Doripenem Research Articles

Stability-indicating HPLC method optimization using quality by design with design of experiments approach for quantitative estimation of organic related impurities of Doripenem in pharmaceutical formulations

Doripenem (DM), an antibiotic used for kidney, lung, and urinary infections, underwent the development of a robust high-performance liquid chromatography (HPLC) technique using the quality-by-design approach. This method, integrating design-of-experiments, detected organic impurities in both drug substances and formulated products. Operating with a C18 analytical column in a binary gradient mode with potassium phosphate buffer (pH 6.1) and acetonitrile as mobile phases, the method ran at a flow rate of 1.20 ml/minutes, with an injection volume of 20-μl and a column temperature of 45°C. Stability testing under various conditions, including hydrolysis, oxidation, heat, humidity, and light exposure, confirmed the method’s reliability without interference. Validation studies, compliant with ICH guidelines, revealed quantitation limits of 0.006%, linearity between 0.060 and 1.800 μg/ml (R2 > 0.999), and recoveries ranging from 96.8% to 99.1%. This HPLC method was effectively used for stability assessment in quality control testing, assessing doripenemic acid, doripenem assay, and organic impurities.

Novel insights on the adsorption ability of bentonite and its chitosan composite: Deep understanding of antibiotics removal as hazardous agents

Due to the inappropriate wastewater discharge, antibiotic contamination in the environment has caused significant public health issues and local ecosystem disruption. Given its benefits, which include low cost and a large variety of efficient adsorbents, the adsorption process represents a favorable way to reduce antibiotic contamination. This work theoretically investigated the adsorption of amoxicillin (AMO), ampicillin (AMP), and doripenem (DOR) onto raw bentonite (B) and its composite with chitosan (BC). Simulation studies using molecular dynamics were carried out to comprehend the interactions between these antibiotics and B and BC adsorbents between 30 and 50 °C, of which the interaction energies of −59.999, −59.279, and −66.877 kcal mol−1 were obtained for AMO/B, AMP/B, and DOR/B systems, respectively. Statistical physics models, i.e., the Gaussian Monolayer Multisite Model (GMMM) and Monolayer Model Coupled to Real Gas (MMRG) were also used to fit the experimental data with good results (R2>0.999). The findings indicated that the interactions between the chosen antibiotics and the adsorbents were mostly take place by Van der Waals forces (Non-bond energies of −20.442, −20.403, and −20.884 kcal mol−1 for AMO/B, AMP/B, and DOR/B systems, respectively), with multi-molecular (1 < n < 2.5) antibiotic adsorptions occurring primarily on both bentonite and BC.

Efficacy of Novel Combinations of Antibiotics against Multidrug-Resistant-New Delhi Metallo-Beta-Lactamase-Producing Strains of Enterobacterales.

The emergence of multidrug-resistance (MDR)-New Delhi metallo-beta-lactamase (NDM)-producing microorganisms-has become a serious concern for treating such infections. Therefore, we investigated the effective antimicrobial combinations against multidrug-resistant New Delhi metallo-beta-lactamase-producing strains of Enterobacterales. The tests were carried out using the 2D(two-dimensional) checkerboard method. Of 7 antimicrobials, i.e., doripenem (DRP), streptomycin (STR), cefoxitin (FOX), imipenem (IPM), cefotaxime (CTX), meropenem (MER), and gentamicin (GEN), 19 different combinations were used, and out of them, three combinations showed synergistic effects against 31 highly drug-resistant strains carrying blaNDM and other associated resistance markers. Changes in the minimum inhibitory concentration (MIC) values were interpreted using the test fractional inhibitory concentration index (FIC Index). The FIC Index values of these combinations were found in the range of 0.1562 to 0.5, which shows synergy, whereas no synergism was observed in the remaining antimicrobial combinations. We conclude that these antibiotic combinations can be analyzed in in vivo and pharmacological studies to establish an effective therapeutic approach.

QbD green analytical procedure for Novel study of a genotoxic and carcinogenic compound trace determination in physiological solution compatibility

Regulatory bodies more focusses on the safety and efficacy of the pharmaceuticals, through this work we want to express the necessary control of 5-Hydroxymethyl furfural (5-HMF) impurity level in intra-venous (IV) injections. Genotoxic and carcinogenic compound 5-HMF determination in IV injections was determined by using the simple, sensitive, green, and eco-friendly HPLC method. Box-Behnken Design (BBD) was utilized to optimize the final method conditions prior to method validation, resulting in 15 design of experiments (DOE) using critical method parameters (CMPS) and critical assumptions. The identification and quantification were done with Phenomenex prodigy C8 (150 × 4.6) mm, 5 μm column with a flow rate of 0.6 mL/min. The peak detection was done at 284 nm and with a total run time of 6 min. The mobile phase consists of 0.1 M potassium dihydrogen phosphate (PDP) pH 2.5 buffer and acetonitrile (ACN) in the ratio of 80:20 (v/v) used for the isocratic elution. The method was validated as per the current regulatory guidelines. The accuracy results from LOQ to 150% level were attained between 95.1% and 103.4%. The 5-HMF response is linear from LOQ to 150% with a correlation coefficient (r) > 0.999. The %coefficient of variation (CV) from method precision and intermediate precision (n = 6) results were found to be 1.67% and 3.45%, respectively. Trace analysis of 5-HMF was done in selected IV injections Pancuronium Bromide (PMB), Meropenem (MPM), Doripenem (DPM), and Cefotaxime (CTM) injections at different time points. The method greenness was evaluated by utilizing the Green analytical procedure index (GAPI), Analytical GREEness (AGREE), National environmental procedure index (NEMI), and analytical eco-scale and concluded that the method is green.

Risk evaluation of carbapenem-induced liver injury based on machine learning analysis

IntroductionInformation regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of liver injury. Thus, we aimed to compare the rate of liver injury between MEPM and DRPM and construct a flowchart that can be used to predict carbapenem-induced liver injury. MethodsWe investigated patients treated with MEPM (n = 310) or DRPM (n = 320) and confirmed liver injury as the primary outcome. We used a chi-square automatic interaction detection algorithm to construct DT models. The dependent variable was set as liver injury from a carbapenem (MEPM or DRPM), and factors including alanine aminotransferase (ALT), albumin-bilirubin (ALBI) score, and concomitant use of acetaminophen were used as explanatory variables. ResultsThe rates of liver injury were 22.9% (71/310) and 17.5% (56/320) in the MEPM and DRPM groups, respectively; no significant differences in the rate were observed (95% confidence interval: 0.710–1.017). Although the DT model of MEPM could not be constructed, DT analysis showed that the incidence of introducing DRPM in patients with ALT >22 IU/L and ALBI scores > −1.87 might be high-risk. ConclusionsThe risk of developing liver injury did not differ significantly between the MEPM and DRPM groups. Since ALT and ALBI score are evaluated in clinical settings, this DT model is convenient and potentially useful for medical staff in assessing liver injury before DRPM administration.

UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

786. Facility Reported vs. CLSI MIC Breakpoint Comparison of Carbapenem Non-susceptible (Carb-NS) Pseudomonas aeruginosa (PSA) From 2016-2019: A Multicenter Evaluation

BackgroundCLSI lowered Pseudomonas aeruginosa (PSA) Carbapenem (Carb) interpretive breakpoint minimum inhibitory concentrations (MICs) in 2012. It often takes several years for commercial test manufacturers and microbiology labs to incorporate revised breakpoints. We compare facility-reported rates of Carb-NS PSA to the 2012 CLSI MIC breakpoints, using a large nationwide database for isolates tested in 2016-2020 at United States (US) facilities.Table. Imipenem (IPM)/meropenem (MEM)/doripenem (DOR) interpretation (evaluable isolates) results for PSA. MethodsAll adults with a positive non-contaminant PSA culture (first isolate per 30-day period from blood, respiratory, urine, skin/wound, intra-abdominal, or other) in ambulatory and inpatient settings from 298 US hospitals from Q1 2016-Q4 2020 were evaluated (BD Insights Research Database, Becton, Dickinson & Company). Facility-reported Carb-non susceptible (NS) was defined as lab information system feed designations of susceptible (S), intermediate (I) or resistant (R) to imipenem (IPM), meropenem (MEM) and/or doripenem (DOR) per commercial panels. Where available, MICs were interpreted using CLSI 2012 Carb breakpoints (µg/ml) of ≤2 (S), 4 (I), ≥8 (R) for IPM/MEM/DOR. For evaluable PSA isolates we compared susceptibility results as reported by the facility to those using CLSI MIC breakpoints.ResultsOverall, 86.9% (255,844/294,426) of non-duplicate PSA isolates with facility-reported IPM/MEM/DOR susceptibility interpretations also had interpretable MIC results. S rates were 84.9% and 83.3% as reported by facilities and determined by CLSI criteria, respectively (Table). Facilities under-reported Carb-NS by 9.8%, using CLSI criteria as the standard (10.4% and 7.7% of R and I isolates, respectively, were missed by facility reporting).ConclusionSystematic application of CLSI breakpoints in 2016-20 would have had minimal impact on PSA S rates in the US. However, facility reporting failed to identify ~10% of Carb-NS isolates. The clinical implications of this observation are unknown. Facilities should know their local epidemiology, decide if under-reporting might be an issue, and assess if there is any impact on their patients. Disclosures Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder) Kalvin Yu, MD, BD (Employee) Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Cornelius J. Clancy, MD, Merck (Grant/Research Support)

642. Facility Reported vs. CLSI MIC Breakpoint Comparison of Carbapenem Non-susceptible (Carb-NS) Enterobacteriaceae (ENT) from 2016-2019: A Multicenter Evaluation

BackgroundCarbapenem (Carb) minimum inhibitory concentration (MIC) breakpoints were lowered by CLSI in 2010 and recognized by FDA in 2012. Adoption of revised breakpoints is often slow, which may lead to under-reporting of Carb non-susceptibility (NS) by facilities. We compare facility-reported rates of Carb-NS ENT to the CLSI MIC breakpoints for a large nationwide collection of isolates in the United States (US) from 2016-2019. MethodsAll adults with a positive non-contaminant ENT culture (first isolate of a species per 30-day period from blood, respiratory, urine, skin/wound, intra-abdominal, or other) in ambulatory/inpatient settings from up to 300 US hospitals from 2016-2019 were evaluated (BD Insights Research Database). Facility-reported Carb-NS was defined as: susceptible (S), intermediate (I) or R to ertapenem (ETP), imipenem (IPM), meropenem (MEM) and/or doripenem (DOR) per commercial panels. Where available, MICs were interpreted using CLSI 2010 MIC breakpoints (µg/ml): ≤ 0.5 (S), 1 (I), ≥ 2 (R) for ETP and ≤1 (S), 2 (I), and ≥ 4 (R) for IPM/MEM/DOR. For evaluable ENT isolates we compared susceptibility results as reported by the facility to CLSI MIC breakpoints.ResultsOverall, 77.4% (937,926/1,211,845) and 90.6% (2,157,785/2,381,824) non-duplicate ENT isolates with facility-reported susceptibility results also had interpretable MIC results for ETP and IPM/MEM/DOR, respectively (Tables). ETP S rates were 99.3% and 99.1% as reported by facilities and using CLSI criteria, respectively. S rates of other Carbs were 98.9% and 98.4% by facility reporting and CLSI criteria, respectively. Systematic application of CLSI breakpoints under-reported EPT-I and –R isolates by 24.2% and 16.4%, respectively, and identification of IPM/MEM/DOR-I and –R isolates by 31.3% and 22.7%, respectively.ConclusionSystematic application of CLSI breakpoints in 2016-19 would have had minimal impact on ENT S rates in the US. However, facility reporting failed to identify 18.8% of ETP I or R and 26.5% of IPM/MEM/DOR I or R isolates. The clinical implications of this observation are unknown. Facilities should know their local epidemiology, decide if under-reporting might be an issue, and assess if there is any impact on their patients.Disclosures Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder) Kalvin Yu, MD, BD (Employee) Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Cornelius J. Clancy, MD, Merck (Grant/Research Support)

1578. Treatments for complicated urinary tract infections (cUTI) caused by multidrug resistant (MDR) Gram-negative (GN) pathogens- a systematic review and network meta-analysis (NMA)

BackgroundAntimicrobial resistance is a major and growing threat to global public health. Cefiderocol (CFDC) is a new siderophore-cephalosporin with a wide activity spectrum covering all aerobic GN pathogens including all WHO critical priority pathogens, that was recently approved by FDA for the treatment of GN cUTI in susceptible organisms. We aim to understand the relative efficacy and safety of current treatment options for cUTI caused by MDR GN pathogens.MethodsWe conducted a systematic review to identify all relevant trials that investigated the efficacy and safety of antimicrobial regimens, for the treatment of GN pathogens in cUTI. Outcomes of interest included clinical cure and microbiological eradication (ME) at time of cure (TOC) and sustained follow up (SFU), and safety. Evidence networks were constructed using data for outcomes of interest and analyses were conducted in a frequentist framework using NMA methods outlined by the NICE decision support unit using the netmeta package in R.ResultsA total of 5 studies, 6 interventions and 2,349 randomised patients were included in the final analysis. Interventions included CFDC, imipenem-cilastatin (IPM-CIL), ceftazidime-avibactam (CAZ/AVI), doripenem (DOR), levofloxacin and ceftolozane-tazobactam (CEF/TAZ). Trials included predominantly Enterobacterales, and Pseudomonas aeruginosa and very few Acinetobacter baumannii. The patient population presented some clinical differences across trials, which were not adjusted for the NMA. Overall, there were numerical differences (especially in endpoints at SFU favouring CFDC), but all treatments showed similar efficacy and safety, with exception of higher ME rate at TOC for CFDC vs IPM, Table 1, also observed at SFU, consistent with the data from the individual clinical trial.Table 1- Results for microbiological eradicationTable 1- Results for microbiological eradication ConclusionThis NMA, showed superiority of CFDC vs IPM-CIL in ME at TOC and SFU and similar efficacy and safety vs all other comparators, with numeric differences favouring CFDC for outcomes at SFU. These traditional methodologies for NMA, are only valid within a similar pathogens pool and population across the trials, and may not reflect the full value of breadth of coverage that new therapeutic options bring for the treatment of MDR GN pathogens.DisclosuresTim Reason, PhD, Shionogi (Consultant) Karan Gill, MSc, Shionogi BV (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Rachael McCool, PhD, York Health Economics Consortium (Employee, YHEC was commissioned by Shionogi to conduct the systematic review) Katy Wilson, PhD, York Health Economics Consortium (Employee, Shionogi commissioned YHEC to conduct the systematic review) Sara Lopes, PharmD, Shionogi BV (Employee)

Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h−1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h−1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

Ertapenem and Faropenem against Mycobacterium tuberculosis: in vitro testing and comparison by macro and microdilution

BackgroundInterest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB).The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution.Results19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC.MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition.18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates.10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 μg/mL).Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status.ConclusionsThe lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation.No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging.This work highlighted some of the limitations of carbapenem use. More evidence is needed to clarify their true impact in TB treatment and outcome, considering the financial burden, complications and microbiota changes associated with their use.

In-vitro Activity of Ceftolozane-Tazobactam in Combination with Various Antibiotics Against Multidrug-resistant Acinetobacter baumannii Isolated from Intensive Care Patients

Acinetobacter species lead to nosocomial infections in immunocompromised patients hospitalized in intensive care units or services. Acinetobacter baumannii is a bacterium that is difficult to treat because it is intrinsically resistant to many antibiotics and can develop resistance afterwards. This situation limits the use of existing antibiotics and directs the clinician to new agents, different treatment options and the use of various antibiotic combinations. The aim of this study was to determine the sensitivities of doripenem (DOR), tigecycline (TGC), minocycline (MIN), amikacin (AK) and a newly developed agent ceftolozane-tazobactam (CT) in multidrug resistant A.baumannii strains which were isolated from inpatients in intensive care units and to investigate the in vitro interactions of CT/DOR, CT/TGC, CT/MIN and CT/AK combinations by using antibiotic gradient test method. Thirty-five A.baumannii strains isolated from various clinical specimens (blood, urine, sputum, tracheal aspirate, wound, abscess and catheter) between January 2017 and July 2017 were included in the study. Strains isolated from inpatients in intensive care units and resistant to at least three antibiotic classes were selected. The identification of A.baumannii isolates and the determination of routine antibiotic susceptibility profile were performed according to EUCAST 2017 criteria by the use of BD Phoenix 100 (Becton Dickinson, USA) automated system. Minimum inhibitor concentration values of CT, DOR, TGC, MIN, AK and combinations of CT with four other antibiotics (CT/DOR, CT/TGC, CT/MIN and CT/AK) were determined by antibiotic gradient test method. Fractional inhibitor concentration index (FICI) was used to determine the interactions of the combinations in vitro. According to the data obtained; the FICI was evaluated as synergy if FICI ≤ 0.5, additive if 0.5 > FICI ≤ 1, indifferent (unidentified interaction) if 1 <FICI <2 and antagonist interaction if FICI ≥ 2. According to FICI results of the antibiotic combinations, the highest synergistic interaction was observed between CT/TGC as 11.4%. No synergistic interaction was observed between CT/DOR antibiotics. The highest additive interaction rates were between CT/AK (60%) and CT/MIN (45.7%), while no additive interaction between CT/DOR was observed. Antagonist interaction was observed in CT/DOR (71.4%) combination only. In conclusion, in our study it was observed that CT, a novel beta-lactam/ beta-lactamase inhibitor, did not sufficiently affect A.baumannii isolates, but was able to induce synergistic interaction in combination with TGC, AK and MIN. CT should be carefully monitored in clinical use because of the antagonist interaction detected with DOR.

Highly sensitive cadmium sulphide quantum dots as a fluorescent probe for estimation of doripenem in real human plasma: application to pharmacokinetic study.

Thioglycolic acid-capped cadmium sulphide quantum dots (TGA-CdS QDs) have been synthesized and utilized as a fluorescent probe for the estimation of doripenem (DOR). Monitoring of DOR in different biological fluids is required to estimate the efficient dose to avoid bacterial infections and resistance. The investigated method is based on the measurement of fluorescence quenching of TGA-CdS QDs after the addition of DOR. The synthesized TGA-CdS QDs were characterized using transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRD) and ZETA sizer. The TGA-CdS QDs showed unique photophysical properties with high quantum yield (0.32) using a comparison method with rhodamine B. Different experimental parameters affecting the synthesis process of the TGA-CdS QDs and their behavior with the studied drug DOR were examined and optimized. The values of the fluorescence quenching were linearly correlated to DOR concentration over the range of 10–500 ng mL−1 with a good correlation coefficient of 0.9991. The proposed method showed higher sensitivity over several reported methods, with LOD reaching 2.0 ng mL−1. The method was effectively applied for the estimation of DOR in human plasma and urine with good recovery results ranged from 95.16% to 99.51%. Furthermore, the stability of DOR in the human plasma was studied and a pharmacokinetic study of DOR in real human plasma was conducted.

Carbapenems vs alternative antibiotics for the treatment of complicated urinary tract infection: A systematic review and network meta-analysis.

Complicated urinary tract infections (cUTI) are universal reasons for hospitalization, and highly likely to develop into sepsis or septic shock. Carbapenem antibiotics with potentially higher efficacy or with fewer and milder side effects have increased in popularity, but evidence is limited by a scarcity of randomized controlled trials (RCTs) comparing different carbapenem antibiotics for cUTI. Network meta-analysis is a useful tool to compare multiple treatments when there is limited or no direct evidence available. The aim of this study is to compare the efficacy and safety of different carbapenems with alternative antibiotics for the treatment of cUTI. Pubmed, Medline, CENTRAL, and Embase were searched in November 2018. Studies of cUTI patients receiving carbapenem were included. We performed network meta-analysis to estimate the risk ratio (RR) and 95% credible interval (CrI) from both direct and indirect evidence; traditional meta-analysis was also performed. Primary outcomes were clinical and microbiological treatment success. A total of 19 studies and 7380 patients were included in the analysis. Doripenem (DOPM) was associated with lower clinical treatment success rates than other carbapenems. Although the efficacy of other carbapenems by RRs with 95% CrIs did not show statistical differences, the cumulative rank probability indicated that meropenem/vaborbactam (MV), ertapenem (ETPM), and biapenem (BAPM) had higher clinical and microbiological treatment success rates; imipenem/cilastatin (IC) and MV showed higher risk of adverse events (AEs). MV was associated with higher treatment success rates for cUTI, especially for cUTI caused by carbapenem-resistant uropathogens, but also with higher risk of AEs. Our findings suggest MV as a first-choice treatment of carbapenem-resistant cUTI. ETPM, BAPM, and meropenem (MEPM) is another reasonable choice for cUTI empiric therapy.

Doripenem Versus Meropenem As the First-Line Mono-Therapy in High-Risk Febrile Neutropenic Patients with Acute Leukemia: A Randomized, Controlled Trial

BACKGROUND: Febrile neutropenia (FN) is often observed in patients with hematological malignancies (HEM), especially in those with acute leukemia (AL). Monotherapy with antipseudomonal beta-lactams, such as cefepime, carbapenem, or piperacillin-tazobactam, is recommended as first-line empiric antibacterial therapy in FN patients. The efficacy of meropenem (MEPM) as empiric monotherapy for FN patients with cancer has been assessed in randomized comparative trial against cefepime, imipenem/cilastain, ceftazidime with or without amikacin, and piperacillin-tazobactom. Because of those studies, MEPM is considered a standard antibiotic for the empiric treatment of FN patients with HEM.In contrast, doripenem (DRPM) is a relatively new carbapenem, and the clinical study about efficacy and safety of DRPM in FN patients with HEM is limited. Therefore, we conducted a randomized, cooperative group, open-label trial comparing DRPM (1.0 g every 8 hours) with MEPM (1.0 g every 8 hours) as the first-line empirical antibacterial therapy for high-risk FN patients with AL and myelodysplastic syndrome (MDS). METHODS: One hundred and thirty-three hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed high-risk FN during or after chemotherapy (AML 77, ALL 43, APL 9, ATL 1, MDS (RAEB-2) 3cases) were randomized to each drug group (DRPM, 65; MEPM, 68). The study drug was started to administer as a mono-therapy and continued at least for 5 days without drug toxicity, and the efficacy and safety were evaluated. RESULTS: The success rate (Resolution of fever within 3 to 5 days without treatment modification: the primary endpoint) was higher in the DRPM group than in the MEPM group (60.0% vs. 45.6%), although the difference was not significant (P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the DRPM group than in the MEPM group (78.4% vs. 60.2%, respectively, P = 0.037). Otherwise, the cumulative number of afebrile cases by day14 was 87.7% and 83.8% in the DRPM and MEPM group, respectively (P = 0.523). The success rate did not depend on neutrophil recovery: success rates for the DRPM group were 58.3% and 60.9%, with and without neutrophil recovery, respectively; success rates for the MEPM group were 33.3% and 40.9%, with and without neutrophil recovery, respectively (P = 0.233, P = 0.346). In all, 40.0% of the DRPM group and 32.3% of the MEPM group received anti-MRSA agent, as empiric or targeted antibacterial therapy of persistent or recurrent fever considering of infections by gram-positive bacteria, including methicillin-resistant species. Antifungal medications were added to 21.5% of the DRPM group and 13.2% of the MEPM group, as empiric or preemptive therapy of persistent or recurrent fevers believed to be caused by fungal infections. Survival rates at 30 days after the start of administration were 98.5% and 100% in the DRPM and MEPM group, respectively (P = 0.304). The rates of adverse events did not significantly differ between the DRPM and MEPM group (38.5% vs. 41.2%, respectively, P = 0.749), and these adverse events were clinically acceptable in the two groups, and most of patients could continue the treatment by both study drugs. CONCLUSIONS: Our clinical study suggested that DRPM had the non-inferiority of efficacy in comparison with MEPM as the first-line therapy in high-risk FN patients with AL and MDS, and both drugs could be well tolerated clinically. Disclosures Oyake: Kyowa-Hakko Kirin: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Astellas: Speakers Bureau. Hanamura:Sanofi: Research Funding; Taiho: Research Funding; MSD: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Fujimoto: Research Funding; Zenyaku: Research Funding; Yamada Yohojo: Research Funding; Chugai: Research Funding; Astellas: Research Funding; Shionogi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Mundi: Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ito:Bristol-Myers Squibb: Honoraria; Ono: Honoraria; Celgene: Honoraria.

1485. Trends in Important-Resistant Gram-Negative (GN) and Gram-Positive (GP) Urine Bacterial Pathogens in Hospitalized Patients in the United States: A Multicenter Evaluation from 2013 to 2018

BackgroundThe US CDC has identified a number of antibiotic-resistant (AR) bacteria as urgent or serious public health threats. This study sought to quantify the prevalence and incidence of extended-spectrum β-lactamase (ESBL) Enterobacteriaceae (ENT), Carbapenem-resistant ENT (CRE), P. aeruginosa (Carb NS-PsA), vancomycin-resistant enterococci (VRE), and methicillin-resistant S. aureus (MRSA) in the urine of adult hospitalized patients.MethodsAll hospitalized adult patients with a positive urine culture (first urine isolate of a species per 30-day period) were evaluated from over 400 US hospitals (2013–2018; BD Insights Research Database, Becton, Dickinson and Company). The following five groups of AR bacteria were examined: (1) ESBL ENT if ESBL-positive per commercial panels or intermediate/resistant (non-susceptible [NS]) to a third-generation cephalosporin; (2) CRE ENT if NS to imipenem (IPM), meropenem (MEM), doripenem (DOR) or ertapenem; (3) Carb-NS PsA if NS to IPM, MEM or DOR; (4) VRE if resistant to vancomycin; and (5) MRSA as resistant to methicillin/oxacillin. For each AR grouping, % NS and rates of NS per 100 admissions were calculated and trends were examined using Logistic regression and Poisson models.ResultsAcross the 6-year study period, there were 24,558,856 admissions, accounting for 2,285,971 non-duplicate urine isolates; 1,016,642 were ENT, 87,450 were PSA, 203,231 were enterococci, and 41,979 were S. aureus. The % of NS for ESBL, CRE ENT, Carb-NS PsA, VRE, and MRSA were 12%, 0.9%, 13%, 19%, and 55%, respectively. The % of NS for ESBL increased from 2013 to 2018 (P < 0.001) whereas % NS for PsA and % MRSA decreased during the same time period (P < 0.001) (Figure 1). The rates of NS per 100 admissions for ESBL, CRE ENT, Carb-NS PsA, VRE, and MRSA were 0.44, 0.04, 0.05, 0.16, and 0.09, respectively. The annual NS rates per 100 admission trends for ESBL and CRE ENT were increasing (all P < 0.0001) while the trends for Carb-NS PsA, VRE, and MRSA were decreasing (all P < 0.0001).ConclusionWhile the percent of ESBL, CRE ENT, Carb-NS PsA, VRE, and MRSA have remained relatively constant over the past 6 years, there has been a notable increase in the rates of ESBL and CRE ENT per 100 admissions among adult hospitalized patients with positive urine cultures. Disclosures All authors: No reported disclosures.

In vitro and in vivo assessment of the antibacterial activity of colistin alone and in combination with other antibiotics against Acinetobacter baumannii and Escherichia coli.

Limited therapeutic options exist for treating severe infections caused by multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria (GNB). In this study, the activity of colistin (COL) as monotherapy and in combination with other antibiotics against Acinetobacter baumannii in vitro was investigated. In addition, the efficacy of intravenous colistimethate sodium (CMS) was evaluated in a murine model of urinary tract infection (UTI) induced by MDR Escherichia coli. Minimum inhibitory concentration (MIC), Monte Carlo simulation, fractional inhibitory concentration index (FICI), time-kill study and erythrocyte lysis assay were applied to evaluate the effect and cytotoxicity of COL, meropenem, imipenem, doripenem (DOR) and sulbactam alone and in combination. For the in vivo experiment, determination of the bacterial burden and histopathological examination were performed to evaluate the efficacy of CMS against UTI. Of 106 A. baumannii isolates, 104 (98.1%) were susceptible to COL. In the chequerboard assay, COL + DOR showed the highest rate of synergism (60%). No antagonism or cytotoxicity was observed. All COL-based combinations were able to inhibit or slow bacterial re-growth in a time-kill assay. In an in vivo activity study, intravenous CMS reduced not only the bacterial load but also inflammation and maintained structural integrity of infected bladders and kidneys. The effectiveness of COL alone in vitro and in vivo suggested that intravenous CMS will be an effective and available therapeutic strategy for UTI due to MDR-GNB. In-depth in vitro tests demonstrated that COL + DOR could be an attractive option, especially when the COL MIC is ≥1 μg/mL.

In Vitro Activities of Ceftaroline/Avibactam, Ceftazidime/Avibactam, and Other Comparators Against Pathogens From Various Complicated Infections in China.

We conducted a national antimicrobial surveillance study of both gram-positive and gram-negative organisms isolated from hospitalized patients. This report presents data on antimicrobial susceptibility among 4998 organisms collected in China between 2012 and 2014. The minimum inhibitory concentrations (MICs) and susceptibilities of ceftaroline/avibactam (CPA), ceftazidime/avibactam (CZA) and a range of comparative agents were determined according to guidelines established by the Clinical and Laboratory Standards Institute (CLSI). The highest overall susceptibility levels for all Enterobacteriaceae during the study period were observed for CPA, CZA, doripenem (DOR), meropenem (MEM), and amikacin (AMK), which were all >90%. However, both CPT and CAZ alone and in combination with avibactam showed low activities for Acinetobacter spp., whereas CPA and CZA exhibited MIC90 values for Pseudomonas aeruginosa that were reduced by 4- and 8-fold, respectively, compared with those of CPT and CAZ. High susceptibilities of Acinetobacter spp. and P. aeruginosa to colistin and P. aeruginosa to AMK were observed. For the gram-positive strains, no significant activity changes were seen for Enterococcus, Staphylococcus, and viridans group streptococci to CPT or CAZ alone or in combination with avibactam, whereas Streptococcus pneumoniae and β-hemolytic Streptococcus showed almost 100% susceptibility to both CPT and CPA. The addition of 4 mg/L avibactam greatly increased the activities of CPT and CAZ against most Enterobacteriaceae and P. aeruginosa isolates, whereas no significant changes were observed in Acinetobacter spp. or any of the gram-positive strains.

Effect of sodium mercaptoacetic acid on different antimicrobial disks in the sodium mercaptoacetic acid double disk synergy test for detection of IMP-1 metallo-β-lactamase-producing Pseudomonas aeruginosa isolates in Japan

We determined the optimal antimicrobial in the sodium mercaptoacetic acid double disk synergy test (SMA-DDST) for the detection of IMP-1-producing Pseudomonas aeruginosa isolates in Japan and evaluated the performance of the test. Fifty-four P.aeruginosa clinical isolates were tested, including 39 IMP-1 producers and 15 non-metallo-β-lactamase (MBL)-producing carbapenem- and ceftazidime (CAZ)-resistant isolates. The SMA-DDST was performed with CAZ, cefepime (CFPM), imipenem (IPM), meropenem (MEPM), doripenem (DRPM), or biapenem (BIPM)-containing disks. The sensitivity of the SMA-DDST with CAZ, CFPM, IPM, MEPM, DRPM, and BIPM was 39/39 (100%), 36/39 (92%), 18/39 (46%), 8/39 (21%), 19/39 (49%), and 36/39 (92%), respectively. The specificity was 15/15 (100%) for all SMA-DDSTs. This suggests that the isolates may have a resistance mechanism other than MBL production for IPM, MEPM, or DRPM. Since the CAZ resistance mechanism in P.aeruginosa is the same as that of CFPM, but differs from that of carbapenems, we conclude that combining CAZ with BIPM SMA-DDSTs can prevent any failure in the detection of IMP-1-producing P.aeruginosa.

Investigation of genotoxic effects of doripenem using cytogenetic and molecular methods.

The main aim of this study was to investigate the genotoxic effects of doripenem (DRP) using both cytogenetic and molecular test systems. Although there have been some studies reporting the effects of DRP, none of them has shown the genotoxic effects of DRP. In order to achieve the main aim of the study, the human peripheral lymphocytes were treated with 100 μg/ml, 200 μg/ml, and 400 μg/ml concentrations of DRP for 24 and 48 hours, and the chromosome aberration (CA) and micronucleus (MN) methods were used as the cytogenetic tests and RAPD-PCR method was used as the molecular test to determine the genotoxic effects of DRP. DRP did not induce the chromosome aberrations and micronucleus frequencies at all concentrations and at all treatment periods. So, it was concluded that DRP did not show any cytotoxic effect. However, DRP increased the number of polymorphic bands and decreased the ratio of genomic template stability, especially at the 48-hour treatment period. In this study, according to the obtained results, it was determined that DRP failed to show any genotoxic risk at the therapeutic doses. This result also indicates that DRP could be a reliable antibiotics according to its rapid metabolism.