In vitro activity of taurolidine against clinical Candida auris isolates: relevance to catheter-related bloodstream infections.

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.

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired renal function and those requiring hemodialysis.

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed. DESIGN: Open-label, Phase-1 pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 ml/min), eight with "Severe" renal impairment (glomerular filtration rate <30 ml/min/1.73 m2 ), and eight subjects requiring hemodialysis. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On dialysis), as well as, on a non-dialysis day (Off dialysis). Plasma, urine, and dialysate fluid were collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during on and off dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment-emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate. CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired-hepatic function.

STUDY OBJECTIVE: Lefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that, lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects. DESIGN: Open-label, Phase-1 clinical pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of IV lefamulin 150 mg over 1 h. Plasma was collected for 48 h and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in Cmax and increases in renal clearance for Moderate and Severe groups, as well as, the increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h.ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma-protein binding was seen in hepatically-impaired versus normal subjects. CONCLUSION: Lefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding.

Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens.

Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log10 CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log10 CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections.

In vivo efficacy of humanized high dose meropenem and comparators against Pseudomonas aeruginosa isolates producing verona integron-encoded metallo-ß-lactamase (VIM).

INTRODUCTION: We aimed to describe the in vivo efficacy of meropenem, in addition to cefepime and levofloxacin as comparators against VIM-producing Pseudomonas aeruginosa and compare the findings to our previous observations with Enterobacteriaceae. METHODS: Eight clinical P. aeruginosa isolates with meropenem MICs from 4 to 512 mg/L were studied in a murine neutropenic thigh infection model. Animals were treated with doses of the antibiotics to simulate the human exposure of meropenem 2 g q8 h 30-min infusion, cefepime 2 g q8 h 30-min infusion and levofloxacin 500 mg q24 h. After 24 hours, the animals were euthanized and efficacy was calculated as the change in thigh bacterial density (log10 CFU) relative to the starting inoculum (0 h). RESULTS: As expected, levofloxacin was ineffective against all isolates due to their resistant phenotype (8 to>64 mg/L). Cefepime also showed minimal activity against all isolates consistent with its failure to achieve pharmacodynamic target exposures due to high MICs of 32 to>512 mg/L. In the presence of low MICs (4 to 16 mg/L), the fT> MIC of meropenem was sufficiently high to result in CFU reductions. However, conflicting activity was noted for isolates with MICs = 128 mg/L that possessed the same enzymatic profile, suggesting that other mechanisms of resistance are responsible for driving CFU outcomes. No activity was noted for organisms with a meropenem MIC = 512 mg/L. CONCLUSION: Unlike previous observations with MBL-producing Enterobacteriaceae that showed discordance between in vitro resistance and in vivo efficacy in the murine infection model, we found that the efficacy of humanized cefepime and meropenem was generally concordant with the phenotypic profile of VIM-producing P. aeruginosa.

Pharmacodynamics of carbapenems for the treatment of Pseudomonas aeruginosa ventilator-associated pneumonia: associations with clinical outcome and recurrence.

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% (P = 0.016) and 47.9% (P < 0.001), 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 (∼20%) and 1 log decreases in cfu (∼40%). Although in vitro studies have suggested a link between drug exposure and development of resistance, we were unable to identify such a relationship clinically.

Evaluation of a disease state management guideline for urinary tract infection.

A urinary tract infection (UTI) disease state management guideline, including risk-based antimicrobial recommendations, Foley catheter management and transitions of care, was implemented. This study evaluated the outcomes associated with implementation of the guideline. A retrospective study was conducted between 1 July 2013 and 30 September 2013 (pre-implementation) and between 1 July 2014 and 30 September 2014 (post-implementation). Symptomatic patients treated for UTI within 24 h with an identified pathogen were included. Risk-based patient groups were community-acquired UTI, healthcare-associated UTI, or extended-spectrum ß-lactamase (ESBL) history in prior 12 months. Recommended antimicrobials were ceftriaxone, cefepime ± vancomycin, or doripenem ± vancomycin, respectively. Given the low post-implementation guideline adherence, pre- and post-groups were combined to evaluate potential guideline value. Length of stay (LOS) decreased when guidelines were followed [5 (IQR 4-7) days vs. 6 (IQR 4-8) days; P = 0.03] or appropriate therapy (according to in vitro susceptibilities) was given [5 (IQR 4-7) days vs. 6 (IQR 4-9) days; P = 0.03]. Those receiving guideline-recommended antimicrobials were more likely to have appropriate therapy within 24 h (84.4% vs. 64.2%; P <0.001). On multivariate analysis, intensive care unit (ICU) admission and admission from home were associated with longer and shorter LOS, respectively. Despite less than anticipated adherence, these data suggest that the established disease state management guideline can improve outcomes in patients admitted with UTI.

Antibacterial activity of achievable epithelial lining fluid exposures of Amikacin Inhale with or without meropenem.

OBJECTIVES: While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of ∼ 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 ∼ 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 ∼ 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.

Epidemiology and economics of adult patients hospitalized with urinary tract infections.

BACKGROUND: Urinary tract infections (UTI) are among the most common bacterial diseases worldwide, with significant clinical and economic burden. Surveillance of pathogen epidemiology and risk factors for resistant pathogens in the hospital setting may improve the management of UTI. OBJECTIVE: To evaluate microbiology and antimicrobial susceptibility of UTI pathogens, with associated costs, in hospitalized patients. METHODS: Patients diagnosed with UTI between July and September 2013 were retrospectively screened for clinical symptoms and treatment within 24 hours of admission, then categorized into groups: community acquired (Group 1); recent healthcare exposure (Group 2); or a history of identification of an extended-spectrum beta lactamase (ESBL)-producing organism (Group 3). Clinical, epidemiological, and financial data were compared between groups. RESULTS: From 308 included patients, a total of 216 pathogens were identified. Escherichia coli was most commonly identified pathogen, but frequencies differed between groups (p = 0.002), as did those of ESBL-producing pathogens (p < 0.001) and Pseudomonas aeruginosa (p = 0.005). Appropriate empirical therapy also differed between groups (p = 0.003). Length of stay was longer for healthcare associated UTI with inappropriate empirical therapy (5.2 versus 6.3 days, p = 0.016). Increased cost was associated with factors other than antimicrobial costs. Intensive care unit (ICU) stay (p < 0.001), care facility at discharge (p = 0.001), Foley catheter (FC) present on admission (p = 0.002), and Charlson comorbidity index (CCI) (p = 0.017) predicted increased cost overall, while ICU stay (p < 0.001), time to appropriate therapy (p < 0.001), and CCI (p = 0.015) predicted higher cost in patients with pathogens identified. CONCLUSIONS: Changes in antimicrobial susceptibility are evident with exposure to healthcare, the presence of a FC, and a history of resistant pathogens. Risk-based empirical prescribing and rapid de-escalation may improve care and reduce costs.

Poor outcomes of empiric ceftriaxone ± azithromycin for community-acquired pneumonia caused by methicillin-susceptible Staphylococcus aureus.

While ceftriaxone 1 g q24h is commonly used for hospitalized patients with community-acquired pneumonia (CAP), the prescribing information recommends 2-4 g a day to treat methicillin-susceptible Staphylococcus aureus (MSSA). Similarly, recent pharmacodynamic analyses suggest shortcomings of 1 g q24h against the bulk of the MSSA. We evaluated the outcomes of empiric ceftriaxone 1 g q24h ± azithromycin in patients with MSSA pneumonia, as compared with Streptococcus pneumoniae. Adult patients admitted to Hartford Hospital from 1/2005 to 12/2014 with respiratory culture for MSSA or S. pneumoniae were considered for inclusion. Non-ICU, CAP patients were included. Early clinical failure (ECF) was defined as persistent signs/symptoms or change of antibiotic due to poor response at 72-96 h. A multivariate analysis was performed to evaluate predictors of ECF. Over the study period, 403 MSSA and 227 S. pneumoniae positive respiratory cultures were identified. The majority of patients were excluded due to the following: no signs/symptoms of pneumonia, hospital-acquired pneumonia, alternative antibiotics, and polymicrobial infection. Thirty-nine patients met inclusion/exclusion criteria. All but three patients in the S. pneumoniae group received ceftriaxone + azithromycin. ECF was greater in the MSSA group (53 vs. 4 %, P = 0.003), as was length of stay (7.5 ± 5.4 vs. 4.6 ± 3.3 days, P = 0.006). When controlling for disease severity and macrolide non-susceptibility in a multivariate analysis, MSSA was significantly correlated with ECF (OR 12.3, 95 % CI 0.8-188.8). Poor clinical outcomes were observed in patients empirically treated with ceftriaxone ± azithromycin for MSSA CAP. Despite the popularity of ceftriaxone 1 g q24h, these data suggest this dose or compound may be inadequate for CAP caused by MSSA.

Defining Extended Spectrum ß-Lactamases: Implications of Minimum Inhibitory Concentration-Based Screening Versus Clavulanate Confirmation Testing.

INTRODUCTION: While the Clinical and Laboratory Standards Institute (CLSI) recommends against routine screening for extended spectrum ß-lactamases (ESBLs), knowledge of these data can provide valuable insights regarding epidemiology and drug therapy decisions. The purpose of this study was to compare the impact of minimum inhibitory concentration (MIC)-based screening versus phenotypic confirmatory testing of ESBLs on the susceptibility profile of selected antimicrobials. METHODS: Broth microdilution MICs were determined for various antimicrobial agents against a collection contemporary clinical Escherichia coli and Klebsiella pneumoniae isolates. Isolates identified as ESBL-positive by MIC screening were then subjected to confirmatory phenotypic testing. Percent susceptibility was based on CLSI or United States Food and Drug Administration breakpoints. RESULTS: Four-hundred and forty-two (18%) isolates screened positive for ESBL production. Of these, 274 (62%) were confirmed positive for ESBL production; 28 (10%) were also carbapenem non-susceptible. We found an under-prediction of activity for ceftolozane/tazobactam (C/T), ertapenem (ETP), meropenem (MEM), and piperacillin/tazobactam (TZP) when considering only the screen-positive testing. CONCLUSION: For agents with potential activity against ESBLs such as C/T, TZP, ETP, and MEM, reduced susceptibility was noted when only considering the MIC screen-positive test. Although phenotypic screening selects for resistant organisms, inclusion of other genotypes besides ESBL (i.e., AmpC, carbapenemase) may falsely under-predict the potency against some ESBL producers and may limit applicability of surveillance data to geographic areas not plagued with carbapenemase producers. FUNDING: Cubist Pharmaceuticals.

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy.

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.

Efficacy of humanized high-dose meropenem, cefepime, and levofloxacin against Enterobacteriaceae isolates producing Verona integron-encoded metallo-ß-lactamase (VIM) in a murine thigh infection model.

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.

In Vitro Activity of Cefepime/AAI101 and Comparators against Cefepime Non-susceptible Enterobacteriaceae.

We evaluated the in vitro potency of cefepime combined with AAI101, a novel extended-spectrum ß-lactamase inhibitor, against a population of clinical Escherichia coli and Klebsiella pneumoniae collected from USA hospitals. Of the 223 cefepime non-susceptible isolates, 95% were ceftazidime non-susceptible, 49% ertapenem non-susceptible, 57% piperacillin/tazobactam non-susceptible, 90% were multidrug-resistant (resistant to ≥3 drug classes), 22% produced carbapenemases, and 67% produced ESBLs. Addition of AAI101 restored the activity of cefepime such that the MIC50 was reduced from >64 mg/L for cefepime to 0.13 mg/L for cefepime/AAI101, supporting its continued development treatment for infections caused by these organisms.

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.

Pharmacodynamic Profile of GSK2140944 against Methicillin-Resistant Staphylococcus aureus in a Murine Lung Infection Model.

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.

Effects of Urine Matrix and pH on the Potency of Delafloxacin and Ciprofloxacin against Urogenic Escherichia coli and Klebsiella pneumoniae.

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.

In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae.

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.

Potentiation of antibacterial activity of the MB-1 siderophore-monobactam conjugate using an efflux pump inhibitor.

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.