Nationwide genome surveillance of carbapenem-resistant Pseudomonas aeruginosa in Japan.

Japan is a country with an approximate 10% prevalence rate of carbapenem-resistant Pseudomonas aeruginosa (CRPA). Currently, a comprehensive overview of the genotype and phenotype patterns of CRPA in Japan is lacking. Herein, we conducted genome sequencing and quantitative antimicrobial susceptibility testing for 382 meropenem-resistant CRPA isolates that were collected from 78 hospitals across Japan from 2019 to 2020. CRPA exhibited susceptibility rates of 52.9%, 26.4%, and 88.0% against piperacillin-tazobactam, ciprofloxacin, and amikacin, respectively, whereas 27.7% of CRPA isolates was classified as difficult-to-treat resistance P. aeruginosa. Of the 148 sequence types detected, ST274 (9.7%) was predominant, followed by ST235 (7.6%). The proportion of urine isolates in ST235 was higher than that in other STs (P = 0.0056, χ2 test). Only 4.1% of CRPA isolates carried the carbapenemase genes: blaGES (2) and blaIMP (13). One ST235 isolate carried the novel blaIMP variant blaIMP-98 in the chromosome. Regarding chromosomal mutations, 87.1% of CRPA isolates possessed inactivating or other resistance mutations in oprD, and 28.8% showed mutations in the regulatory genes (mexR, nalC, and nalD) for the MexAB-OprM efflux pump. Additionally, 4.7% of CRPA isolates carried a resistance mutation in the PBP3-encoding gene ftsI. The findings from this study and other surveillance studies collectively demonstrate that CRPA exhibits marked genetic diversity and that its multidrug resistance in Japan is less prevailed than in other regions. This study contributes a valuable data set that addresses a gap in genotype/phenotype information regarding CRPA in the Asia-Pacific region, where the epidemiological background markedly differs between regions.

Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Risk and Time-to-Onset of Acute Kidney Injury With Vancomycin Plus Piperacillin-tazobactam Combination: Analysis Using JADER.

BACKGROUND/AIM: Pharmacovigilance data and clinical studies have indicated a risk of acute kidney injury (AKI) associated with concomitant administration of vancomycin and piperacillin-tazobactam. However, no pharmacovigilance studies have evaluated time-to-onset and outcomes of AKI related to this combination. Therefore, this study used a pharmacovigilance database to investigate the incidence, time-to-onset, and outcomes of AKI in patients treated with intravenous vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics. PATIENTS AND METHODS: From data in the Japanese Adverse Drug Event Report (JADER) database, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs), time-to-onset, and outcomes of AKI following intravenous administration of vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics and with other vancomycin regimens, including monotherapy. RESULTS: The JADER database contained 4,471 reports of intravenous vancomycin treatment, including 517 reports of AKI. The adjusted RORs (95%CIs) of AKI in cases with co-administration of intravenous vancomycin and piperacillin-tazobactam was 2.58 (2.06-3.24). The median time-to-onset for AKI in vancomycin plus piperacillin-tazobactam was 6.0 (interquartile range=3.0-10.3). Weibull shape parameter analysis showed that the pattern of onset of AKI in vancomycin plus piperacillin-tazobactam represented a wear out failure, predicting an increasing hazard with time. For the outcome of AKI, there was no significant difference between all vancomycin regimen and the piperacillin-tazobactam combination groups. CONCLUSION: Concomitant use of intravenous vancomycin and piperacillin-tazobactam may increase the incidence of AKI but may not affect the outcome. This combination does not necessarily have to be avoided, but long-term use is not advisable.

Refractory pneumonia caused by Prevotella heparinolytica: a case report.

BACKGROUND: Prevotella heparinolytica is a Gram-negative bacterium that is commonly found in the oral, intestinal, and urinary tracts. It has been extensively studied in lower respiratory tract infections in horses, which has heparinolytic activity and can secrete heparinase and further induces virulence factors in cells and causes disease. However, no such cases have been reported in humans. CASE PRESENTATION: A 58-year-old male patient from China presented to the respiratory clinic in Suzhou with a productive cough producing white sputum for 20 days and fever for 3 days. Prior to this visit, a chest computed tomography scan was conducted, which revealed multiple patchy nodular opacities in both lungs. On admission, the patient presented with a temperature of 38.1 °C and a pulse rate of 110 beats per minute. Despite routine anti-infective treatment with moxifloxacin, his temperature fluctuated and the treatment was ineffective. The patient was diagnosed with Prevotella heparinolytica infection through metagenomic next-generation sequencing. Therefore, the antibiotics were switched to piperacillin-tazobactam in combination with ornidazole, which alleviated his symptoms; 1 week after discharge, the patient returned to the clinic for a follow-up chest computed tomography, and the opacities on the lungs continued to be absorbed. CONCLUSION: Prevotella heparinolytica is an opportunistic pathogen. However, it has not been reported in human pneumonia. In refractory pneumonia, measures such as metagenomic next-generation sequencing can be used to identify pathogens and help guide antibiotic selection and early support.

Meropenem versus piperacillin-tazobactam for the treatment of pancreatic necrosis.

PURPOSE: To date, there are three published guidelines discussing management of infected pancreatic necrosis (IPN) with conflicting recommendations. Specifically, The World Society of Emergency Surgery lists piperacillin-tazobactam as a treatment option in addition to meropenem and ciprofloxacin plus metronidazole. Piperacillin-tazobactam may serve as an effective carbapenem-sparing alternative. Although previous studies shed light on antimicrobial penetration data, there is a lack of clinical data comparing piperacillin-tazobactam to meropenem. The purpose of this study is to compare the efficacy of meropenem and piperacillin-tazobactam for the treatment of IPN. METHODS: This was a multicenter, retrospective cohort study conducted across three institutions. Patients with IPN who received either meropenem or piperacillin-tazobactam from January 2015 to December 2020 were included. The primary composite outcome was the incidence of 90-day clinical failure, which encompassed 90-day all-cause mortality and 90-day intra-abdominal infection recurrence. Secondary outcomes included length of hospital stay, antimicrobial duration of therapy, and the need for surgical intervention. RESULTS: We identified 229 patients with IPN that received either meropenem or piperacillin-tazobactam during hospital admission. After screening, 63 patients were included in the study. Incidence of 90-day clinical failure was observed in 33 % of the meropenem group and 50 % in the piperacillin-tazobactam group (OR, 1.98; 95 % CI 0.57 to 7.01, p = 0.259). The meropenem group had a lower incidence of 90-day infection recurrence in the piperacillin-tazobactam group (56 % vs 29 %, p = 0.047). CONCLUSIONS: Piperacillin-tazobactam may be an efficacious carbapenem-sparing treatment alternative for infected pancreatic necrosis.

Towards optimizing cefepime/tazobactam (WCK 4282) exposure to achieve efficacy against piperacillin/tazobactam-resistant ESBL infections: dose recommendations for various renal functions, including intermittent haemodialysis, in healthy individuals.

OBJECTIVES: WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. METHODS: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination. RESULTS: We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required. CONCLUSIONS: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L.

Frequency of drug-resistant bacterial isolates among pregnant women with UTI in maternity and children's hospital, Bisha, Saudi Arabia.

Urinary tract infections (UTIs) are one of the most prevalent bacterial infections affecting humans, with a higher incidence among women. Pregnant women are at an increased risk of developing UTIs, which can have detrimental consequences for both the mother and fetus. UTIs can be caused by various bacteria, and the prevalence of drug-resistant UTIs in maternity and children's hospitals is a cause for concern due to the potential for severe complications if left untreated. The primary objective of the current study was to determine the distribution of UTI-causing bacteria and investigate the antibiotic sensitivity patterns of isolated cultures obtained from pregnant women with UTIs at the Maternity and Children's Hospital, Bisha, Saudi Arabia. This cross-sectional study was conducted from October 2021 to October 2023, involving the analysis of urine samples collected from 321 participants who acquired UTIs during pregnancy. Using biochemical tests and standard cultures, the urine samples were examined for pathogenic bacteria and their anti-microbial sensitivity patterns. The study analyzed susceptibility results according to the Clinical Laboratory Standards Institute guidelines (M100, 28th Edition, 2018). Bacterial strains demonstrating resistance to three or more antibiotics were classified as multidrug-resistant (MDR). This study revealed the distribution of UTI-causing bacteria to be as follows: Escherichia coli, 57.01%; Klebsiella pneumoniae, 24.61%; Pseudomonas aeruginosa, 4.36%; Proteus mirabilis and Enterobacter cloacae, 3.74%; Streptococcus agalactiae, 3.11%; Enterococcus faecalis, 2.18%; and Staphylococcus aureus, 1.24%. Antimicrobial susceptibility testing varied among gram-positive and gram-negative bacteria. Gentamicin demonstrated the highest sensitivity among both gram-positive and gram-negative bacteria; piperacillin-tazobactam was the second most effective drug against gram-negative bacteria. The bacterial isolates showed varying susceptibility to different antibiotics, with Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa being mainly sensitive to gentamicin, piperacillin-tazobactam, and ciprofloxacin, respectively. The strategies for reducing the risk of UTIs need to be improved to limit the spread of MDR bacteria. These strategies may include promoting hygienic practices and administering appropriate antibiotics to prevent the emergence and spread of drug-resistant bacteria. Further research is required to monitor the trends in antibiotic resistance among UTI-causing bacteria and develop effective strategies for managing this public health menace.

In vitro development of resistance against antipseudomonal agents: comparison of novel ß-lactam/ß-lactamase inhibitor combinations and other ß-lactam agents.

We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane-tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other ß-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and meropenem. These alterations, along with ones in mexR and amrR, provided resistance to most ß-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in ß-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer ß-lactam/ß-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other ß-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents.

Lessons learned from an external quality assurance program in applying CLSI interpretive criteria for reporting piperacillin/tazobactam susceptibility.

We evaluated the performance of automated susceptibility testing for piperacillin/tazobactam (PTZ) MICs against the reference microbroth dilution method. The Minimum Inhibitory Concentration of PTZ against a clinical isolate of Klebsiella pneumoniae was determined by reference broth micro-dilution method in 10 replicates which yielded a modal MIC of 16 mg/L (susceptible dose-dependent). Out of 434 laboratories who obtained MIC of 16 mg/L correctly, only 301 interpreted the result as susceptible dose dependent as per 2022 revised CLSI criteria. Educating the clinical laboratories in validating AST methods as per latest CLSI guidelines is of utmost important.

Beta-lactam antibiotic concentrations in critically ill patients with standard and adjusted dosages: A prospective observational study.

INTRODUCTION: Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and those with bacterial species with intermediate susceptibility. The aim of this study was to investigate the variation of antibiotic concentration in critically ill patients with standard or adjusted dosing regimens. METHODS: The concentration of three beta-lactam antibiotics used in the intensive care unit (ICU) setting, cefotaxime, piperacillin/tazobactam, and meropenem, was measured in patients with confirmed or suspected infection. Mid-dose and trough values were collected during a single dosing interval. The pharmacokinetic endpoints were a free antibiotic concentration that, during the whole dosing interval, was above MIC (100% ƒT > MIC, primary endpoint) or above four times MIC (100% ƒT > 4MIC, secondary endpoint). Non-species related MIC breakpoints were used (1 mg/L for cefotaxime, 8 mg/L for piperacillin/tazobactam, and 2 mg/L for meropenem). RESULTS: We included 102 patients (38 cefotaxime, 30 piperacillin/tazobactam, and 34 meropenem) at a single ICU, with a median age of 66 years. In total, 73% were males, 40% were obese (BMI ≥30) and the median SAPS 3 score was 63 points. Of all patients, 78 patients (76%) reached the primary endpoint (100%ƒT > MIC), with 74% for cefotaxime, 67% for piperacillin/tazobactam and 88% for meropenem. Target attainment for 100% ƒT > 4MIC was achieved in 40 (39%) patients, overall, with 34% for cefotaxime, 30% for piperacillin/tazobactam and 53% for meropenem. In patients with standard dose 71% attained 100%ƒT > MIC and 37% for 100%ƒT > 4MIC. All patients with reduced dose attained 100%ƒT > MIC and 27% attained 100% ƒT > 4MIC. In patients with increased dose 79% attained 100%ƒT > MIC and 48% 100%ƒT > 4MIC respectively. CONCLUSIONS: Beta-lactam antibiotics concentration vary widely in critically ill patients. The current standard dosing regimens employed during the study were not sufficient to reach 100% ƒT > MIC in approximately a quarter of the patients. In patients where dose adjustment was performed, the group with increased dose also had low target attainment, as opposed to patients with dose reduction, who all reached target. This suggests the need for further individualization of dosing where therapeutic drug monitoring can be an alternative to further increase target attainment.

Removal of common antimicrobial agents by sustained low-efficiency dialysis.

Adequate dosing of antimicrobials is paramount for treating infections in critically ill patients undergoing kidney replacement therapy; however, little is known about antimicrobial removal by sustained low-efficiency dialysis (SLED). The objective was to quantify the removal of cefepime, daptomycin, meropenem, piperacillin-tazobactam, and vancomycin in patients undergoing SLED. Adult patients ≥18 years with acute kidney injury (AKI) or end-stage kidney disease receiving one of the select antimicrobials and requiring SLED were included. Blood and dialysate flow rates were maintained at 250 and 100 mL/min, respectively. Simultaneous arterial and venous blood samples for the analysis of antibiotic concentrations were collected hourly for 8 hours during SLED (on-SLED). Arterial samples were collected every 2 hours for up to 6 hours while not receiving SLED (off-SLED) for the calculation of SLED clearance, half-life (t1/2) on-SLED and off-SLED, and the fraction of removal by SLED (fD). Twenty-one patients completed the study: 52% male, mean age (±SD) 53 ± 13 years, and mean weight of 98 ± 30 kg. Eighty-six percent had AKI, and 4 patients were receiving cefepime, 3 daptomycin, 10 meropenem, 6 piperacillin-tazobactam, and 13 vancomycin. The average SLED time was 7.3 ± 1.1 hours, and the mean ultrafiltration rate was 95 ± 52 mL/hour (range 10-211). The t1/2 on-SLED was substantially lower than the off-SLED t1/2 for all antimicrobials, and the SLED fD varied between 44% and 77%. An 8-hour SLED session led to significant elimination of most antimicrobials evaluated. If SLED is performed, modification of the dosing regimen is warranted to avoid subtherapeutic concentrations.

Antibiotic prophylaxis with piperacillin-tazobactam reduces organ/space surgical site infection after pancreaticoduodenectomy: a retrospective and propensity score-matched analysis.

BACKGROUND: The occurrence of surgical site infection (SSI) after pancreaticoduodenectomy (PD) is still relatively high. The aim of this retrospective study is to evaluate the efficacy of piperacillin-tazobactam as perioperative prophylactic antibiotic on organ/space SSI for patients underwent PD. METHODS: Four hundred seven consecutive patients who underwent PD between January 2018 and December 2022 were enrolled and analyzed retrospectively. The univariate and multivariate analysis were used to identify independent risk factors of organ/space SSI. Postoperative complications were compared between the two groups according to the use of prophylactic antibiotics by a ratio of 1:1 propensity score-matched (PSM) analysis. RESULTS: Based on perioperative prophylactic antibiotic use, all 407 patients were divided into the ceftriaxone group (n = 192, 47.2%) and piperacillin-tazobactam group (n = 215, 52.8%). The rate of organ/space SSI was 31.2% with the choice of perioperative antibiotics (OR = 2.837, 95%CI = 1.802-4.465, P < 0.01) as one of independent risk factors. After PSM, there were similar baseline characteristics among the groups. Meanwhile, the piperacillin-tazobactam group had a significant lower rate of organ/space SSI compared to the ceftriaxone group both before and after PSM(P < 0.05). CONCLUSIONS: The adoption of piperacillin-tazobactam as perioperative prophylaxis for patients underwent PD reduced organ/space SSI significantly.

Antibiotic dosing recommendations in critically ill patients receiving new innovative kidney replacement therapy.

BACKGROUND: The Tablo Hemodialysis System is a new innovative kidney replacement therapy (KRT) providing a range of options for critically ill patients with acute kidney injury. The use of various effluent rate and treatment durations/frequencies may clear antibiotics differently than traditional KRT. This Monte Carlo Simulation (MCS) study was to develop antibiotic doses likely to attain therapeutic targets for various KRT combinations. METHODS: Published body weights and pharmacokinetic parameter estimates were used to predict drug exposure for cefepime, ceftazidime, imipenem, meropenem and piperacillin/tazobactam in virtual critically ill patients receiving five KRT regimens. Standard free ß-lactam plasma concentration time above minimum inhibitory concentration targets (40-60%fT> MIC and 40-60%fT> MICx4) were used as efficacy targets. MCS assessed the probability of target attainment (PTA) and likelihood of toxicity for various antibiotic dosing strategies. The smallest doses attaining PTA ≥ 90% during 1-week of therapy were considered optimal. RESULTS: MCS determined ß-lactam doses achieving ∼90% PTA in all KRT options. KRT characteristics influenced antibiotic dosing. Cefepime and piperacillin/tazobactam regimens designed for rigorous efficacy targets were likely to exceed toxicity thresholds. CONCLUSION: The flexibility offered by new KRT systems can influence ß-lactam antibiotic dosing, but doses can be devised to meet therapeutic targets. Further clinical validations are warranted.

Antibiotic definitive treatment in ventilator associated pneumonia caused by AmpC-producing Enterobacterales in critically ill patients: a prospective multicenter observational study.

BACKGROUND: Ventilator associated pneumonia (VAP) due to wild-type AmpC-producing Enterobacterales (wtAE) is frequent in intensive care unit (ICU) patients. Despite a low level of evidence, definitive antimicrobial therapy (AMT) with third generation cephalosporins (3GCs) or piperacillin is discouraged. METHODS: Observational prospective study including consecutive wtAE VAP patients in 20 French ICUs. The primary objective was to assess the association of the choice of definitive AMT, i.e. piperacillin ± tazobactam (PTZ), 3GCs or other molecule (4GCs, carbapenems, quinolones, cotrimoxazole; control group), with treatment success at day-7. Recurrence of infection was collected as a secondary outcome, and analyzed accounting for the competing risk of death. RESULTS: From February 2021 to June 2022, 274 patients were included. Enterobacter cloacae was the most prevalent specie (31%). Seventy-eight patients (28%) had PTZ as definitive AMT while 44 (16%) had 3GCs and 152 (56%) were classified in the control group. Day-7 success rate was similar between the 3 groups (74% vs. 73% vs. 68% respectively, p = 0.814). Recurrence probability at day-28 was 31% (95% CI 21-42), 40% (95% CI 26-55) and 21% (95% CI 15-28) for PTZ, 3GCs and control groups (p = 0.020). In multivariable analysis, choice of definitive AMT was not associated with clinical success, but definitive AMT with 3GCs was associated with recurrence at day-28 [csHR(95%CI) 10.9 (1.92-61.91)]. CONCLUSION: Choice of definitive antimicrobial therapy was not associated with treatment success at day 7. However, recurrence of pneumonia at day-28 was higher in patients treated with third generation cephalosporins with no differences in mortality or mechanical ventilation duration.

Identification of a CTX-M-255 ß-lactamase containing a G239S substitution selectively conferring resistance to penicillin/ß-lactamase inhibitor combinations.

OBJECTIVES: An Escherichia coli isolate, WGS1363, showed resistance to piperacillin/tazobactam but susceptibility to cephalosporins and contained a previously unrecognized ß-lactamase, CTX-M-255, as the only acquired ß-lactamase. CTX-M-255 was identical to CTX-M-27 except for a G239S substitution. Here, we characterize the hydrolytic spectrum of CTX-M-255 and a previously reported ß-lactamase, CTX-M-178, also containing a G239S substitution and compare it to their respective parental enzymes, CTX-M-27 and CTX-M-15. METHODS: All ß-lactamase genes were expressed in E. coli TOP10 and MICs to representative ß-lactam-antibiotics were determined. Furthermore, blaCTX-M-15,  blaCTX-M-27, blaCTX-M-178 and blaCTX-M-255 with C-terminal His-tag fusions were affinity purified for enzyme kinetic assays determining Michaelis-Menten kinetic parameters against representative ß-lactam-antibiotics and IC50s of clavulanate, sulbactam, tazobactam and avibactam. RESULTS: TOP10-transformants expressing blaCTX-M-178 and blaCTX-M-255 showed resistance to penicillin/ß-lactamase combinations and susceptibility to cephalothin and cefotaxime in contrast to transformants expressing blaCTX-M-15 and blaCTX-M-27. Determination of enzyme kinetic parameters showed that CTX-M-178 and CTX-M-255 both lacked hydrolytic activity against cephalosporins and showed impaired hydrolytic efficiency against penicillin antibiotics compared to their parental enzymes. Both enzymes appeared more active against piperacillin compared to benzylpenicillin and ampicillin. Compared to their parental enzymes, IC50s of ß-lactamase-inhibitors were increased more than 1000-fold for CTX-M-178 and CTX-M-255. CONCLUSIONS: CTX-M-178 and CTX-M-255, both containing a G239S substitution, conferred resistance to piperacillin/tazobactam and may be characterized as inhibitor-resistant CTX-M ß-lactamases. Inhibitor resistance was accompanied by loss of activity against cephalosporins and monobactams. These findings add to the necessary knowledge base for predicting antibiotic susceptibility from genotypic data.

Antimicrobial use and appropriateness in neutropenic fever: a study of the Hospital National Antimicrobial Prescribing Survey data.

BACKGROUND: Neutropenic fever (NF) is a common complication in patients receiving chemotherapy. Judicious antimicrobial use is paramount to minimize morbidity and mortality and to avoid antimicrobial-related harms. OBJECTIVES: To use an Australian national dataset of antimicrobial prescriptions for the treatment of NF to describe antimicrobial use, prescription guideline compliance and appropriateness; and to compare these findings across different healthcare settings and patient demographics. We also aimed to identify trends and practice changes over time. METHODS: Data were extracted from the Hospital National Antimicrobial Prescribing Survey (Hospital NAPS) database from August 2013 to May 2022. Antimicrobial prescriptions with a NF indication were analysed for antimicrobial use, guideline compliance and appropriateness according to the Hospital NAPS methodology. Demographic factors, hospital classifications and disease characteristics were compared. RESULTS: A total of 2887 (n = 2441 adults, n = 441 paediatric) NF prescriptions from 254 health facilities were included. Piperacillin-tazobactam was the most prescribed antimicrobial. Overall, 87.4% of prescriptions were appropriate. Piperacillin-tazobactam and cefepime had the highest appropriateness though incorrect piperacillin-tazobactam dosing was observed. Lower appropriateness was identified for meropenem, vancomycin, and gentamicin prescribing particularly in the private hospital and paediatric cohorts. The most common reasons for inappropriate prescribing were spectrum too broad, incorrect dosing or frequency, and incorrect duration. CONCLUSIONS: This study provides insights into antimicrobial prescribing practices for NF in Australia. We have identified three key areas for improvement: piperacillin-tazobactam dosing, paediatric NF prescribing and private hospital NF prescribing. Findings from this study will inform the updated Australian and New Zealand consensus guidelines for the management of neutropenic fever in patients with cancer.

Optimizing antibiotic management for patients with acute appendicitis: A quality improvement study.

BACKGROUND: To decrease surgical site infections after appendectomy for acute appendicitis, preoperative broad-spectrum antibiotics are often used in clinical practice. However, this treatment strategy has come under scrutiny because of increasing rates of antibiotic-resistant infections. METHODS: The aim of this multisite quality improvement project was to decrease the treatment of uncomplicated acute appendicitis with piperacillin-tazobactam without increasing the rate of surgical site infections. Our quality improvement intervention had 2 distinct components: (1) updating electronic health record orders to encourage preoperative administration of narrow-spectrum antibiotics and (2) educating surgeons and emergency department clinicians about selecting appropriate antibiotic therapy for acute appendicitis. Patient demographics, clinical characteristics, and outcomes were compared 6 months before and after implementation of the quality improvement intervention. RESULTS: A total of 352 laparoscopic appendectomies were performed during the 6-month preintervention period, and 369 were performed during the 6-month postintervention period. The preintervention period and postintervention period groups had similar baseline demographics, vital signs, and laboratory test values. The rate of preoperative piperacillin-tazobactam administration significantly decreased after the intervention (51.4% preintervention period vs 20.1% postintervention period, P < .001). The rate of surgical site infections was similar in both groups (superficial surgical site infections = 1.4% preintervention period vs 0.8% postintervention period, P = .50; deep surgical site infections = 1.1% preintervention period vs 0.0% postintervention period, P = .06; and organ space surgical site infections = 3.1% preintervention period vs 3.0% postintervention period, P > .99). Rates of 30-day readmission, reoperation, and Clostridioides difficile infection also did not differ between groups. CONCLUSION: Our quality improvement intervention successfully decreased piperacillin-tazobactam administration without increasing the rate of surgical site infections in patients with acute appendicitis.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.