taking
• Extensive physical examination
• Blunted inflammatory response
• Unusual manifestations
• Diagnostic tests
• Microbiologic examinations
• Antigen detection tests
• Serologic tests
• Imaging techniques
 Potential etiology of infection can be anything
 Risk factors
• Exposure to infectious pathogens (endogenous and exogenous)
• Net state of immunosuppression
 Polymicrobial infections more common
 Serologic testing is generally not useful in the acute diagnostic
management of ICH, as they often fail to generate an adequate
antibody response to infection.
 Microbiologic testing should include antigen detection and/or nucleic
acid detection-based assays as well as appropriate cultures.
 Aggressive approach to diagnosis: CT scan, bronchoscopy, early biopsy
 Presumptive treatment without delay (treat as medical emergency)
 Early appropriate antimicrobial must be initiated
 Antimicrobial
• Broad spectrum cover
• Consider drug interaction
• High chances of resistance
• Early surgical intervention
• De-escalation after the results
 Major causes of morbidity and mortality
• Allograft loss
• Life-long requirement of exogenous immunosuppression
• Chronic rejection-immunologically mediated, but poorly responsive to
immunosuppression
• Life-threatening infections
• ~ 67% transplant recipients develop infection in first year post-
transplant
• ~ 25% eventually die of infection
• Malignancy
• Cardiovascular complications
 Complex, poorly explained, combination of
• Exogenous immunosuppression
• Neutropenia
• Metabolic abnormalities (e.g. protein calorie malnutrition, uremia)
• Infection with immunomodulating viruses (Herpes group viruses
particularly CMV, EBV, hepatitis viruses, HIV)
 The immunosuppressive effects of medications can be additive in
sometimes unpredictable ways, and may last for months or years
following administration (particularly with biologic agents).
Medication Effect
Corticosteroids Lymphopenia (predominantly T-cell), impaired chemotaxis, others
Cyclosporine, tacrolimus Depressed T-cell response
Mycophenolate Lymphopenia, depressed B-cell response
Ibrutinib, acalabrutinib Depressed B-cell response
Rituximab, ocrelizumab, B-cell apoptosis
obinutuzumab
Alemtuzumab Profound lymphopenia
Antithymocyte globulin Profound T-cell lymphopenia
Conventional chemotherapy Significant leukopenia
 Immune defect Commonly associated pathogens
Barrier breakdown
Burns S. aureus, P. aeruginosa
Trauma S. epidermidis, S. pyogenes
Phagocytic function
Absolute decrease Enteric GNB, P. aeruginosa, Aspergillus spp., Candida spp.
Impaired chemotaxis Enteric GNB, S. aureus
Impaired microbial killing Enteric GNB, S. aureus, Aspergillus spp., Burkholderia
Humoral immunity
Encapsulated bacteria (e.g. S. pneumoniae, N. meningitidis, H.
influenzae, S. agalactiae, Capnocytophaga canimorsus, Bordetella
holmesii); Salmonella, Campylobacter, parasites (e.g.
Cryptosporidia, Giardia)
 High level
• Primary combined immunodeficiency
• Receiving cancer chemotherapy
• Within 2 months after solid organ
transplantation
• HIV with CD4 < 200 cells/mm3
• Daily corticosteroid therapy > 14 days
• Receiving certain biologic immune modulators
(TNF-alpha inhibitors or rituximab)
Low level
• Asymptomatic HIV with CD4 > 200 cells/mm3
• Lower daily dose of systemic corticosteroids
• Methotrexate < 0.4 mg/kg/week
• Azathioprine < 3 mg/kg/day
• 6-mercaptopurine < 1.5 mg/kg/day
Bacterial Infections and
Fungal Prophylaxis
 Pre-engraftment phase (day 0): patients usually profoundly neutropenic
and standard complications from cytotoxic chemotherapy
 Post-engraftment phase (day 15-45): patients have neutrophil recovery
or have prolonged neutropenia
• Bacterial causes decrease as neutropenia resolves and lines are removed
• The risk of opportunistic infections increases due to B-cell defects
 Late phase (day > 100): neutropenia resolved and little graft versus
host disease (GVHD)
Pathogens Pre-engraftment phase Post-engraftment phase Late phase
Bacteria • GNB • GNB can still occur • Encapsulated bacteria
• GPC (S. epidermidis, (especially if prolonged - S. pneumoniae
Enterococcus spp.) neutropenia) - N. meningitidis
• GI streptococcus - H. influenzae
(related to GI - S. agalactiae (Group
translocation or line B Streptococcus)
infections)
Fungal • Candida spp. (related • Aspergillus or other molds • Aspergillus or other
to GI translocation and becoming dominant molds
line infections) • Pneumocystis jiroveci • Pneumocystis jiroveci
due to ongoing steroid use if patient remains on high
or prolonged neutropenia dose steroids for GVHD
Viral • HSV • CMV • Varicella zoster virus
• Seasonal respiratory • Human herpes virus 6 (VZV)
viruses (especially if (HHV-6) • CMV reactivation
transplant occurs
during cold/flu
season)
Biol Blood Marrow Transplant. 2009;15(10):1143-238.
 Infection risk increases with degree and duration of neutropenia
• highest risk patients are those with leukemia/myeloid malignancies that
already have baseline neutrophil dysfunction
 GNB infections (e.g. P. aeruginosa, E. coli)
• Associated with the most morbidity and mortality
• Most prophylaxes target GNB
 GPC infections (e.g. S. epidermidis, oral streptococci)
• Partially due to widespread use of antimicrobial prophylaxis targeting GNB
and presence of in-dwelling lines
 Prophylaxis recommended in patients with hematologic malignancy
• Fluoroquinolones are preferred, as they are the most studied option and are
associated with the best benefit.
 Antibiotic prophylaxis in afebrile neutropenic patients significantly
reduces all-cause mortality

Cochrane Database Syst Rev. 2012;1(1):CD004386.

 Decision whether or not to give prophylaxis is a center-specific decision
 Recommended antibiotic prophylaxis in cancer patients
• Levofloxacin has the most supporting evidence in neutropenic patients and
provides Gram-positive coverage
• Ciprofloxacin may also be used as an alternative, however, it has minimal
Gram-positive coverage, so breakthrough infections seen in patients using
this option are predominantly Gram-positive
 Guidelines are only recommended for patients with anticipated
prolonged neutropenia and profound neutropenia (usually not including
solid-transplant recipients)
 Organization
National Comprehensive Cancer
Network (NCCN)1
Infectious Diseases Society of
America (IDSA)2
American Society for Blood and
Marrow Transplantation (ASBMT)3
Antimicrobial prophylaxis recommendation
Consider fluoroquinolone prophylaxis in intermediate/high-
risk patients
Consider fluoroquinolone prophylaxis for patients with
anticipated prolonged, profound neutropenia (i.e. ANC < 100
cells/mm3 for > 7 days)
• Strongly consider fluoroquinolone prophylaxis in adult
HSCT recipients with anticipated duration of neutropenia >
7 days
• Oral penicillin recommended for pneumococcal prophylaxis
in patients with chronic graft-versus-host disease (GVHD)
1National
Comprehensive Cancer Network, 2019.
2Clin Infect Dis. 2011;52(4):427-31.
3Biol Blood Marrow Transplant. 2009;15(10):1143-238.
 IDSA risk criteria for fever and neutropenia
High risk Low risk
• Prolonged and profound neutropenia (ANC < 100 • Neutropenia expected to resolve
cells/mm3) anticipated to extend beyond 7 days within 7 days
• Presence of any medical comorbidities • Absence of any comorbidity listed
• Hemodynamic instability in high risk criteria
• Oral or GI mucositis with dysphagia • Adequate hepatic and renal
• Abdominal or peri-rectal pain function
• Nausea/vomiting • MASCC score > 21
• Diarrhea (6 loose stools daily)
• Neurologic or mental status changes of new onset
• Intravascular catheter infection
• New pulmonary infiltrate or hypoxemia, or
underlying chronic lung disease
• Evidence of hepatic insufficiency (AST, ALT > 5 UNL) or
renal insufficiency (CrCl < 30 mL/min)
 Multinational Association for Supportive Care in Cancer Risk-Index
Score (MASCC)
Characteristic Weight
Burden of febrile neutropenia with no or mild symptoms 5
No hypotension (systolic blood pressure > 90 mmHg) 5
No chronic obstructive pulmonary disease 4
Solid tumor or hematologic malignancy with no previous fungal infection 4
No dehydration requiring parenteral fluids 3
Burden of febrile neutropenia with moderate symptom 3
Outpatient status 3
Age < 60 years 2
• The maximum value of MASCC score is 26
Clin Infect Dis. 2011;52(4):427-31.
 High-risk patients: initial inpatient management
• Monotherapy with anti-pseudomonas beta-lactam (studies have shown
monotherapy is equivalent to combination therapy): piperacillin-
tazobactam, cefepime, meropenem, imipenem-cilastatin or ceftazidime (not
frequently used due to its lack of Gram-positive activity)
• Considerations when choosing therapy
• Known colonization with resistant organisms (e.g. if colonized with
ESBL, meropenem may be a good option for patients with neutropenic
fever)
• Prior antimicrobial exposure
• Allergies
• Presumed site of infection
 Indications for addition of an expanded Gram-positive agents (e.g.
vancomycin, linezolid)
• Hemodynamic instability/sepsis
• Pneumonia (typically healthcare related or multiple risk factors for MDRO)
• Blood culture positive for Gram-positive bacteria
• Clinically suspected central venous catheter (CVC) infection
• Skin/soft tissue infection
• Colonization with MRSA
• Severe mucositis only if ceftazidime used AND the patient was on
fluoroquinolone prophylaxis
 Stop the Gram-positive agent in 2-3 days if it is started and no specific need
identified (did’t meet the criteria above)
 Low-risk patients: inpatient IV or oral antibiotics
• IV regimens as for high risk patients OR
• Oral regimen: ciprofloxacin + amoxicillin/clavulanate
• Oral regimen for PCN-allergic patients:
• Levofloxacin
• Moxifloxacin
• Ciprofloxacin + clindamycin
• Ciprofloxacin + azithromycin
 NCCN guidelines for antifungal prophylaxis in cancer patients
Risk group Predominant fungal infections Recommended prophylaxis
Low-risk neutropenia (e.g. solid None None
tumors, autologous HSCT
without mucositis)
Autologous HSCT with mucositis Candida spp. 1st line: FLU, MIC
Allogeneic HSCT (early post- Candida spp. 1st line: FLU, MIC
HSCT) Less commonly mold 2nd line: VOR, POS, AMB
Allogeneic HSCT with significant Mold (e.g. Aspergillus)* 1st line: POS**
GVHD Less commonly Candida spp. 2nd line: VOR, Echinocandins,
AMB
AML/myelodysplastic syndrome Mold (e.g. Aspergillus)* 1st line: POS**
on CMT Candida spp. 2nd line: VOR, FLU, MIC, AMB
• *Mold becomes a higher consideration in patients receiving more immunosuppressive transplants
• **Posaconazole as 1st line for last two risk groups was based on RCT demonstrating mortality benefits
 IDSA guidelines for antifungal prophylaxis in neutropenic cancer patients
Risk group Recommended prophylaxis
Low-risk patients Not recommended
Patients at substantial risk (e.g. allogenic HSCT Prophylaxis against Candida is recommended
recipients, patients receiving intensive (e.g. FLU, MIC)
induction chemotherapy for acute leukemia)
Selected patients receiving intensive Prophylaxis against Aspergillus is recommended
chemotherapy for acute leukemia (e.g. POS, VOR)

ASTCT guidelines for preventing infectious complications in HSCT recipients

Risk group Recommended prophylaxis
Autologous HSCT, low-risk allogeneic HSCT FLU and MIC are preferred
High-risk allogeneic HSCT VOR and POS are preferred
Patients with graft-versus-host disease (GVHD) VOR is preferred
 Antifungal t½ Bioavailability Spectrum of activity Drug interaction
(hr) Candida Aspergillus Mucorales (as inhibitor)

Fluconazole 31 Excellent + - - 3A4, 2C9 > 2C19

Voriconazole 6 Extremely + + - 2C19 > 3A4, 2C9

variable
Posaconazole 25 • Poor (susp- + + + 3A4 > P-gp
ension)
• Excellent
(tablet)
Isavuconazole 130 Excellent + + + 2C19 > 3A4 > P-gp

• Itraconazole is not included due to infrequency of use in this patient population

• Major considerations include drug interactions and QT prolongation (except isavuconazole)
• Therapy is frequently modified due to drug-drug interactions, adverse effects, and cost
considerations
Clin Infect Dis. 2006;43(Supplement 1):S28-S39.
 Preferred: TMP/SMX
 Alternatives (if intolerant to TMP/SMX): atovaquone, dapsone,
pentamidine (aerosolized/IV)
Risk group Disease state Time period
High Allogeneic HSCT > 6 months and while on immunosuppression
Acute lymphoblastic leukemia Duration of chemotherapy
Alemtuzumab > 2 months and CD4 > 200 cells/mm3
• Idelalisib w or w/o rituximab Duration of therapy
• High-dose corticosteroids
• Temozolomide and radiation
Moderate Purine analog therapy or T-cell Until CD4 > 200 cells/mm3
(consider depletion
prophylaxis) Autologous HSCT 3-6 months
Viral infection Recommended antiviral Prophylaxis recommendations
agents
HSV • Acyclovir • HSV-seropositive patients receiving CMT for acute
• Famciclovir leukemia
• Valacyclovir • Allogeneic and autologous HSCT recipients during
neutropenia or GVHD
VZV • Acyclovir • Allogeneic HSCT recipients for > 1 year (longer if
• Famciclovir GVHD present)
• Valacyclovir • Patients receiving proteasome inhibitors or
alemtuzumab
• Consider in autologous HSCT recipients for 6-12
months
CMV • Preemptive therapy • CMV-seropositive allogeneic HSCT recipients
• Letermovir recommended • Patients receiving alemtuzumab (screening
(HSCT only) preemptive)
• Consider prophylaxis for HSV and VZV in other intermediate-risk groups (e.g. lymphoma,
autologous HSCT, multiple myeloma, CML, purine analog therapy)
 CMV prevention in HSCT recipients
• All CMV seropositive allogeneic HSCT recipients (i.e. donor and/or recipient
with evidence of past CMV infection) should receive anti-CMV prophylaxis
with letermovir or weekly serum screening (viral PCR or pp65 antigen) if
unable through 100 days post-HSCT (longer in presence of GVHD and
prolonged immunosuppression)
• Letermovir is a novel CMV antiviral agent available in both IV and oral
formulations
• MOA: inhibits CMV terminase complex, preventing successful viral replication
• Dosing: 480 mg PO/IV daily (reduce to 240 mg PO/IV daily when given
concomitantly with cyclosporine). Start between day 0-28, continue through day
100
• Patients with evidence of asymptomatic viral reactivation require treatment
 Outcomes of Patients with Detectable CMV DNA at Randomization in The
Phase III Trial of Letermovir for the Prevention of CMV Infection in Allogeneic
Hematopoietic Cell Transplantation

• Risk of clinically significant CMV infections

(CS-CMVi) in CMV-seropositive allogeneic
HSCT recipients through week 24 were
64.6% and 90.9% in the letermovir and
placebo groups, respectively, P = 0.010)

Am J Transplant. 2020;20(6):1703-11.
 Randomized Multicenter Trial of Foscarnet versus Ganciclovir for Preemptive
Therapy of CMV Infection After Allogeneic Stem Cell Transplantation
Outcome Foscarnet
(n=110)
Ganciclovir
(n=103)
• 218 allogeneic HSCT recipients with CMV
Event-free survival 66% 73% reactivation within 100 days post-
Overall mortality 26% 22% transplant randomly assigned to open-
Development of CMV 4.5% 4.8% label foscarnet or ganciclovir
disease
Retreatment required 43% 28%
• Evidence of CMV reactivation by PCR or
Severe neutropenia 4% 11%
pp65 antigenemia without evidence of
AKI 5% 2% CMV end-organ disease
Hypocalcemia 22% 4% • Full-dose treatment continued for 2 weeks,
Hypomagnesemia 18% 6% followed by 2 weeks of reduced-dose
Hypokalemia 17% 6% maintenance therapy
Hypophosphatemia 6% 0%
Blood. 2002;99(4):1159-64.
 Choice of therapy depends on patient risk factors and tolerance for
disparate toxicities
• Foscarnet and ganciclovir are similarly effective in the treatment of early
CMV reactivation in HSCT recipients
• Foscarnet may be preferred if patient has myelosuppression or at high risk
for myelosuppressive adverse events (usually of concern early on post-
transplantation)
• Ganciclovir may be preferred if patients has renal or electrolyte
abnormalities
 Recommendations are slightly different for solid organ transplant (SOT)
recipients versus cancer patients

Viral infection Recommended antiviral Prophylaxis recommendations

agents
HSV • Acyclovir • Administer > 1 month post-transplant
• Famciclovir • Administer > 1 month during treatment of
• Valacyclovir rejection
VZV • Acyclovir • Consider if not receiving HSV or CMV prophylaxis
• Valacyclovir but not well-studied
CMV • Valganciclovir • Low risk (D-/R-): no specific prophylaxis
• Ganciclovir IV • Intermediate risk: prophylaxis versus preemptive
• Serial monitoring with therapy
preemptive therapy • High risk: prophylaxis for 3-6 months (or longer in
some cases)
 NCCN Guidelines and ASTCT guidelines
• First-line: ganciclovir or valganciclovir
• Valganciclovir should not be used in patients with significant gastrointestinal
GVHD (grade III/IV) due to inadequate absorption
• Alternative: foscarnet
• Treatment should continue for > 2 weeks, followed by a reduced
maintenance/secondary prophylaxis dose
 Antiviral-resistant CMV
 UL97 mutations generally confer resistance to ganciclovir and valganciclovir 
Foscarnet should be used with or without adjunctive therapy (e.g. leflunomide)
 UL54 mutations may confer resistance to any or all of the following: foscarnet,
ganciclovir, valganciclovir, and cidofovir  Treatment of choice highly dependent
on specific mutation present
 Severity Recommended treatment

Non-severe disease • Preferred: Valganciclovir (unless concern for poor

absorption of oral medications or low adherence)
• Alternative: Ganciclovir

Severe disease • Preferred: IV Ganciclovir

(e.g. CMV colitis)
 Therapy should be continued for ≥ 2 weeks and until screening assays are
negative (highly variable)
 Dose reduction due to adverse events (e.g. myelosuppression) is not
recommended to avoid the development of resistance; rather, a change in
therapy is preferred.
 Standard diagnostic criteria from EORTC/MSG for IFIs
• Categories are based on host presentation and diagnostic assays
• Criteria are not specific to any one particular fungus (e.g. Aspergillus,
Fusarium, Mucor)
Category Criteria
Proven • Direct pathologic evidence or culture from sterile site
Probable • Compatible host AND
• Clinical and/or radiologic findings AND
• Culture from non-sterile site* OR indirect serologic evidence
Possible • Compatible host AND
• Clinical and/or radiologic findings WITHOUT mycological
evidence
*Respiratory is not considered a sterile site, therefore respiratory samples do not
qualify towards the “proven” category
 Standard diagnostic criteria from EORTC/MSG for IFIs (cont.)
Host criteria for IFIs
• Recent history of prolonged
neutropenia (< 500 cells/mm3) or
hematologic malignancy
• Receipt of an allogeneic HSCT or
solid organ transplant
• Prolonged use of corticosteroids at
> 0.3 mg/kg/day prednisone
equivalent for > 3 weeks
• Treatment with T-cell or B-cell
immunosuppressants within the
last 90 days
• Inherited severe immunodeficiency
• CD4 lymphopenia (cryptococcus,
pneumocystis only)
Site of infection Clinical criteria for IFIs
Lower respiratory At least one of the following: Dense,
tract well-circumscribed lesions; Air-
crescent sign; Cavity; Wedge-
shaped, segmental/lobar
consolidation; Reverse halo sign
Tracheobronchitis Bronchoscopic findings compatible
with IFI
Sinonasal infection At least one of the following:
Sinusitis on imaging and acute
localized pain; Nasal ulcer with black
eschar; Extension from sinus across
bone
CNS Focal lesions on imaging OR
Meningeal enhancement on imaging
 Aspergillus is a ubiquitous mold commonly found in the environment and is
the most common invasive mold infection in immunocompromised patients.
 Indirect serum tests for IA
• Galactomannan: component of Aspergillus cell wall released into systemic
circulation in angioinvasive disease
• Serum and/or bronchoalveolar lavage galactomannan recommended as
diagnostic marker for IA in patients with hematologic malignancy
• Not recommended for screening in non-neutropenic patients or patients
receiving mold-active prophylaxis (due to high risk of false negative and false
positive)
• Cross-reactivity possible with Fusarium, Scedosporium, other less common
molds, medications (e.g. piperacillin-tazobactam*)

*Clin Infect Dis. 2004;38(6):917-20.

 Indirect serum tests for IA (cont.)
• (13)-beta-D-glucan: component of cell wall in many fungi (can be tested in
blood)
• Recommended for patients at high risk for IA
• Not specific for Aspergillus (galactomannan is the more specific assay)
• High rate of false positivity due to cross-reactivity with yeast (including
Candida), numerous medications* (e.g. colistin, ertapenem, cefazolin, TMP/SMX,
cefotaxime, cefepime, ampicillin-sulbactam), and laboratory error

*Antimicrob Agents Chemother. 2006;50(10): 3450-3.

 IDSA guidelines for treatment of IPA ASTCT guidelines for treatment of IPA
First-line • Voriconazole 6 mg/kg IV q 12 hr x 2 doses, • Voriconazole
followed by 4 mg/kg IV q 12 hr
• Oral voriconazole may be used as step-down
at 200 mg PO q 12 hr (fixed-dose) or weight-
based (4 mg/kg PO q 12 hr)
Alternative • Liposomal amphotericin B 3-5 mg/kg IV daily • Liposomal amphotericin B
• Isavuconazonium sulfate* 372 mg IV/PO q 8 • Isavuconazonium sulfate*
hr x 6 doses, then 372 mg IV /PO OD • Posaconazole*
Salvage • None of the following have been extensively
studied in this context:
• Amphotericin B lipid complex
• Caspofungin
• Micafungin
• Posaconazole
• Itraconazole
*ISA 1ClinInfect Dis. 2016;63(4):e1-e60.
and POS were better tolerated than VOR.
2Transplant Cell Ther. 2021;27(3):201-11.
  Voriconazole vs Amphotericin B for Primary Therapy of Invasive Aspergillosis

Outcome VOR AMB • 277 patients with definite or probable IA (both

(n=144) (n=133)
pulmonary and non-pulmonary IA included)
Complete response 52.8% 31.6%
were randomized to voriconazole (6 mg/kg IV q
Partial response 20.8% 16.5%

Overall survival 70.8% 57.9%

12 hr on D1, then 4 mg/kg IV q 12 hr x > 7 days
Visual disturbances 44.8% 4.3% followed by 200 mg PO BID) or IV amphotericin
Skin reactions 8.2% 3.2% B deoxycholate (1-1.5 mg/kg/day)
Hallucinations/confusion 6.7% 2.7% • Absolute difference in success 21.2% (95% CI
Chills/fever 3.1% 24.9% 10.4-32.9%), indicating statistical superiority of
Renal impairment 1.0% 10.3% voriconazole
Hypokalemia 0% 3.2% • HR for overall survival 0.59 (95% CI 0.40-0.88)
favoring voriconazole

N Engl J Med. 2002;347(6):408-15.

  Isavuconazole versus Voriconazole for Primary Treatment of Invasive Mould
Disease Caused by Aspergillus and Other Filamentous Fungi (SECURE)

Outcome ISA VOR • 527 patients with suspected invasive mould

(n=258) (n=258)
disease were randomized to isavuconazonium
Day 42 all-cause mortality 19% 20%
sulfate 372 mg (equivalent to 200 mg
Complete response 12% 10%
isavuconazole; IV q 8 hr D1-2, then either IV/PO
Partial response 23% 26%
OD) or voriconazole (6 mg/kg IV q 12 hr on D1,
Skin/subcutaneous tissue 33% 42%
disorders (e.g. rash, then 4 mg/kg IV q 12 hr on D2, then 4 mg/kg IV
erythema, drug eruption)
q 12 hr or 200 mg PO BID)
Eye disorders (e.g. visual 15% 27%
impairment, photophobia, • Absolute difference in day 42 all-cause mortality
reduced visual acuity,
retinal hemorrhage)
-1.0% (95% CI -7.8 to 5.7), indicating ISA was
Hepatobiliary disorders 9% 16% non-inferior to VOR
(e.g. hyperbilirubinemia,
abnormal LFT, jaundice,
cholestasis)
Lancet. 2016;387(10020):760-9.
  Posaconazole versus Voriconazole for Primary Treatment of Invasive
Aspergillosis: A Phase 3, Randomised, Controlled, Non-inferiority trial

Outcome POS VOR • 575 patients with proven, probable, or possible

(n=288) (n=287)
IA were randomized to posaconazole (300 mg
Day 42 all-cause mortality 15% 21%

Complete response 7% 5%
IV/PO q 12 hr on D1, then 300 mg OD for D2-
Partial response 38% 40% 84) or voriconazole (6 mg/kg IV or 300 mg PO q
Skin/subcutaneous tissue 2% 4% 12 hr on D1, then 4 mg/kg IV or 200 mg PO q 12
disorders
hr for D2-84) for < 12 weeks
Eye disorders (e.g. 2% 10%
dyschromatopsia, • Absolute difference in day 42 all-cause mortality
photopsia, vision blurred,
visual impairment) -5.3% (95% CI -11.6 to 1.0), indicating POS
Hepatobiliary disorders 3% 3% was non-inferior to VOR
Psychiatric disorders (e.g. 2% 8%
hallucination, visual
hallucination)
Lancet. 2021;397(10273):499-509.
 Combination Antifungal Therapy for Invasive Aspergillosis: A Randomized Trial
• 454 patients with hematologic malignancies or
HSCT and suspected or documented IA were
randomized to voriconazole and anidulafungin
(ANI 200 mg IV on D1, followed by 100 mg IV q
24 hr for the first 2-4 weeks) or voriconazole
alone for 6 weeks.
• Overall mortality at 6 weeks was 19.3% in
combination arm vs. 27.5% in monotherapy arm
(p = 0.087); not statistically significant
• Post-hoc analysis suggested statistical benefit in
subgroup diagnosed by galactomannan
positivity, overall mortality 15.7% vs. 27.3%, P
= 0.037).
Ann Intern Med. 2015;162(2):81-9.
 Combination Antifungal Therapy for Invasive Aspergillosis
• IDSA guidelines: “suggest consideration for an echinocandin with
voriconazole for primary therapy in the setting of severe disease, especially
in patients with hematologic malignancy and those with profound and
persistent neutropenia”

Clin Infect Dis. 2016;63(4):e1-e60.

 TDM of azole antifungals guidelines from British Society of Mycology

Drug Minimal trough Maximum trough Timing relative to

Voriconazole • Prophylaxis: undefined
• Therapeutic: > 1 mcg/mL
Posaconazole • Prophylaxis: > 700 ng/mL
• Therapeutic: > 1000 ng/mL
*No data supporting utility of TDM for isavuconazonium sulfate
initiation of therapy
or dose modification
• All indications: < 4 to 6 2 to 5 days
mcg/mL (due to
hallucinations/visual
effects and hepatobiliary
concerns)
• All indications: undefined > 7 days

J Antimicrob Chemother. 2014;69(5):1162-76.

 Mucormycosis refers to a group of ubiquitous environmental molds (e.g.
Rhizopus, Mucor, Rhizomucor)
 Relatively uncommon compared with Aspergillus, but increasing worldwide
 Intrinsically less susceptible to antifungal agents than other invasive molds
 Causes rapid, destructive disease in compatible hosts (e.g. relapsed leukemia,
high-risk allogeneic HSCT, severe GVHD) but rarely affects patients without
significant immunocompromise
 Differentiation of invasive mucormycosis from invasive aspergillosis
Epidemiologic/host factors
• Institution/geographic location with high
rate of mucormycosis (more common in
areas with humid, moist climates)
• Iron overload
• Prior treatment with voriconazole or
echinocandins (or failed therapy with
these)
Clinical/radiologic/laboratory factors
• Community-onset sinusitis
• Necrotic lesions in hard palate or nasal
turbinates
• Chest wall cellulitis next to lung infarct
• >10 nodules on chest CT scan
• Reverse halo sign on chest imaging
• Presumptive diagnosis of IFI with
therapeutic voriconazole levels
• Presumptive diagnosis of IFI with negative
serum biomarkers
Lancet Infect Dis. 2019;19(12):e405-21.
 Treatment based largely on expert opinion and small case series. No
RCT data to guide therapy.
 European Confederation of Medical Mycology/Mycoses Study Group
Education and Research Consortium Guidelines
• Liposomal amphotericin B 5-10 mg/kg IV daily
• Posaconazole or isavuconazonium sulfate is only recommended when
preexisting renal insufficiency exists

Lancet Infect Dis. 2019;19(12):e405-21.

Lancet Infect Dis. 2019;19(12):e405-21.
Lancet Infect Dis. 2019;19(12):e405-21.
 Treatment of Pulmonary Mucormycosis with Adjunctive Nebulized
Amphotericin B (MUCONAB trial): Results of An Open-label RCT
• 30 patients with pulmonary mucormycosis were randomized to IV liposomal
amphotericin B (3-5 mg/kg/day) alone or along with nebulized amphotericin B
deoxycholate (NAB, 10 mg twice a day, every alternate day).
• Overall treatment success was not significantly different between the control and
NAB arms (71.4% vs. 53.3%, P = 0.45).
• 90-day mortality was not significantly different between the control and NAB arms
(28.6% vs. 53.3%, P = 0.26)

Mycoses. 2023;66(8):688-96.