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Addition of 17-(allylamino)-17-demethoxygeldanamycin to a suboptimal caspofungin treatment regimen in neutropenic rats with invasive pulmonary aspergillosis delays the time to death but does not enhance the overall therapeutic efficacy.

ABSTRACT: Caspofungin (CAS) which is used as salvage therapy in patients with invasive pulmonary aspergillosis (IPA) inhibits the 1,3-β-D-glucan synthesis in Aspergillus fumigatus. Inhibiting 1,3-β-D-glucan synthesis induces a stress response and in an invertebrate model it was demonstrated that inhibiting this response with geldamycin enhanced the therapeutic efficacy of CAS. Since geldamycin itself is toxic to mammalians, the therapeutic efficacy of combining geldamycin with CAS was not studied in rodent models. Therefore in this study we investigated if the geldamycin derivate 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was able to enhance the therapeutic efficacy of CAS in vitro and in our IPA model in transiently neutropenic rats. In vitro we confirmed the earlier demonstrated synergy between 17-AAG and CAS in ten A. fumigatus isolates. In vivo we treated A. fumigatus infected neutropenic rats with a sub-optimal dose of 0.75 mg/kg/day CAS and 1 mg/kg/day 17-AAG for ten days. Survival was monitored for 21 days after fungal inoculation. It appeared that the addition 17-AAG delayed death but did not improve overall survival of rats with IPA. Increasing the doses of 17-AAG was not possible due to hepatic toxicity. This study underlines the need to develop less toxic and more fungal specific geldamycin derivatives and the need to test such drugs not only in invertebrate models but also in mammalian models.

SUBMITTER: Refos JM

PROVIDER: S-EPMC5524388 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Despite best available therapy, cerebral aspergillosis is an often-lethal complication of disseminated aspergillosis. There is an urgent need to expand the currently limited therapeutic options. In this study, we assessed cerebral drug exposure and efficacy of caspofungin (CAS) using a lethal infant rat model of cerebral aspergillosis. Eleven-day-old Wistar rats were infected by intracisternal injection of Aspergillus fumigatus conidia. Treatment started after 22 h and was continued for 10 days. Regimens were CAS 1 mg/kg/day intraperitoneally (i.p.), liposomal amphotericin B (L-AmB) 5 mg/kg/day i.p., and both drugs combined at the same dose i.p. Infected controls were given NaCl 0.85% i.p. Primary endpoints assessed were survival, cerebral fungal burden, galactomannan index, and drug concentrations in brain homogenate at 2, 3, 5, and 11 days after infection. Compared to those of controls (4.4 ± 2.7 days), survival times were increased by treatment with CAS alone (10.3 ± 1.7 days; P < 0.0001) and CAS combined with L-AmB (9.3 ± 2.8 days; P < 0.0001). In contrast, survival time of L-AmB-treated animals (4.3 ± 3.1 days) was not different from that of controls. Cerebral fungal burden and galactomannan index declined in all animals over time, without significant differences between controls and treated animals. CAS trough levels in brain tissue were between 0.84 and 1.4 μg/g, concentrations we show to be associated with efficacy. AmB trough levels in brain tissue were higher than the MIC of the A. fumigatus isolate. In summary, CAS concentrations in brain tissue suggest it may be therapeutically relevant and it significantly improved survival in this lethal model of cerebral aspergillosis in nonneutropenic rats. The clinical efficacy of CAS treatment for cerebral aspergillosis merits further study. IMPORTANCE Treatment options for cerebral aspergillosis, an often-lethal disease, are limited. The echinocandins (caspofungin is one of them) are not recommended treatment because their brain tissue penetration is often considered insufficient. In a nursing rat model of cerebral aspergillosis that mimics human disease, we found potentially therapeutically relevant concentrations of caspofungin in brain tissue and prolonged survival of caspofungin-treated animals. The efficacy of caspofungin in the treatment of cerebral aspergillosis documented here, if confirmed in other animal models (especially immunosuppressed murine models) and by using additional Aspergillus isolates across a range of CAS minimal effective concentrations (MECs), would suggest that caspofungin merits further study as a treatment option for patients suffering from aspergillosis disseminated to the brain.

Project description:Non-neutropenic pulmonary aspergillosis is one of the most common and serious fungal infections. Previous studies have shown that single nucleotide polymorphisms (SNPs) of pattern recognition receptors genes are associated with susceptibility to aspergillosis. NOD-like receptors (NLRs) play an important role in the immunological response against fungal infection. In this study, we investigated the relationship between polymorphisms of three NLRs and susceptibility to pulmonary aspergillosis disease in non-neutropenic patients. We included 73 patients with proven pulmonary aspergillosis and 103 healthy controls. A total of sixteen SNPs in the NLRP3, NLRC4, and NLRC5 genes were detected by PCR-direct sequencing. Then, we evaluated the association between these polymorphisms and susceptibility to aspergillosis. Fifteen SNPs were consistent with Hardy-Weinberg equilibrium except for NLRP3 rs7525979. A total of eight SNPs (NLRP3 rs3806265, NLRC4 rs212704 and NLRC5 rs1684579, rs12598522, rs3995817, rs3995818, rs34531240, rs28438857) were observed an association with susceptibility of pulmonary aspergillosis. The CC homozygote of NLRP3 rs3806265, TT homozygote of NLRC5 rs1684579 and T allele of NLRC5 rs12598522 were associated with a higher risk of aspergillosis while TT homozygote of NLRC4 rs212704 was associated with a lower risk of aspergillosis. Especially in the invasive pulmonary aspergillosis subgroup, the TT homozygote of NLRC5 rs1684579 and rs3995817, the CC homozygote of NLRC5 rs34531240 and rs28438857, GG homozygote of NLRC5 rs3995818, the C allele and CC homozygote of NLRP3 rs3806265 were associated with higher susceptibility. This study showed an association between polymorphisms of NLRP3, NLRC4, and NLRC5 and susceptibility to pulmonary aspergillosis for the first time. Further investigations in larger populations are needed, and functional studies are also required to investigate the function of these NLRs in aspergillosis, as well as other fungal infection diseases.

Project description:Caspofungin (CAS) is approved for second-line management of proven or probable invasive aspergillosis at a dose of 50 mg once daily (QD). Preclinical and limited clinical data support the concept of the dose-dependent antifungal efficacy of CAS with preservation of its favorable safety profile. Little is known, however, about the pharmacokinetics (PKs) of higher doses of CAS in patients. In a formal multicenter phase II dose-escalation study, CAS was administered as a 2-h infusion at doses ranging from 70 to 200 mg QD. CAS PK sampling (n = 468 samples) was performed on day 1 and at peak and trough time points on days 4, 7, 14, and 28 (70 mg, n = 9 patients; 100 mg, n = 8 patients; 150 mg, n = 9 patients; 200 mg, n = 20 patients; total, n = 46 patients). Drug concentrations in plasma were measured by liquid chromatography tandem mass spectroscopy. Population pharmacokinetic analysis (PopPK) was performed using NONMEM (version 7) software. Model evaluation was performed using bootstrap analysis, prediction-corrected visual predictive check (pcVPC), as well as standardized visual predictive check (SVPC). The four investigated dose levels showed no difference in log-transformed dose-normalized trough levels of CAS (analysis of variance). CAS concentration data fitted best to a two-compartment model with a proportional-error model, interindividual variability (IIV) fitted best on clearance (CL), central and peripheral volume of distribution (V(1) and V(2), respectively) covariance fitted best on CL and V(1), interoccasion variability (IOV) fitted best on CL, and body weight fitted best as a covariate on CL and V(1) (CL, 0.411 liters/h ± 29% IIV; IOV on CL, 16%; V(1), 5.785 liters ± 29% IIV; intercompartmental clearance, 0.843 liters/h; V2, 6.53 liters ± 67% IIV). None of the other examined covariates (dose level, gender, age, serum bilirubin concentration, creatinine clearance) improved the model further. Bootstrap results showed the robustness of the final PopPK model. pcVPC and SVPC showed the predictability of the model and further confirmed the linear PKs of CAS over the dosage range of 70 to 200 mg QD. On the basis of the final model, geometric mean simulated peak plasma levels at steady state ranged from 13.8 to 39.4 mg/liter (geometric coefficient of variation, 31%), geometric mean trough levels ranged from 4.2 to 12.0 mg/liter (49%), and geometric mean areas under the concentration-time curves ranged from 170 to 487 mg · h/liter (34%) for the dosage range of 70 to 200 mg QD. CAS showed linear PKs across the investigated dosage range of 70 to 200 mg QD. Drug exposure in the present study population was comparable to that in other populations. (This study has been registered with the European Union Drug Regulating Authorities Clinical Trials website under registration no. 2006-001936-30 and at ClinicalTrials.gov under registration no. NCT00404092.).

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Addition of 17-(allylamino)-17-demethoxygeldanamycin to a suboptimal caspofungin treatment regimen in neutropenic rats with invasive pulmonary aspergillosis delays the time to death but does not enhance the overall therapeutic efficacy.

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