ABSTRACT
Candida auris is an evolving and concerning global threat. Of particular concern are bloodstream infections related to central venous catheters. We evaluated the activity of taurolidine, a broad-spectrum antimicrobial in catheter lock solutions, against 106 C. auris isolates. Taurolidine was highly active with a MIC50/MIC90 of 512/512 mg/L, over 20-fold lower than lock solution concentrations of ≥13,500 mg/L. Our data demonstrate a theoretical basis for taurolidine-based lock solutions for prevention of C. auris catheter-associated infections.
Subject(s)
Antifungal Agents , Candida auris , Catheter-Related Infections , Microbial Sensitivity Tests , Taurine , Thiadiazines , Thiadiazines/pharmacology , Taurine/analogs & derivatives , Taurine/pharmacology , Catheter-Related Infections/microbiology , Catheter-Related Infections/drug therapy , Catheter-Related Infections/prevention & control , Humans , Antifungal Agents/pharmacology , Candida auris/drug effects , Central Venous Catheters/microbiology , Central Venous Catheters/adverse effects , Candidiasis/microbiology , Candidiasis/drug therapy , Candidemia/microbiology , Candidemia/drug therapyABSTRACT
OBJECTIVES: While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of â¼ 5000 mg/L, its target site pharmacodynamics are unknown. We evaluated the pharmacodynamics of ELF exposure of inhaled amikacin ± meropenem. METHODS: ELF exposures of inhaled amikacin (400 mg every 12 h), intravenous meropenem (2 g every 8 h) and a combination of both were studied in an in vitro pharmacodynamic model. Seven Klebsiella pneumoniae and 10 Pseudomonas aeruginosa with amikacin/meropenem MICs of 1 to 32,768/≤ 0.125 to >128 mg/L were included. Efficacy was assessed over 24-72 h. RESULTS: The mean ± SD 0 h bacterial density was 6.5 ± 0.1 log10 cfu/mL. Controls grew to 8.0 ± 0.5 log10 cfu/mL by the end of the experiments. Simulation of inhaled amikacin monotherapy rapidly achieved and sustained bactericidal activity near the limit of detection over 24 h for all 13 isolates with amikacin MIC ≤ 256 mg/L except only â¼ 2 log10 cfu/mL reduction was observed in K. pneumoniae 375 (amikacin/meropenem MIC 64/32 mg/L) and P. aeruginosa 1544 (amikacin/meropenem MIC 64/128 mg/L). No activity was seen against the three isolates with amikacin MIC ≥ 2048 mg/L. Among the six isolates tested with meropenem monotherapy, five (meropenem MIC ≥ 16 mg/L) grew similarly to the controls while one (meropenem MIC 2 mg/L) achieved â¼ 2.5 log10 cfu/mL decrease. Among seven isolates tested in combination, four (amikacin/meropenem MIC ≤ 64/32 mg/L), including K. pneumoniae 375, maintained limit of detection until 72 h, whereas P. aeruginosa 1544 sustained a 1 log reduction. Combination therapy had no activity against the two isolates with amikacin MIC ≥ 2048 mg/L. CONCLUSIONS: Inhaled amikacin monotherapy showed bactericidal activity against most isolates tested with amikacin MICs ≤ 256 mg/L. Adjunct inhaled amikacin plus meropenem sustained this activity for 72 h for the tested isolates with amikacin/meropenem MIC ≤ 64/32 mg/L.
Subject(s)
Amikacin/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Body Fluids/chemistry , Klebsiella pneumoniae/drug effects , Pseudomonas aeruginosa/drug effects , Thienamycins/pharmacokinetics , Administration, Inhalation , Adult , Aged , Amikacin/administration & dosage , Amikacin/pharmacology , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Female , Humans , Male , Meropenem , Microbial Sensitivity Tests , Microbial Viability/drug effects , Middle Aged , Thienamycins/administration & dosage , Thienamycins/pharmacology , Young AdultABSTRACT
OBJECTIVES: This study was designed to evaluate the pharmacodynamics of doripenem, imipenem and meropenem as a predictor of clinical success, mortality, 28 day recurrence and development of resistance in patients treated for Pseudomonas aeruginosa ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: Previously published demographic and outcome data derived from patients treated for P. aeruginosa VAP with doripenem, imipenem or meropenem were utilized. Patient-specific data were used in conjunction with published population pharmacokinetic models to construct concentration-time profiles for each patient. Etest MICs were used to determine pharmacodynamic profiles. Classification and regression tree (CART) analysis was utilized to partition pharmacodynamics based on outcomes with P values of 0.05. RESULTS: Eighty-six patients were included in the analysis. Initial carbapenem MICs ranged from 0.03 to 32 mg/L. VAP recurred in 28 patients; of these, 17 patients were initially infected with susceptible organisms, and 14 of them developed resistance. CART fT>MIC partitions identified for clinical success and survival were 19.2% (Pâ=â0.016) and 47.9% (Pâ<â0.001), respectively. No statistically significant partitions for fT>MIC were identified for recurrence or resistance development. CONCLUSIONS: We identified fT>MIC cut-offs for positive clinical outcomes in patients with P. aeruginosa VAP that were similar to those observed in animal models of infection for stasis (â¼20%) and 1 log decreases in cfu (â¼40%). Although in vitro studies have suggested a link between drug exposure and development of resistance, we were unable to identify such a relationship clinically.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/pharmacokinetics , Carbapenems/pharmacology , Carbapenems/pharmacokinetics , Pneumonia, Ventilator-Associated/drug therapy , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Adult , Aged , Aged, 80 and over , Animals , Anti-Bacterial Agents/administration & dosage , Carbapenems/administration & dosage , Disk Diffusion Antimicrobial Tests , Doripenem , Female , Humans , Imipenem/administration & dosage , Imipenem/pharmacokinetics , Imipenem/pharmacology , Male , Meropenem , Middle Aged , Prospective Studies , Recurrence , Thienamycins/administration & dosage , Thienamycins/pharmacokinetics , Thienamycins/pharmacology , Treatment OutcomeABSTRACT
The combination of cefepime with AAI101, a novel extended-spectrum ß-lactamase inhibitor, possesses potent in vitro activity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the family Enterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and the in vivo efficacy 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 (log10 number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10 CFU (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 log10 CFU 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 of in vivo activity for the studied regimen.
Subject(s)
Cephalosporins/therapeutic use , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae/drug effects , Enterobacteriaceae/pathogenicity , beta-Lactamase Inhibitors/therapeutic use , Animals , Cefepime , Female , Humans , Mice , Microbial Sensitivity TestsABSTRACT
GSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log10 CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log10 CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ± 34.6 and 148.4 ± 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA.
Subject(s)
Anti-Bacterial Agents/pharmacology , Lung Diseases/drug therapy , Methicillin-Resistant Staphylococcus aureus/drug effects , Respiratory Tract Infections/drug therapy , Staphylococcal Infections/drug therapy , Animals , Disease Models, Animal , Female , Lung/drug effects , Lung/microbiology , Lung Diseases/microbiology , Methicillin/pharmacology , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests/methods , Neutropenia/drug therapy , Neutropenia/microbiology , Respiratory Tract Infections/microbiology , Staphylococcal Infections/microbiologyABSTRACT
Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability.
Subject(s)
Anti-Bacterial Agents/pharmacology , Monobactams/pharmacology , Pyridones/pharmacology , Siderophores/pharmacology , ATP-Binding Cassette Transporters/antagonists & inhibitors , Drug Resistance, Bacterial/drug effects , Drug Resistance, Bacterial/genetics , Microbial Sensitivity Tests , Mutation , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Reserpine/pharmacologyABSTRACT
We aimed to describe the in vivo activity of humanized pharmacokinetic exposures of meropenem and comparators against Verona integron-encoded metallo-ß-lactamase (MBL) (VIM)-producing Enterobacteriaceae in a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despite in vitro resistance, high-dose meropenem may be a possible option against infections caused by Enterobacteriaceae producing MBL-type carbapenemases.
Subject(s)
Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Bacterial Proteins/metabolism , Enterobacteriaceae/drug effects , Enterobacteriaceae/enzymology , Thigh/microbiology , beta-Lactamases/metabolism , Animals , Bacterial Proteins/genetics , Cefepime , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Enterobacteriaceae Infections/drug therapy , Levofloxacin/pharmacology , Levofloxacin/therapeutic use , Meropenem , Mice , Microbial Sensitivity Tests , Thienamycins/pharmacology , Thienamycins/therapeutic use , beta-Lactamases/geneticsABSTRACT
The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated ß-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.
Subject(s)
Anti-Bacterial Agents/pharmacology , Azetidines/pharmacology , Drug Resistance, Bacterial/genetics , Pseudomonas aeruginosa/metabolism , Siderophores/pharmacology , Sulfonamides/pharmacology , Animals , Anti-Bacterial Agents/pharmacokinetics , Azetidines/pharmacokinetics , Female , Iron/metabolism , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Oligopeptides/metabolism , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Siderophores/pharmacokinetics , Sulfonamides/pharmacokinetics , beta-Lactamases/metabolismABSTRACT
PURPOSE: We assessed the effects of the urine matrix and its varying pH on the potency of the novel broad-spectrum fluoroquinolone delafloxacin and of ciprofloxacin against 16 urogenic Enterobacteriaceae in the urine of patients with suspected urinary tract infection. MATERIALS AND METHODS: We determined minimum inhibitory concentrations in broth and urine using microdilution in 9 Escherichia coli and 7 Klebsiella pneumoniae specimens. The change in potency between broth and urine was calculated. RESULTS: Against 16 highly ciprofloxacin resistant Enterobacteriaceae with a broth minimum inhibitory concentration of 32 mg/l or greater the minimum inhibitory concentration in delafloxacin in broth was 2 mg/l (1 and 0 isolates of E. coli and K. pneumoniae, respectively), 4 mg/l (3 and 0), 8 mg/l (3 and 1), 16 mg/l (2 and 4) and 32 mg/l (0 and 2). Across the 143 collected urines pH ranged from 4.7 to 9.0 with 71% at pH 6.5 or less. The delafloxacin minimum inhibitory concentration measured in 80% urine from 100 unique patient samples (pH 5.0 to 8.3) was 2 mg/l or less (18% and 0.8% for E. coli and K. pneumoniae, respectively), 4 mg/l (23% and 6%), 8 mg/l (21% and 18%), 16 mg/l (23% and 33%) and 32 mg/l or greater (15% and 42%). For E. coli and K. pneumoniae combined the median changes in the delafloxacin minimum inhibitory concentration were a 1 doubling dilution decrease at pH 6.0 or less, no change at pH 6.1 to 7.0 and a 1 doubling dilution increase at pH 7.1 or greater. Unlike delafloxacin, ciprofloxacin showed a 1 doubling dilution increase for E. coli and no change for K. pneumoniae at pH 7.0 or less with no change observed at pH 7.1 or greater. CONCLUSIONS: Most urines collected from patients with urinary tract infection had a pH of 6.5 or less. Delafloxacin broth minimum inhibitory concentrations were twofold to fivefold doubling dilutions lower than those of ciprofloxacin. In contrast to ciprofloxacin, the potency of delafloxacin was further enhanced in the acidic environment commonly observed in the setting of urinary tract infection.
Subject(s)
Ciprofloxacin/pharmacology , Escherichia coli Infections/drug therapy , Escherichia coli/isolation & purification , Fluoroquinolones/pharmacology , Klebsiella pneumoniae/isolation & purification , Urinary Tract Infections/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Escherichia coli Infections/microbiology , Escherichia coli Infections/urine , Female , Humans , Hydrogen-Ion Concentration , Klebsiella Infections , Klebsiella pneumoniae/drug effects , Male , Microbial Sensitivity Tests , Middle Aged , Retrospective Studies , Urinalysis , Urinary Tract Infections/microbiology , Urinary Tract Infections/urine , Urine/chemistry , Urine/microbiology , Young AdultABSTRACT
Pharmacodynamic profiling data of carbapenems for Acinetobacter spp. are sparse. This study aimed to determine the pharmacodynamic targets of carbapenems for Acinetobacter baumannii based on a range of percentages of the dosing interval in which free drug concentrations remained above the MIC (fT>MIC) in the neutropenic murine thigh infection model. fT>MIC values of 23.7%, 32.8%, and 47.5% resulted in stasis, 1-log reductions, and 2-log reductions in bacterial density after 24 h, respectively. The pharmacodynamic targets of carbapenems for A. baumannii demonstrated in vivo are similar to those of other Gram-negative bacteria.
Subject(s)
Acinetobacter baumannii/drug effects , Carbapenems/therapeutic use , Thigh/microbiology , Acinetobacter Infections/drug therapy , Acinetobacter baumannii/pathogenicity , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Carbapenems/pharmacokinetics , Mice , Microbial Sensitivity TestsABSTRACT
The emergence of the New Delhi metallo-ß-lactamase (NDM) among Enterobacteriaceae has become a global concern because of its high levels of in vitro resistance to nearly all available antibiotics. However, recent in vivo studies demonstrated the efficacies of carbapenems against NDM-1-producing isolates despite high MICs. Herein, we report in vivo findings with ceftazidime and ceftazidime-avibactam against an isogenic pair (wild type and NDM-1) and four clinical NDM-producing isolates that demonstrate discordance between MICs measured in vitro and the in vivo activity of ceftazidime-avibactam against this resistant genotype.
Subject(s)
Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds/pharmacology , Carbapenems/pharmacology , Ceftazidime/pharmacology , Escherichia coli/drug effects , Klebsiella pneumoniae/drug effects , Animals , Disease Models, Animal , Drug Combinations , Escherichia coli/genetics , Escherichia coli/isolation & purification , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Klebsiella Infections/drug therapy , Klebsiella Infections/microbiology , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/isolation & purification , Mice , Microbial Sensitivity Tests , beta-Lactamases/metabolismABSTRACT
Ceftazidime-avibactam is a ß-lactam ß-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-ß-lactam ß-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D ß-lactamases. However, little is known of the in vivo efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant Enterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against Enterobacteriaceae exhibiting MICs of ≥8 µg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical Enterobacteriaceae isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10 CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the Enterobacteriaceae isolates, exhibiting MICs of ≤16 µg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 µg/ml (fT>MIC of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant Enterobacteriaceae.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/therapeutic use , Ceftazidime/therapeutic use , Enterobacteriaceae Infections/drug therapy , Pseudomonas Infections/drug therapy , beta-Lactamase Inhibitors/therapeutic use , Animals , Anti-Bacterial Agents/pharmacokinetics , Azabicyclo Compounds/pharmacokinetics , Ceftazidime/pharmacokinetics , Drug Combinations , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae/drug effects , Enterobacteriaceae/isolation & purification , Enterobacteriaceae Infections/microbiology , Female , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Neutropenia/immunology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/isolation & purification , beta-Lactamase Inhibitors/pharmacokineticsABSTRACT
This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 µg/ml, and those of ceftazidime were 8 to >128 µg/ml. The change in log10 CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10 CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 µg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 µg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 µg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 µg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 µg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 µg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 µg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/therapeutic use , Ceftazidime/therapeutic use , Pneumonia, Bacterial/drug therapy , Pseudomonas Infections/drug therapy , Animals , Anti-Bacterial Agents/administration & dosage , Azabicyclo Compounds/administration & dosage , Ceftazidime/administration & dosage , Disease Models, Animal , Drug Therapy, Combination , Female , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Pneumonia, Bacterial/microbiology , Pseudomonas Infections/microbiology , Treatment OutcomeABSTRACT
Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent- and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced ≥1-log10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, ≥1-log10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Enterobacteriaceae/drug effects , beta-Lactamase Inhibitors , beta-Lactams/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Carbapenems/administration & dosage , Disease Models, Animal , Doripenem , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae/enzymology , Enterobacteriaceae Infections/drug therapy , Ertapenem , Humans , Klebsiella pneumoniae/drug effects , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , beta-Lactam Resistance , beta-Lactamases , beta-Lactams/administration & dosageABSTRACT
Enterobacteriaceae producing the OXA-48 carbapenemase are emerging worldwide, leaving few treatment options. Efficacy has been demonstrated in vivo with ceftazidime against a ceftazidime-susceptible OXA-48 isolate but not with imipenem despite maintaining susceptibility. The relationship between phenotype and in vivo efficacy was assessed for OXA-48 producers using humanized regimens of 2 g doripenem every 8 h (q8h; 4 h infusion), 1 g ertapenem q24h, 2 g ceftazidime q8h (2 h inf), and 500 mg levofloxacin q24h. Each regimen was evaluated over 24 h against an isogenic pair (wild-type and OXA-48 Klebsiella pneumoniae strains) and six clinical OXA-48 isolates with and without other extended-spectrum ß-lactamases in immunocompetent and neutropenic murine thigh infection models. Efficacy was determined using the change in bacterial density versus 24-h growth controls in immunocompetent studies and 0-h controls in neutropenic studies. Bacterial reductions of ≥1 log CFU were observed with all agents for the wild-type strain. Consistent with low MICs, ceftazidime and levofloxacin exhibited efficacy against the isogenic OXA-48 strain, whereas doripenem did not, despite having a susceptible MIC; no activity was observed with ertapenem, consistent with a resistant MIC. Similar trends were observed for the clinical isolates evaluated. Ceftazidime, levofloxacin, and ertapenem efficacy against isogenic and clinical OXA-48-producing strains correlated well with phenotypic profiles and pharmacodynamic targets, whereas efficacy with doripenem was variable over the MIC range studied. These data suggest that carbapenems may not be a reliable treatment for treating OXA-48 producers and add to previous observations with KPC and NDM-1 suggesting that genotype may better predict activity of the carbapenems than the phenotypic profile.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Carbapenems/therapeutic use , Ceftazidime/therapeutic use , Klebsiella pneumoniae/drug effects , beta-Lactamase Inhibitors , Animals , Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Ceftazidime/pharmacology , Disease Models, Animal , Doripenem , Ertapenem , Humans , Klebsiella pneumoniae/enzymology , Levofloxacin/pharmacology , Levofloxacin/therapeutic use , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , beta-Lactam Resistance , beta-Lactamases , beta-Lactams/pharmacology , beta-Lactams/therapeutic useABSTRACT
In light of the in vivo/in vitro discordance among beta-lactams against Gram-negative pathogens, we compared the in vivo pharmacodynamics of humanized ceftaroline against 9 Staphylococcus aureus strains (MICs of 0.13 to 1 mg/liter) from published in vitro studies using standard and high inocula in the murine thigh infection model. Consistent with the in vitro findings, mean reductions of ≥1 log10 CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest in vivo/in vitro concordance with no observed inoculum effect.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cephalosporins/pharmacology , Cephalosporins/pharmacokinetics , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Colony Count, Microbial , Female , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Neutropenia/immunology , Penicillin-Binding Proteins/metabolism , Staphylococcal Infections/microbiology , Staphylococcus aureus/classification , CeftarolineABSTRACT
Secondary to the stability of aztreonam against metallo-ß-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum ß-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-ß-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-ß-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, ≤ 32 µg/ml; fT>MIC, ≥ 38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥ 128 µg/ml; fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, ≤16 µg/ml; fT>MIC, ≥ 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P. aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤ 16 µg/ml and variable efficacy noted when the MICs were ≥ 32 µg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-ß-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/therapeutic use , Aztreonam/therapeutic use , Enterobacteriaceae Infections/drug therapy , Pseudomonas Infections/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds/pharmacology , Aztreonam/pharmacology , Bacterial Proteins/metabolism , Enterobacteriaceae Infections/microbiology , Escherichia coli/drug effects , Escherichia coli/isolation & purification , Escherichia coli Infections/drug therapy , Humans , Klebsiella Infections/drug therapy , Klebsiella Infections/microbiology , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/isolation & purification , Mice , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/isolation & purification , beta-Lactamases/metabolismABSTRACT
P-873 is a novel compound in the RX-04 pyrrolocytosine series of protein synthesis inhibitors currently under development by Rib-X Pharmaceuticals. We evaluated the pharmacodynamic and pharmacokinetic properties of this compound against Klebsiella pneumoniae using a murine neutropenic thigh infection model. P-873 demonstrated potent and rapid in vivo activity against this organism with enhanced penetration and duration of exposure in thigh tissue.
Subject(s)
Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/pathogenicity , Neutropenia/drug therapy , Neutropenia/microbiology , Protein Synthesis Inhibitors/therapeutic use , Thigh/microbiology , Animals , Female , MiceABSTRACT
While reports of Klebsiella pneumoniae carbapenemase (KPC) production among Pseudomonas aeruginosa strains have emerged from a number of countries worldwide, outcome data are lacking. This is the first report evaluating how KPC production in P. aeruginosa impacts the efficacy of carbapenems by using the murine thigh infection model. Our findings suggest that the impact of KPC-2 in vivo is less pronounced than would be anticipated based on the in vitro potency.