voriconazole
Regulatory sources consulted
Approved indications
- Invasive aspergillosis, candidemia, and other severe invasive fungal infections due to susceptible organisms.
Contraindications
Absolute
- Hypersensitivity to voriconazole.
- Concomitant rifampin, carbamazepine, phenobarbital, sirolimus, ergot derivatives, quinidine, pimozide, ivabradine, or other CYP/QT combinations expressly contraindicated.
Clinical warnings
- It may cause severe hepatotoxicity; monitor liver tests at baseline and during treatment. — CIMA/AEMPS, ficha técnica 02212015
- It may prolong QT and cause torsades; correct potassium, magnesium, and calcium and monitor ECG in at-risk patients. — CIMA/AEMPS, ficha técnica 02212015
- Major warning · Monitor visual disturbances if treatment exceeds 28 days and protect from sunlight; discontinue for severe phototoxicity, SCAR, or a lesion suspicious for squamous-cell carcinoma. — CIMA/AEMPS, ficha técnica 02212015
Drug interactions
- ModeratePotent CYP inducers such as rifampin, carbamazepine, or phenobarbital
Mechanism: They markedly reduce voriconazole exposure.
Recommendation: Do not combine.
CIMA/AEMPS, ficha técnica 02212015
- HighNarrow-therapeutic-index CYP2C19, CYP2C9, or CYP3A4 substrates
Mechanism: Voriconazole may increase exposure and toxicity.
Recommendation: Review each combination, monitor concentrations or toxicity, and adjust.
CIMA/AEMPS, ficha técnica 02212015
Adverse events
Common (≥1%)
Visual disturbances, fever, rash, nausea, vomiting, diarrhea, and headache
Rare but serious
Hepatotoxicity, torsades de pointes, SCAR, and cutaneous squamous-cell carcinoma
Pregnancy and lactation
Avoid during pregnancy unless benefit is life-saving and use effective contraception. Decide on breastfeeding according to risk and treatment need.
Recent literature (PubMed)
These European Society of Clinical Microbiology and Infectious Diseases guidelines are intended for clinicians involved in diagnosis and treatment of brain abscess in children and adults. Key questions were developed, and a systematic review was carried out of all studies published since 1 January 1996, using the search terms 'brain abscess' OR 'cerebral abscess' as Mesh terms or text in electronic databases of PubMed, Embase, and the Cochrane registry. The search was updated on 29 September 2022. Exclusion criteria were a sample size <10 patients or publication in non-English language. Extracted data was summarized as narrative reviews and tables. Meta-analysis was carried out using a random effects model and heterogeneity was examined by I2 tests as well as funnel and Galbraith plots. Risk of bias was assessed using Risk Of Bias in Non-randomised Studies - of Interventions (ROBINS-I) (observational studies) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (diagnostic studies). The Grading of Recommendations Assessment, Development and Evaluation approach was applied to classify strength of recommendations (strong or conditional) and quality of evidence (high, moderate, low, or very low). Magnetic resonance imaging is recommended for diagnosis of brain abscess (strong and high). Antimicrobials may be withheld until aspiration or excision of brain abscess in patients without severe disease if neurosurgery can be carried out within reasonable time, preferably within 24 hours (conditional and low). Molecular-based diagnostics are recommended, if available, in patients with negative cultures (conditional and moderate). Aspiration or excision of brain abscess is recommended whenever feasible, except for cases with toxoplasmosis (strong and low). Recommended empirical antimicrobial treatment for community-acquired brain abscess in immuno-competent individuals is a 3rd-generation cephalosporin and metronidazole (strong and moderate) with the addition of
Invasive aspergillosis (IA) is a severe fungal infection caused by Aspergillus species, particularly Aspergillus fumigatus, although new species, sometimes resistant to antifungals are becoming more common. IA predominantly affects immunocompromised patients, such as those with haematological malignancies, solid organ transplant recipients, and critically ill patients. However, new at-risk populations have emerged in recent years, such as IA associated with severe viral infections. Advanced diagnostic methods are crucial, especially considering the rising concern of antifungal resistance. Early detection is critical for successful treatment, typically involving antifungal medications like voriconazole or amphotericin B, but new antifungals are arriving to complete the therapeutic strategies. Despite advancements, mortality rates remain high, underscoring the importance of timely interventions and ongoing research. Healthcare providers should maintain a high index of suspicion, especially in immunocompromised patients and other new risk factors that are arising, to promptly diagnose and manage invasive aspergillosis. No information is available on the use of voriconazole during breastfeeding. If voriconazole is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.
Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.