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Drugs for Invasive and Other Serious Fungal Infections In Children [keywords]
- Candida infections in non-neutropenic children after the neonatal period. [Journal Article, Review]
- Expert Rev Anti Infect Ther 2011 Oct; 9(10):923-40.
There are a variety of diseases, from local mucous membrane infections to invasive systemic infections, that are caused by Candida species. As a causative agent, Candida albicans is the most common; however, the other Candida species can also cause the same clinical syndromes. Most invasive fungal infections in children occur in the hospital setting. Candidemia is a serious condition associated with high morbidity and mortality and increased healthcare costs in pediatric patients. Children at the highest risk are those with prolonged intensive care unit stays, reduced immune function, recent surgery, prior bacterial infection, prior use of antibiotics and/or corticosteroids and other immunosuppressive agents, as well as use of a central venous catheter, total parenteral nutrition, mechanical ventilation and dialysis. Positive blood culture is the gold standard of candidemia; it should not be accepted as contamination or colonization in children with an intravascular catheter. However, in oropharyngeal or vulvovaginal candidiasis, culture of lesions is rarely indicated unless the disease is recalcitrant or recurrent. Recovery of Candida from the sputum should usually be considered as colonization and should not be treated with antifungal therapy. Antigen and antibody detecting tests are evaluated in invasive Candida infections; however, there are no published results in children, and their roles in diagnosis are also unclear. For the therapy of invasive Candida infections in non-neutropenic patients, fluconazole or an echinocandin is usually recommended. Alternatively, amphotericin B deoxycholate or lipid formulations of amphotericin B can also be used. The recommended therapy of Candida meningitis is amphotericin B combined with flucytosine. The combination therapy for Candida infections is usually not indicated. Prophylaxis in non-neonatal, immunocompetent children is not recommended.
- Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease. [Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- Mycoses 2011 Nov; 54(6):e838-47.
The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (≤7.7%) vs. no malignancy (≤8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis.
- Echinocandin antifungal drugs in fungal infections: a comparison. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Review]
- Drugs 2011 Jan 1; 71(1):11-41.
This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2 μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.
- Voriconazole : a review of its use in the management of invasive fungal infections. [Journal Article, Review]
- Drugs 2007; 67(2):269-98.
Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis. In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.
- Tolerability, safety and efficacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. [Journal Article, Research Support, Non-U.S. Gov't]
- Swiss Med Wkly 2002 Aug 10; 132(31-32):455-8.
Fungal infections cause serious morbidity and mortality in lung transplant recipients. Expensive lipid formulations of amphotericin B (AmB) are generally used because of fear of adverse effects due to concomitant cyclosporine A and other nephrotoxic drugs. However, a 24-hour dosing regimen of AmB may be well tolerated even in these patients.In an open pilot study 6 out of 94 lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections (3 paraspilosis, 2 glabrata, 1 krusei) were treated for 40 (17-73) days by 24-hour continuous infusions of AmB 1 mg/kg. Additionally, patients received at least 1000 ml of 0.9% saline intravenously per day. Beside cyclosporine A at serum trough levels of 240 (195-273) microg/l, five patients additionally received aminoglycosides for at least 2 weeks, and 4 were treated with ganciclovir.Calculated creatinine clearance decreased from 57 (43-73) ml/min to a nadir of 35 (28-39) and recovered to 52 (33-60) after cessation of therapy. One patient needed temporary haemofiltration for 7 days after 30 days of AmB, most probably because of the use of contrast media in conjunction with furosemide and hypovolaemia. Besides three episodes of mild hypokalaemia no other side effects attributable to AmB were recorded. While in one case an asymptomatic candidal colonisation persisted for 10 months, the other 5 were cured from their infection.These preliminary data show that conventional AmB administered by 24-hour infusion is well tolerated, safe, and efficacious in lung transplant recipients receiving cyclosporine A and other nephrotoxic substances.
- [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigía Group]. [English Abstract, Journal Article, Multicenter Study]
- Rev Panam Salud Publica 2000 Sep; 8(3):185-95.
Community-acquired pneumonia is one of the leading causes of infant morbidity and mortality. Studies conducted in developing countries indicate that the most serious symptoms of pneumonia are associated with bacterial causes, mainly Streptococcus pneumoniae, followed by Haemophilus influenzae type b. Managing those infections in children under two years of age is hindered by the lack of appropriate vaccines and by the decreased susceptibility of S. pneumoniae to penicillin and other antibiotics. In 1993, at the initiative of the Regional System for Vaccines of the Pan American Health Organization, and with funding from the Canadian International Development Agency, a study was designed to identify the S. pneumoniae capsular types that cause invasive disease in Latin American children under 5 years of age. The objective of the study was to determine the ideal composition of a conjugate vaccine that could be used in Latin America, and the penicillin susceptibility of the S. pneumoniae isolates. The initiative was undertaken in Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay. This report analyzes the information that the participating countries generated on pneumococcal pneumonia. A total of 3,393 children were found with systemic S. pneumoniae infections, of which 1,578 corresponded to pneumonias. The analysis focused on 1,409 cases of pneumonia in Argentina, Brazil, Colombia, Mexico, and Uruguay. Of the children, 63.8% of them were under two years of age. Twelve prevalent capsular types were identified, of which serotypes 14, 5, and 1 were the three most common in the majority of the countries. At the beginning of the study the highest level of penicillin resistance was found in Mexico (47.0%), and the lowest in Colombia (12.1%). Over the 1993-1998 period, resistance to penicillin increased in the five countries. Penicillin resistance was associated with a small number of capsular serotypes, mainly 14 and 23F. The first of those serotypes was resistant to penicillin and to trimethoprim-sulfamethoxazole, and the second was multiresistant. The frequency of resistance to trimethoprim-sulfamethoxazole was high in all of the countries; Argentina had the highest level, 58.0%. A decrease in susceptibility to chloramphenicol was uncommon, except in Colombia, where there was a resistance level of 23.4%. Resistance to erythromycin was low in all the countries, and all the isolates were susceptible to vancomycin.
- Safety and efficacy of liposomal amphotericin B in allogeneic bone marrow transplant recipients. [Journal Article, Research Support, Non-U.S. Gov't]
- Mycoses 1996 May-Jun; 39(5-6):185-93.
In a retrospective analysis, 79 allogeneic bone marrow recipients treated with AmBisome prophylactically or because of proven or suspected invasive fungal infection (IFI) were evaluated in 92 episodes. The median duration of treatment was 14 (range 1-112) days. The mean maximum dose given was 1.64 +/- 0.8 mg kg-1 day-1 and the mean total dose was 1.29 +/- 2.28 g. The overall incidence of reported adverse events was 194, of which none had a serious outcome. In six cases, the drug was withdrawn as a result of toxic or allergic reactions: dyspnoea and flush (3), urticaria (1), cholecystitis (1) and disorientation (one case, probably not related to AmBisome). No anaphylactoid reactions were seen. Laboratory findings, including low serum potassium (48% of the episodes), increased serum creatinine (38%) and increased serum sodium levels (7%), caused no major clinical problems. Thirteen cases of verified IFI were evaluated regarding the efficacy of AmBisome. Survival or cure of the mycotic infection occurred in 5/13 patients (38%). Two patients were treated with AmBisome (3.6 and 3.3 mg kg-1 day-1) because of verified IFI before BMT. One died of IFI. The other died of venoocclusive disease of the liver (VOD) without histological evidence of active IFI. We found a significant (P < 0.05) reduction in autopsy-proven IFI, 12/199 (6%) compared to the period when only conventional doses of amphotericin B were used, 26/227 (11%).