Real-World Impact of the Accelerate PhenoTest BC Kit on Patients With Bloodstream Infections in the Improving Outcomes and Antimicrobial Stewardship Study: A Quasiexperimental Multicenter Study.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of morbidity and mortality. The Improving Outcomes and Antimicrobial Stewardship study seeks to evaluate the impact of the Accelerate PhenoTest BC Kit (AXDX) on antimicrobial use and clinical outcomes in BSIs. METHODS: This multicenter, quasiexperimental study compared clinical and antimicrobial stewardship metrics, prior to and after implementation of AXDX, to evaluate the impact this technology has on patients with BSIs. Laboratory and clinical data from hospitalized patients with BSIs (excluding contaminants) were compared between 2 arms, 1 that underwent testing on AXDX (post-AXDX) and 1 that underwent alternative organism identification and susceptibility testing (pre-AXDX). The primary outcomes were time to optimal therapy (TTOT) and 30-day mortality. RESULTS: A total of 854 patients with BSIs (435 pre-AXDX, 419 post-AXDX) were included. Median TTOT was 17.2 hours shorter in the post-AXDX arm (23.7 hours) compared with the pre-AXDX arm (40.9 hours; P<.0001). Compared with pre-AXDX, median time to first antimicrobial modification (24.2 vs 13.9 hours; P<.0001) and first antimicrobial deescalation (36.0 vs 27.2 hours; P=.0004) were shorter in the post-AXDX arm. Mortality (8.7% pre-AXDX vs 6.0% post-AXDX), length of stay (7.0 pre-AXDX vs 6.5 days post-AXDX), and adverse drug events were not significantly different between arms. Length of stay was shorter in the post-AXDX arm (5.4 vs 6.4 days; P=.03) among patients with gram-negative bacteremia. CONCLUSIONS: For BSIs, use of AXDX was associated with significant decreases in TTOT, first antimicrobial modification, and time to antimicrobial deescalation.

Improving outcomes and antibiotic stewardship (IOAS) for patients with Gram-positive bloodstream infections through use of rapid testing: a quasi-experimental multicentre study of the Accelerate PhenoTest™ BC Kit.

BACKGROUND: Data from the Improving Outcomes and Antibiotic Stewardship for Patients with Bloodstream Infections: Accelerate PhenoTest™ BC Kit (AXDX) Registry Study were analysed to determine the impact of rapid organism identification and antimicrobial susceptibility testing (AST) for Gram-positive bacteraemia. PATIENTS AND METHODS: This multicentre, quasi-experimental study evaluated clinical and antimicrobial stewardship metrics following the implementation of AXDX. Data from hospitalized patients with bacteraemia were compared between groups, one that underwent testing on AXDX (post-AXDX) and one that underwent traditional identification and AST (pre-AXDX). An analysis of patients with Gram-positive bacteraemia was performed. The primary outcome was time to optimal therapy (TTOT). Secondary outcomes included time to first antibiotic modification (overall and Gram-positive), duration of unnecessary MRSA coverage, incidence of adverse events, length of stay and mortality. RESULTS: A total of 219 (109 pre-AXDX, 110 post-AXDX) patients with Gram-positive bacteraemia were included. Median TTOT was 36.3 h (IQR, 16.9-56.7) in the pre-AXDX group and 20.4 h (IQR, 7.5-36.7) in the post-AXDX group (P = 0.01). Compared with pre-AXDX, median time to first antibiotic modification (29.1 versus 15.9 h; P = 0.002), time to first Gram-positive antibiotic modification (33.2 versus 17.2 h; P = 0.003) and median duration of unnecessary MRSA coverage (58.4 versus 29.7 h; P = 0.04) were reduced post-AXDX. A trend towards decreased acute kidney injury (24% versus 13%; P = 0.06) was observed in the post-AXDX group. Groups did not differ in other secondary outcomes. CONCLUSIONS: Implementation of AXDX testing for patients with Gram-positive bacteraemia shortened the TTOT and reduced unnecessary antibiotic exposure due to faster antibiotic modifications.

Performance of ceftriaxone susceptibility testing on the Accelerate Pheno® system of ESBL-producing isolates.

The correlation of ceftriaxone nonsusceptibility and ESBL production was evaluated in 40 characterized isolates. Performance of ceftriaxone susceptibility testing on the Accelerate Pheno was evaluated and compared with reference broth microdilution in triplicate. The CLSI ESBL confirmatory test was also evaluated. Ceftriaxone categorical agreement of the Accelerate Pheno was 97.5% with 1 minor error. The ESBL confirmatory disk test resulted in 4 false-negatives and 1 false positive. The Accelerate Pheno provides an expedited and accurate method of ceftriaxone susceptibility testing allowing for optimization of antimicrobial regimens sooner. These data indicate that ESBL production has a high likelihood of ceftriaxone non-susceptibility.

Impact of antimicrobial therapy on the gut microbiome.

The gut microbiome is now considered an organ unto itself and plays an important role in health maintenance and recovery from critical illness. The commensal organisms responsible for the framework of the gut microbiome are valuable in protection against disease and various physiological tasks. Critical illness and the associated interventions have a detrimental impact on the microbiome. While antimicrobials are one of the fundamental and often life-saving modalities in septic patients, they can also pave the way for subsequent harm because of the resulting damage to the gut microbiome. Contributing to many of the non-specific signs and symptoms of sepsis, the balance between the overuse of antimicrobials and the clinical need in these situations is often difficult to delineate. Given the potency of antimicrobials utilized to treat septic patients, the effects on the gut microbiome are often rapid and long-lasting, in which case full recovery may never be observed. The overgrowth of opportunistic pathogens is of significant concern as they can lead to infections that become increasingly difficult to treat. Continued research to understand the disturbances within the gut microbiome of critically ill patients and their outcomes is essential to help develop future therapies to circumvent damage to, or restore, the microbiome. In this review, we discuss the impact of the antimicrobials often used for the treatment of sepsis on the gut microbiota.

Analyses of a Ceftazidime-Avibactam-Resistant Citrobacter freundii Isolate Carrying blaKPC-2 Reveals a Heterogenous Population and Reversible Genotype.

A blaKPC-2-carrying Citrobacter freundii isolate developed ceftazidime-avibactam resistance during treatment with this agent. The initial and follow-up isolates exhibited ceftazidime-avibactam MICs of 4 and 64 µg/ml, respectively. Overexpression of AcrAB-TolC and porin alterations were detected in both isolates, but no other resistance mechanism was observed. After passaging the initial clinical isolate in ceftazidime-avibactam at a fixed concentration of 4 µg/ml and a 4:1 ratio, resistance to all ß-lactams was noted, and a percentage of the blaKPC-2 sequencing reads had mutations leading to the alterations D176Y (blaKPC-2-D176Y [78%]) or R164S plus P147L (blaKPC-2-R164S + P147L [82%]). Further investigation of the follow-up isolate showed that 11% of the blaKPC-2 reads had mutations leading to D179Y substitution (blaKPC-2-D179Y). In the absence of selective pressure, ceftazidime-avibactam MICs of the passaged and follow-up isolates revealed that 7 or 8 out of 20 screened colonies reverted to susceptible and possessed blaKPC-2 wild-type sequences. Recombinant plasmids carrying the blaKPC-2 alterations observed were transformed in Escherichia coli, and MIC values for ceftazidime ± avibactam were elevated. Lower MICs for ceftriaxone, cefepime, aztreonam, meropenem, and imipenem for the mutated KPC-2-producing isolates were observed compared to those of the isolates producing a wild-type KPC-2. Avibactam at a fixed concentration of 4 µg/ml restored the activity of all ß-lactams tested for the recombinant strains. The heterogenous population of wild-type and mutated blaKPC-2 and the reversibility of the genotypes observed suggest a significant challenge for managing KPC-producing isolates that develop ceftazidime-avibactam resistance during therapy.IMPORTANCE The development of ceftazidime-avibactam resistance among KPC-producing isolates during treatment with this agent has been reported. Usually isolates that become resistant have a mutated blaKPC gene that confers resistance to ceftazidime-avibactam and susceptibility to meropenem. We report a Citrobacter freundii isolate that developed ceftazidime-avibactam resistance due to mutations within the coding region of the blaKPC-2 Ω-loop previously reported; however, in this case, only 11% of the whole-genome sequencing reads had mutations, making this alteration difficult to detect and the treatment of these isolates more challenging. In addition to blaKPC, the initial and the follow-up patient isolates displayed hyperexpression of the AcrAB-TolC efflux system and disruption of the outer membrane protein (OMP) OmpF, which contribute to carbapenem resistance. Experiments performed to confirm our findings included generating mutant isolates from the initial patient isolate, passaging the isolates for purity in drug-free medium, resulting in a reversible phenotype, and cloning the mutations to demonstrate the resistance conferred.

Vancomycin Tissue Pharmacokinetics in Patients with Lower-Limb Infections via In Vivo Microdialysis.

BACKGROUND: Vancomycin is a common treatment option for skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Given the increasing prevalence of MRSA, vancomycin is widely used as empirical therapy. In patients with lower-limb infections, antimicrobial penetration is often reduced because of decreased vascular perfusion. In this study, we evaluated the tissue concentrations of vancomycin in hospitalized patients with lower-limb infections. METHODS: An in vivo microdialysis catheter was inserted near the margin of the wound and was perfused with lactated Ringer's solution. Tissue and serum samples were obtained after steady state for one dosing interval. Tissue concentrations were corrected for percentage of in vivo recovery using the retrodialysis technique. RESULTS: Nine patients were enrolled (mean ± SD: age, 54 ± 19 years; weight, 105.6 ± 31.5 kg). Patients received a mean of 12.8 mg/kg of vancomycin every 12 hours (n = 7), every 8 hours (n = 1), or every 24 hours (n = 1). Mean ± SD steady-state trough vancomycin concentrations in serum and tissue were 11.1 ± 3.3 and 6.0 ± 2.6 µg/mL. The mean ± SD 24-hour free drug areas under the curve for serum and wound were 283.7 ± 89.4 and 232.8 ± 75.7 µg*h/mL, respectively. The mean ± SD tissue penetration ratio was 0.8 ± 0.2. CONCLUSIONS: These data suggest that against MRSA with minimum inhibitory concentrations of 1 µg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 µg/mL.

Supporting the ceftaroline fosamil/avibactam Enterobacteriaceae breakpoint determination using humanised in vivo exposures in a thigh model.

Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600mg every 8h (q8h) showed activity against extended-spectrum ß-lactamase-, AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) ≤ 1 µg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs ≥ 1 µg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 µg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs ≤ 4 µg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs ≥ 8 µg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs ≤ 4 µg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae.

In vitro pharmacodynamics of human simulated exposures of ceftaroline and daptomycin against MRSA, hVISA, and VISA with and without prior vancomycin exposure.

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

Tissue pharmacokinetics of cefazolin in patients with lower limb infections.

Cefazolin, a first-generation cephalosporin with activity against methicillin-susceptible Staphylococcus aureus and streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. An in vivo microdialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringer's solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percent in vivo recovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ± 18.51 kg and a mean age of 54 ± 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC0-8) values for serum and wound were 48.0 ± 18.66 and 56.35 ± 41.17 µg · h/ml, respectively, for the patients receiving 1 g every 8 h. The fAUC0-24 values for serum and wound were 1,326.1 and 253.9 µg · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serum fAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.

In vivo efficacy of humanized ceftaroline fosamil-avibactam exposures in a polymicrobial infection model.

Although Gram-positive cocci are the most common pathogens in diabetic foot infections, these infections often are polymicrobial. The objective of this study was to assess the efficacy of a simulated human dose of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion in a polymicrobial in vivo murine model. Seven isolates were used (3 methicillin-resistant Staphylococcus aureus [MRSA] isolates, 1 methicillin-susceptible S. aureus [MSSA] isolate, 1 Escherichia coli isolate, 1 Enterobacter cloacae isolate, and 1 Bacteroides fragilis isolate) in various combinations in an immunocompromised polymicrobial tissue infection to assess the efficacy of the simulated regimen. Each infection was comprised of at least one S. aureus isolate with a MIC of 0.25 to 1 µg/ml and one Enterobacteriaceae isolate with a MIC of 1 or 4 µg/ml. Eight of 16 infections also included B. fragilis, with a MIC of 0.5 µg/ml, as a third organism. Efficacy was evaluated after 24 h as the change in log10 CFU from the level of 0-h controls. Efficacy was seen against all isolate combinations, with at least a 1-log kill against Enterobacteriaceae and a minimum of a 2-log kill against S. aureus and B. fragilis isolates. These bacterial reductions correlate with free drug concentration above the MIC (fT>MIC) produced by the humanized regimen of 100, 86, and 56% at MICs of 1, 2, and 4 µg/ml, respectively. The humanized regimen of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion showed predictable efficacy against all infections tested in this model. These data support further clinical investigation of ceftaroline fosamil-avibactam for the treatment of polymicrobial tissue infections.

Pharmacokinetics of doripenem in infected patients treated within and outside the intensive care unit.

BACKGROUND: Doripenem often is used in the intensive care unit (ICU) to treat serious infections. However, pharmacokinetics in this population often are altered by various physiologic changes. Current pharmacokinetic data in critically ill patients receiving doripenem are limited. OBJECTIVE: To determine the pharmacokinetics of doripenem in patients treated in the ICU versus outside the ICU. METHODS: A total of 3-4 serum samples were collected from 25 infected patients receiving doripenem. A 2-compartment model was fit to serum pharmacokinetic data with nonparametric adaptive grid with adaptive γ. In the structural pharmacokinetic model, clearance (Cl) was made proportional to creatinine clearance (CrCl) and an intercept term. Bayesian pharmacokinetic parameters were compared between the 2 populations. A 5000-patient Monte Carlo simulation was performed for various CrCl ranges. The probability of pharmacodynamic target attainment was calculated over a range of minimum inhibitory concentrations (MICs), assuming a target of 35% of the dosing interval that unbound drug concentrations remain above the MIC. RESULTS: Mean (range) age, body mass index, and CrCl were 61 (31-90) years, 31.2 (15.1-55.5) kg/m(2), and 86 (15-221) mL/min, respectively. After the Bayesian step, r(2), bias, and precision were 0.97, 0.04, and 1.44 µg/mL, respectively. Mean (SD) parameters for ICU (n = 13) and non-ICU (n = 12) patients were not significantly different (p > 0.05): volume of central compartment (17.3 [11.2] vs 18.5 [11.7] L), Cl (10.1 [10.2] vs 15.5 [16.9] L/h), k12 (4.7 [4.7] vs 4.7 [4.8] h(-1)), and k21 (7.1 [5.5] vs 5.7 [5.3] h(-1)), respectively. Optimal target attainments were obtained for patients with normal renal function up to MICs of 2 µg/mL with a dose of 500 mg every 8 hours as 1-hour and 4-hour infusions. CONCLUSIONS: Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen.

Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults.

The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m(2) receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K(12) and K(21)) of 8.04 ± 6.22 and 7.99 ± 5.46 h(-1), respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 µg · h/ml (P = 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r(2) = 0.524), adjusted body weight (r(2) = 0.587), lean body weight (r(2) = 0.495), and ideal body weight (r(2) = 0.398), but not with BMI (r(2) = 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

Efficacy of ceftaroline fosamil in a staphylococcal murine pneumonia model.

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 µg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log(10) kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log(10) CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log(10) kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.