Jared L. Crandon

Comparative In Vitro and In Vivo Efficacies of Human Simulated Doses of Ceftazidime and Ceftazidime-Avibactam against Pseudomonas aeruginosa

ABSTRACT The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P. aeruginosa isolates with ceftazidime MICs of 8 to 128 mg/liter and ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated. In vivo activity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ≥0.5 log unit for 10/27 isolates, while ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with ceftazidime achieving reductions of ≥0.3 log unit for 10/15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates. In vitro, ceftazidime resulted in regrowth by 24 h against all isolates, while ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studied in vitro; however, no resistant mutants were detected in vivo. Against this highly ceftazidime-nonsusceptible population of P. aeruginosa, treatment with human simulated doses of ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularly in vivo, against isolates with MICs of ≤16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.

Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia.

ABSTRACT A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups—26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment Kslope pharmacokinetic model relating the elimination rate constant (K10) to renal function, as defined by creatinine clearance (CLCR), and central distribution volume (V1) to total body weight (TBW). The final model was described by the following equations: K10 = 0.0027 × CLCR + 0.071 h−1 and V1 = TBW × 0.21 liter/kg. The median intercompartmental transfer constants K12 and K21 were 0.780 h−1 and 0.472 h−1, respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 μg/ml, 24.0 μg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of −1.64 μg/ml, 17.1 μg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 μg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Clinical Pharmacodynamics of Cefepime in Patients Infected with Pseudomonas aeruginosa

ABSTRACT We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fCmin/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 μg/ml, resulting in median fT > MIC, fCmin/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of ≤60% (77.8% failed cefepime therapy when fT > MIC was ≤60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of ≤63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of ≤60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response.

Human Simulated Studies of Aztreonam and Aztreonam-Avibactam To Evaluate Activity against Challenging Gram-Negative Organisms, Including Metallo-β-Lactamase Producers

ABSTRACT Secondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatams neutralizing activity against often coproduced extended-spectrum β-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-β-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-β-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-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.

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

ABSTRACT Ceftaroline exhibits in vitro activity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producing Enterobacteriaceae when 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 against Enterobacteriaceae in a murine thigh infection model. IMPORTANCE Twelve Enterobacteriaceae isolates 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 log10 CFU/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 resistant Enterobacteriaceae.

Adaptation-Based Resistance to Siderophore-Conjugated Antibacterial Agents by Pseudomonas aeruginosa

ABSTRACT Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo.

Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials

Introduction: Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options. Areas covered: An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed. Expert opinion: The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting.

Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

ABSTRACT Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log10 CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults.

ABSTRACT Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC0-τ) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC0-τ in plasma. The mean (standard deviation) half-life and AUC0-τ were 6.9 (2.1) h and 39.5 (19.8) μg·h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) μg·h/ml, respectively, for anidulafungin. The AUC0-τ values for ELF and AM were 282 and 178 μg·h/ml, respectively, for voriconazole, and 21.9 and 1,430 μg·h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC90/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.

Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

ABSTRACT 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.