scholarly journals Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Gemma L. Nixon ◽  
Laura McEntee ◽  
Adam Johnson ◽  
Nicola Farrington ◽  
Sarah Whalley ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Neglected Tropical Diseases ◽  
Infection Model ◽  
Content Type ◽  
Drug Concentrations ◽  
Orally Bioavailable

ABSTRACT Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans . Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans , with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log 10 CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

scholarly journals Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Aleeza C. Gerstein ◽  
Katrina M. Jackson ◽  
Tami R. McDonald ◽  
Yina Wang ◽  
Benjamin D. Lueck ◽  
...  
Keyword(s):  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Candidate Genes ◽  
Cryptococcal Meningitis ◽  
Human Disease ◽  
Whole Genome ◽  
Content Type ◽  
Future Studies ◽  
Human Survival

ABSTRACT Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections. IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

scholarly journals The F-Box Protein Fbp1 Regulates Sexual Reproduction and Virulence in Cryptococcus neoformans

2011 ◽  
Vol 10 (6) ◽  
pp. 791-802 ◽  
Author(s):  
Tong-Bao Liu ◽  
Yina Wang ◽  
Sabriya Stukes ◽  
Qing Chen ◽  
Arturo Casadevall ◽  
...  
Keyword(s):  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Stress Responses ◽  
Membrane Integrity ◽  
Infection Model ◽  
Calcofluor White ◽  
Fungal Virulence ◽  
Content Type ◽  
F Box Protein

ABSTRACTCryptococcus neoformansis the leading cause of fungal meningitis in immunocomprised populations. Although extensive studies have been conducted on signal transduction pathways important for fungal sexual reproduction and virulence, how fungal virulence is regulated during infection is still not understood. In this study, we identified the F-box protein Fbp1, which contains a putative F-box domain and 12 leucine-rich repeats (LRR). Althoughfbp1mutants showed normal growth and produced normal major virulence factors, such as melanin and capsule, Fbp1 was found to be essential for fungal virulence, asfbp1mutants were avirulent in a murine systemic-infection model. Fbp1 is also important for fungal sexual reproduction. Basidiospore production was blocked in bilateral mating betweenfbp1mutants, even though normal dikaryotic hyphae were observed during mating.In vitroassays of stress responses revealed thatfbp1mutants are hypersensitive to SDS, but not calcofluor white (CFW) or Congo red, indicating that Fbp1 may regulate cell membrane integrity. Fbp1 physically interacts with Skp1 homologues in bothSaccharomyces cerevisiaeandC. neoformansvia its F-box domain, suggesting it may function as part of an SCF (Skp1, Cullins, F-box proteins) E3 ligase. Overall, our study revealed that the F-box protein Fbp1 is essential for fungal sporulation and virulence inC. neoformans, which likely represents a conserved novel virulence control mechanism that involves the SCF E3 ubiquitin ligase-mediated proteolysis pathway.

scholarly journals Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Nina T. Grossman ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Antifungal Susceptibility ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Laboratory Conditions ◽  
Physiological Differences ◽  
Sub Saharan

ABSTRACT Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub-Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between the in vivo infection environment and the in vitro AFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid “titan cells,” which rarely occur under laboratory conditions. Understanding whether and how C. neoformans differentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to the in vivo environment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods.

scholarly journals Characterization of High-Level Daptomycin Resistance in Viridans Group Streptococci Developed uponIn VitroExposure to Daptomycin

2015 ◽  
Vol 59 (4) ◽  
pp. 2102-2112 ◽  
Author(s):  
Ronda L. Akins ◽  
Bradley D. Katz ◽  
Catherine Monahan ◽  
Dylan Alexander
Keyword(s):  
Drug Exposure ◽  
Total Drug ◽  
Normal Flora ◽  
Vegetation Model ◽  
Content Type ◽  
Drug Concentrations ◽  
High Level ◽  
Viridans Group Streptococci

ABSTRACTViridans group streptococci (VGS) are part of the normal flora that may cause bacteremia, often leading to endocarditis. We evaluated daptomycin against four clinical strains of VGS (MICs = 1 or 2 μg/ml) using anin vitro-simulated endocardial vegetation model, a simulated bacteremia model, and kill curves. Daptomycin exposure was simulated at 6 mg/kg of body weight and 8 mg/kg every 24 h for endocardial and bacteremia models. Total drug concentrations were used for analyses containing protein (albumin and pooled human serum), and free (unbound) drug concentrations (93% protein bound) were used for analyses not containing protein. Daptomycin MICs in the presence of protein were significantly higher than those in the absence of protein. Despite MICs below or at the susceptible breakpoint, all daptomycin regimens demonstrated limited kill in both pharmacodynamic models. A reduction of approximately 1 to 2 log10CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log10CFU/g against one strain (Streptococcus gordonii1649) in the endocardial model. Activity was similar in both pharmacodynamic models in the presence or absence of protein. Similar activity was noted in the kill curves over all multiples of the MIC. Regrowth by 24 h was seen even at 8× MIC. Postexposure daptomycin MICs for both pharmacodynamic models increased to >256 μg/ml for all isolates by 24 and 72 h. Despite susceptibility to daptomycin by standard MIC methods, these VGS developed high-level daptomycin resistance (HLDR) after a short duration following drug exposure not attributed to modification or inactivation of daptomycin. Further evaluation is warranted to determine the mechanism of resistance and clinical implications.

scholarly journals Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Laura McEntee ◽  
Adam Johnson ◽  
Nicola Farrington ◽  
Jennifer Unsworth ◽  
Aaron Dane ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Drug Product ◽  
Oral Treatment ◽  
Phase Iii ◽  
Dose Fractionation ◽  
Infection Model ◽  
Content Type ◽  
Drug Concentrations ◽  
Tebipenem Pivoxil ◽  
Tract Infections

ABSTRACT Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsiella pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC0-24)/MIC corrected for the length of the dosing interval (fAUC0–24/MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum β-lactamases versus the wild type. The median fAUC0-24/MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC0-24/MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.

scholarly journals Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6773-6781 ◽  
Author(s):  
Xin Li ◽  
Lin Wang ◽  
Xian-Jia Zhang ◽  
Yang Yang ◽  
Wei-Tao Gong ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Interval ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosage Regimens ◽  
Drug Concentrations ◽  
Emergence Of Resistance

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

scholarly journals Cryptococcus neoformansCda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Rajendra Upadhya ◽  
Lorina G. Baker ◽  
Woei C. Lam ◽  
Charles A. Specht ◽  
Maureen J. Donlin ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogenesis ◽  
Mammalian Host ◽  
Infection Model ◽  
Chitin Deacetylase ◽  
Fungal Cell ◽  
Content Type ◽  
Mutant Strains

ABSTRACTChitin is an essential component of the cell wall ofCryptococcus neoformansconferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant ofC. neoformans. Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model.C. neoformanscarries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report thatC. neoformansCda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate thatC. neoformansCda genes are transcribed differently during a murine infection from what has been measuredin vitro.IMPORTANCECryptococcus neoformansis unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall ofC. neoformansis one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis ofC. neoformans.

scholarly journals Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lei Zhang ◽  
Keming Zhang ◽  
Hang Li ◽  
Carolina Coelho ◽  
Diego de Souza Gonçalves ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Extracellular Vesicles ◽  
Transcriptome Analysis ◽  
Cryptococcal Meningitis ◽  
Biological Effects ◽  
Developed Countries ◽  
The Body ◽  
Host Cells ◽  
Content Type

ABSTRACT Cryptococcus neoformans causes deadly mycosis in immunocompromised individuals. Macrophages are key cells fighting against microbes. Extracellular vesicles (EVs) are cell-to-cell communication mediators. The roles of EVs from infected host cells in the interaction with Cryptococcus remain uninvestigated. Here, EVs from viable C. neoformans-infected macrophages reduced fungal burdens but led to shorter survival of infected mice. In vitro, EVs induced naive macrophages to an inflammatory phenotype. Transcriptome analysis showed that EVs from viable C. neoformans-infected macrophages activated immune-related pathways, including p53 in naive human and murine macrophages. Conserved analysis demonstrated that basic cell biological processes, including cell cycle and division, were activated by infection-derived EVs from both murine and human infected macrophages. Combined proteomics, lipidomics, and metabolomics of EVs from infected macrophages showed regulation of pathways such as extracellular matrix (ECM) receptors and phosphatidylcholine. This form of intermacrophage communication could serve to prepare cells at more distant sites of infection to resist C. neoformans infection. IMPORTANCE Cryptococcus neoformans causes cryptococcal meningitis, which is frequent in patients with HIV/AIDS, especially in less-developed countries. The incidence of cryptococcal meningitis is close to 1 million each year globally. Macrophages are key cells that protect the body against microbes, including C. neoformans. Extracellular vesicles are a group of membrane structures that are released from cells such as macrophages that modulate cell activities via the transfer of materials such as proteins, lipids, and RNAs. In this study, we found that Cryptococcus neoformans-infected macrophages produce extracellular vesicles that enhance the inflammatory response in Cryptococcus-infected mice. These Cryptococcus neoformans-infected macrophage vesicles also showed higher fungicidal biological effects on inactivated macrophages. Using omics technology, unique protein and lipid signatures were identified in these extracellular vesicles. Transcriptome analysis showed that these vesicles activated immune-related pathways like p53 in naive macrophages. The understanding of this intermacrophage communication could provide potential targets for the design of therapeutic agents to fight this deadly mycosis.

scholarly journals In VivoActivities of Simulated Human Doses of Cefepime and Cefepime-AAI101 against Multidrug-Resistant Gram-Negative Enterobacteriaceae

2015 ◽  
Vol 59 (5) ◽  
pp. 2688-2694 ◽  
Author(s):  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Multidrug Resistant ◽  
Time Profile ◽  
Free Drug ◽  
Bacterial Density ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Drug Concentrations

ABSTRACTThe combination of cefepime with AAI101, a novel extended-spectrum β-lactamase inhibitor, possesses potentin vitroactivity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the familyEnterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and thein vivoefficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10CFU (mean ± standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of ≥64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of ≥0.5 log10CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive ofin vivoactivity for the studied regimen.

Sign in / Sign up

Export Citation Format

Share Document