Piperacillin/tazobactam Susceptibility Test Interpretive Criteria for Enterobacterales: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing.

The in vitro susceptibility testing interpretive criteria (STIC) for TZP against Enterobacterales were recently updated by the Food and Drug Administration (FDA), Clinical & Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). The United States Committee on Antimicrobial Susceptibility Testing (USCAST) also recently reviewed TZP STIC for Enterobacterales and arrived at different STIC for Enterobacterales and herein we explain our recommendations and rationale behind them. Based on our review of the available data, USCAST does not recommend TZP STIC for certain Enterobacterales species that have a moderate to high likelihood of clinically significant AmpC production (E. cloacae, C. freundii, and K. aerogenes only) or for third-generation cephalosporin-non-susceptible (3GC-NS) Enterobacterales. USCAST recommends a TZP susceptibility breakpoint of ≤ 16/4 mg/L for third-generation cephalosporin-susceptible (3GC-S) Enterobacterales but only endorses the use of extended infusion TZP regimens for patients with infections due to these pathogens.

Dynamic changes in the real-time glomerular filtration rate and kidney injury markers in different acute kidney injury models.

In this study, we dynamically monitored the glomerular filtration rate and other assessment of renal function and markers of injury in various mice models of acute kidney injury. Male C57BL/6 mice were utilized to establish acute kidney injury models of sepsis, ischemia reperfusion, cisplatin, folic acid, aristolochic acid and antibiotic. In addition to the real time glomerular filtration rate, renal LCN-2 and HAVCR-1 mRNA expression levels, and serum creatinine, urea nitrogen and cystatin c levels were also used to evaluate renal function. In addition, the protein levels of LCN-2 and HAVCR-1 in renal, serum and urine were measured. Our results demonstrated that the changes in biomarkers always lagged the real time glomerular filtration rate during the progression and recovery of renal injury. Cystatin-c can reflect renal injury earlier than other markers, but it remains higher in the recovery stage. Perhaps the glomerular filtration rate does not reflect the greater injury caused by vancomycin plus piperacillin.

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.

Clinical emergence of a novel extended-spectrum variant deriving from the OXY-1 ß-lactamase.

The genomic comparison of two Klebsiella michiganensis clinical isolates recovered from the same patient, one resistant to piperacillin-tazobactam and intermediate to cefotaxime, the other resistant to ceftazidime but susceptible to piperacillin-tazobactam, revealed one mutation in the blaOXY-1-24 gene accounting for a L169M substitution in the Ω loop. Cloning experiment in Escherichia coli demonstrated the contribution of this mutation to the hydrolysis spectrum extension towards ceftazidime and cefepime, whereas the resistance to piperacillin-tazobactam was reduced. To the best of our knowledge, this study shows for the first time that ceftazidime resistance can occur in vivo from OXY-1 precursor by structural alteration.

Effect of incremental tazobactam concentrations on the bactericidal activity of piperacillin against ESBL-producing enterobacterales clinical isolates causing bacteraemia.

We evaluated the activity of piperacillin in relation to INCREASING TAZOBACTAM CONCENTRATION against ESBL-producing Enterobacterales collected from patients with bacteraemia. Increasing tazobactam concentration (4, 12 or 24 mg/L) exerted a reduction of piperacillin MICs under the clinical breakpoint in a concentration-dependent manner (0%, 60% and 90% of clinical isolates). Also, activity of piperacillin/tazobactam based at higher achievable serum concentrations (123/14 mg/L) is needed to reduce the bacterial growth in 92% of ESBL-producers. CHANGES IN THE PIPERACILLIN MIC IN RELATION TO INCREASING TAZOBACTAM SUGGEST THAT REALTIME TDM COULD BE USED FOR DRIVEN ANTIMICROBIAL THERAPY WITH PIPERACILLIN/TAZOBACTAM IN BSI DUE TO ESBL STRAINS.

Epidemiology of Vancomycin in Combination With Piperacillin/Tazobactam-Associated Acute Kidney Injury in Children: A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have shown that vancomycin combined with piperacillin/tazobactam (VPT) increased the risk of acute kidney injury (AKI) compared with other antibiotics in children. However, the epidemiology of VPT-associated AKI in children is unknown. OBJECTIVE: To evaluate the incidence and risk factors of VPT-associated AKI in children. DATA SOURCES: Literature databases of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, WanFang Database, and China Biology Medicine Disc were searched from inception to November 2023. References of included studies were also manually checked. STUDY SELECTION AND DATA EXTRACTION: Two independent reviewers selected studies, extracted data, and quality assessment. Meta-analyses were performed to quantify the incidence and risk factors of VPT-associated AKI in children. DATA SYNTHESIS: Sixteen cohort studies were identified. Overall, the incidence of VPT-associated AKI in children was 24.3% (95% CI: 17.9%-30.6%). The incidence of VPT-associated AKI in critically ill children (26.6%) was higher than that in noncritically ill children (10.9%). Moreover, higher serum vancomycin trough concentration (>15 mg/L), use of vasopressors, combination of nephrotoxins and intensive care unit admission were risk factors for VPT-associated AKI in children (P < 0.05). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Identifying high-risk groups and determining safer treatments is critical to reducing the incidence of VPT-associated AKI in children. CONCLUSIONS: The incidence of VPT-associated AKI in children is high, especially in critically ill children. Medication regimens should be personalized based on the presence of individual risk factors. Moreover, renal function was regularly assessed throughout treatment with VPT.

Decreased Hepatic Functional Reserve Increases the Risk of Piperacillin/Tazobactam-Induced Abnormal Liver Enzyme Levels: A Retrospective Case-Control Study.

BACKGROUND: Piperacillin/tazobactam (PIPC/TAZ), which is a combination of a beta-lactam/beta-lactamase inhibitor, often causes liver enzyme abnormalities. The albumin-bilirubin (ALBI) score is a simple index that uses the serum albumin and total bilirubin levels for estimating hepatic functional reserve. Although patients with low hepatic reserve may be at high risk for drug-induced liver enzyme abnormalities, the relationship between PIPC/TAZ-induced abnormal liver enzymes levels and the ALBI score remains unknown. OBJECTIVE: This study aimed to elucidate the relationship between PIPC/TAZ-induced abnormal liver enzyme levels and the ALBI score. METHODS: This single-center retrospective case-control study included 335 patients. The primary outcome was PIPC/TAZ-induced abnormal liver enzyme levels. We performed COX regression analysis with male gender, age (≥75 years), alanine aminotransferase level (≥20 IU/L), and ALBI score (≥-2.00) as explanatory factors. To investigate the influence of the ALBI score on the development of abnormal liver enzyme levels, 1:1 propensity score matching between the ≤-2.00 and ≥-2.00 ALBI score groups was performed using the risk factors for drug-induced abnormal liver enzyme levels. RESULTS: The incidence of abnormal liver enzyme levels was 14.0% (47/335). COX regression analysis revealed that an ALBI score ≥-2.00 was an independent risk factor for PIPC/TAZ-induced abnormal liver enzyme levels (adjusted hazard ratio: 3.08, 95% coefficient interval: 1.207-7.835, P = 0.019). After 1:1 propensity score matching, the Kaplan-Meier curve revealed that the cumulative risk for PIPC/TAZ-induced abnormal liver enzyme levels was significantly higher in the ALBI score ≥-2.00 group (n = 76) than in the <-2.00 group (n = 76) (P = 0.033). CONCLUSION AND RELEVANCE: An ALBI score ≥-2.00 may predict the development of PIPC/TAZ-induced abnormal liver enzyme levels. Therefore, frequent monitoring of liver enzymes should be conducted to minimize the risk of severe PIPC/TAZ-induced abnormal liver enzyme levels in patients with low hepatic functional reserve.

Nephrotoxic Risk Associated With Combination Therapy of Vancomycin and Piperacillin-Tazobactam in Critically Ill Patients With Chronic Kidney Disease.

Background: The combination of vancomycin and piperacillin-tazobactam (VPT) has been associated with acute kidney injury (AKI) in hospitalized patients when compared to similar combinations. Additional studies examining this nephrotoxic risk in critically ill patients have not consistently demonstrated the aforementioned association. Furthermore, patients with baseline renal dysfunction have been excluded from almost all of these studies, creating a need to examine the risk in this patient population. Methods: This was a retrospective cohort analysis of critically ill adults with baseline chronic kidney disease (CKD) who received vancomycin plus an anti-pseudomonal beta-lactam at Emory University Hospital. The primary outcome was incidence of AKI. Secondary outcomes included stage of AKI, time to development of AKI, time to return to baseline renal function, new requirement for renal replacement therapy, intensive care unit and hospital length of stay, and in-hospital mortality. Results: A total of 109 patients were included. There was no difference observed in the primary outcome between the VPT (50%) and comparator (58%) group (P = .4), stage 2 or 3 AKI (15.9% vs 6%; P = .98), time to AKI development (1.7 vs 2 days; P = .5), time to return to baseline renal function (4 vs 3 days; P = .2), new requirement for RRT (4.5% vs 1.5%; P = .3), ICU length of stay (7.3 vs 7.4 days; P = .9), hospital length of stay (19.3 vs 20.1 days; P = .87), or in-hospital mortality (15.9% vs 10.8%; P = .4). A significant difference was observed in the duration of antibiotic exposure (3.32 vs 2.62 days; P = .045 days). Conclusion: VPT was not associated with an increased risk of AKI or adverse renal outcomes. Our findings suggest that the use of this antibiotic combination should not be avoided in this patient population. More robust prospective studies are warranted to confirm these findings.

Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial: Protocol.

BACKGROUND: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. CONCLUSIONS: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.

Comparative effectiveness of cefmetazole versus carbapenems and piperacillin/tazobactam as initial therapy for bacteremic acute cholangitis: A retrospective study.

INTRODUCTION: Carbapenems and piperacillin/tazobactam (PIPC/TAZ) are commonly used as the initial therapy to treat extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales in acute cholangitis. However, the overuse of these antibiotics contributes to the spread of antimicrobial resistance. Cefmetazole (CMZ) is stable to hydrolysis by ESBLs, so it may be an alternative to carbapenems and PIPC/TAZ. However, the effectiveness of CMZ compared with that of carbapenems and PIPC/TAZ as the initial therapy for acute cholangitis is unknown. METHODS: We conducted a retrospective cohort study at a university hospital between April 1, 2014, and December 31, 2022. Patients with bacteremic acute cholangitis who received CMZ, carbapenems, or PIPC/TAZ as the initial therapy were included. The patients were divided into a CMZ group and a carbapenems or PIPC/TAZ (CP) group to compare patient outcomes. RESULTS: A total of 99 patients (54 in the CMZ group and 45 in the CP group) were analyzed. The baseline characteristics of the patients were similar and 30-day mortality did not differ between groups (4% vs. 7%, P = 0.66). However, the CMZ group had a shorter length of stay (LOS) (8 days vs. 15 days, P < 0.001) and lower mean antibiotic cost (98.92 USD vs. 269.49 USD, P < 0.001) than the CP group. CONCLUSIONS: In bacteremic acute cholangitis, initial therapy with CMZ may contribute to a shorter LOS and lower antibiotic costs than treatment with carbapenems and PIPC/TAZ, without worsening patient outcomes.

Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study.

PURPOSE: The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients. METHODS: We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-Cœur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L-1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa. RESULTS: Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0-152.3], 59.3 [21.1-74.4], and 25.3 [6.8-44.6] mg·L-1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L-1. The majority of patients who were underexposed were patients with normal to augmented renal clearance. CONCLUSION: In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.

RéSUMé: OBJECTIF: L'objectif de cette étude était d'évaluer l'exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs. MéTHODES: Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-Cœur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d'échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa. RéSULTATS: Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l'intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée. CONCLUSION: Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l'atteinte des cibles d'efficacité.

Piperacillin/tazobactam-induced sudden severe thrombocytopenia in a patient with a pressure ulcer: a case report.

The standard treatment for an infected pressure ulcer (PU) with osteomyelitis is debridement, wound coverage and antibiotic administration. However, systemic administration of antibiotics in patients with osteomyelitis is controversial, and the optimal treatment duration for chronic osteomyelitis has not been standardised. We report a case of sudden severe thrombocytopenia induced by piperacillin/tazobactam (PIPC/TAZ) in a patient with PU-related osteomyelitis. A 57-year-old male patient with paraplegia, using a wheelchair full-time, presented to our plastic surgery department with infection of a stage IV hard-to-heal ischial PU. We surgically debrided the necrotising tissue and raised an ipsilateral biceps femoris musculocutaneous propeller flap for wound coverage. Polymicrobial infections, including Pseudomonas aeruginosa, were detected in the bone biopsy sample; therefore, systemic PIPC/TAZ was administered for the osteomyelitis. Unexpectedly, during the next 12 days of antibiotic administration, the patient's platelet count acutely dropped to 1×103/µl over three days. Based on a series of examinations, PIPC/TAZ was suspected to be the most likely cause of the severe thrombocytopenia. After drug discontinuation, the thrombocytopenia gradually improved. PIPC/TAZ is one of the most widely used antibiotic combinations in the plastic surgery field; it is conventionally administered for hard-to-heal wounds such as PUs and diabetic foot. The present case suggests that surgeons must take special precautions for patients undergoing PIPC/TAZ treatment. In this report, PIPC/TAZ-induced thrombocytopenia and the efficacy of antibiotic treatment for PU-related osteomyelitis are discussed in light of the available literature.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Is Carbapenem Therapy Necessary for the Treatment of Non-CTX-M ESBL-Producing Enterobacterales Bloodstream Infections?

BACKGROUND: Investigations into antibiotics for extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) bloodstream infections (BSIs) have focused on blaCTX-M genes. Outcomes of patients with non-CTX-M-producing ESBL-E BSIs and optimal treatment are unknown. METHODS: A multicenter observational study investigating 500 consecutive patients with ceftriaxone-resistant Enterobacterales BSIs during 2018-2022 was conducted. Broth microdilution and whole genome sequencing confirmed antibiotic susceptibilities and ESBL gene presence, respectively. Inverse probability weighting (IPW) using propensity scores was employed to ensure patients infected with non-CTX-M and CTX-M ESBL-E BSIs were similar prior to evaluation of outcomes. RESULTS: 396 patients (79.2%) were confirmed to have an ESBL-E BSI. ESBL gene family prevalence was as follows: blaCTX-M (n=370), blaSHV (n=16), blaOXY (n=12), and blaVEB (n=5). ESBL gene identification was not limited to Escherichia coli and Klebsiella species. In the IPW cohort, there was no difference in 30-day mortality or ESBL-E infection recurrence between the non-CTX-M and CTX-M groups (OR=.99, 95% CI 0.87-1.11; p=0.83) and (OR=1.10, 95% CI 0.85--1.42; p=0.47), respectively. In an exploratory analysis limited to the non-CTX-M group, 86% of the 21 patients receiving meropenem were alive on day 30; none of the 5 patients receiving piperacillin-tazobactam were alive on day 30. CONCLUSIONS: Our findings suggest that non-CTX-M and CTX-M ESBL-producing Enterobacterales BSIs are equally concerning and associated with similar clinical outcomes. Meropenem may be associated with improved survival in patients with non-CTX-M ESBL-E BSIs, underscoring the potential benefit of comprehensive molecular diagnostics to enable early antibiotic optimization for patients with ESBL-E BSI, beyond just blaCTX-M genes.

Epidemiology and impact of methicillin-sensitive Staphylococcus aureus with ß-lactam antibiotic inoculum effects in adults with cystic fibrosis.

Staphylococcus aureus is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and small-colony-variants. The inoculum effect (IE) is characterized by reduced ß-lactam susceptibility when assessed at high inoculum. The IE associates with worse outcomes in bacteremia and other high-density infections, and may therefore be relevant to CF. The prevalence of IE amongst a CF cohort (age ≥18 years), followed from 2013 to 2016, was investigated. Yearly methicillin-sensitive S. aureus (MSSA) isolates were screened at standard (5 × 105 CFU/mL) and high (5 × 107 CFU/mL) inoculum against narrow-spectrum anti-Staphylococcal ß-lactams and those with anti-pseudomonal activity common to CF. A ≥ 4-fold increase in minimum inhibitory concentration between standard and high inoculum defined IE. Isolates underwent blaZ sequencing and genotyping and were compared against published genomes. Fifty-six percent (99/177) of individuals had MSSA infection. MSSA was observed at ≥105 CFU/mL in 44.8% of entry sputum samples. The prevalence of the IE was 25.0%-cefazolin; 13.5%-cloxacillin; 0%-meropenem; 1.0%-cefepime; 5.2%-ceftazidime; and 34.4%-piperacillin-tazobactam amongst baseline MSSA isolates assessed. blaZ A associated with cefazolin IE (P = 0.0011), whereas blaZ C associated with piperacillin-tazobactam IE (P < 0.0001). Baseline demographics did not reveal specific risk factors for IE-associated infections, nor were long-term outcomes different. Herein, we observed the IE in CF-derived MSSA disproportionally for cefazolin and piperacillin-tazobactam and this phenotype strongly associated with underlying blaZ genotype. The confirmation of CF being a high density infection, and the identification of high prevalence of MSSA with IE in CF supports the need for prospective pulmonary exacerbation treatment studies to understand the impact of this phenotype.

Evaluation of Piperacillin-Tazobactam Testing against Enterobacterales by the Phoenix, MicroScan, and Vitek2 Tests Using Updated Clinical and Laboratory Standards Institute Breakpoints.

In 2022, the Clinical and Laboratory Standards Institute (CLSI) updated piperacillin-tazobactam (TZP) breakpoints for Enterobacterales, based on substantial data suggesting that historical breakpoints did not predict treatment outcomes for TZP. The U.S. Food and Drug Administration (FDA) has not yet adopted these breakpoints, meaning commercial manufacturers of antimicrobial susceptibility testing devices cannot obtain FDA clearance for the revised breakpoints. We evaluated the Phoenix (BD, Sparks, MD), MicroScan (Beckman Coulter, Sacramento, CA), and Vitek2 (bioMérieux, Durham, NC) TZP MICs compared to reference broth microdilution for a collection of 284 Enterobacterales isolates. Phoenix (n = 167 isolates) demonstrated 84.4% categorical agreement (CA), with 4.2% very major errors (VMEs) and 1.8% major errors (MEs) by CLSI breakpoints. In contrast, CA was 85.0% with 4.3% VMEs and 0.8% MEs for the Phoenix with FDA breakpoints. MicroScan (n = 55 isolates) demonstrated 80.0% CA, 36.4% VMEs, and 4.8% MEs by CLSI breakpoints and 81.8% CA, 44.4% VMEs, and 0.0% MEs by FDA breakpoints. Vitek2 (n = 62 isolates) demonstrated 95.2% CA, 6.3% VMEs, and 0.0% MEs by CLSI and 96.8% CA, 0.0% VMEs, and 2.2% MEs by FDA breakpoints. Overall, the performance of the test systems was not substantially different using CLSI breakpoints off-label than using on-label FDA breakpoints. However, limitations were noted with higher-than-desired VME rates (all three systems) and lower-than-desired CA (MicroScan and Phoenix). Laboratories should consider adoption of the revised CLSI breakpoints with automated test systems but be aware that some performance challenges exist for testing TZP on automated systems, regardless of breakpoints applied.

Effect of restricting piperacillin/tazobactam prescription on rates of antimicrobial resistance in gram-negative bacteria and antibiotic consumption.

The increasing resistance of gram-negative bacteria is a serious global public health concern. One way to prevent increasing antibiotic resistance is by implementing the antibiotic stewardship program. This study aimed to assess the changes in the consumption of antimicrobials and antimicrobial resistance rates after implementing piperacillin/tazobactam restriction. This study was conducted at Kandong Sacred Heart Hospital. We retrospectively collected and analysed data between October 2018 and May 2021 to evaluate antibiotic consumption and resistance patterns after restricting piperacillin/tazobactam. This study included two periods, a 16-month pre-restriction period and a 16-month post-restriction period. During the study period, there was a significant decrease in the consumption of piperacillin/tazobactam after implementing the restriction policy (127.82 ± 9.39 to 104.82 ± 15.66 defined daily doses/1000 patient days, p < 0.001). A significant decrease in the resistance rate of Acinetobacter spp. was observed for cefepime (p = 0.001), ceftazidime (p = 0.004), levofloxacin (p = 0.021), meropenem (p = 0.002) and piperacillin (p = 0.028). The introduction of piperacillin/tazobactam restriction reduced their use and positively impacted the resistance rates of Acinetobacter spp., carbapenem-resistant Pseudomonas spp. and carbapenem-resistant Enterobacteriaceae which are major threats to nosocomial infections.

Early treatment response to piperacillin/tazobactam in patients with bloodstream infections caused by non-ESBL ampicillin/sulbactam-resistant Escherichia coli: a binational cohort study.

PURPOSE: This study aimed to compare treatment outcomes for bloodstream infections (BSI) caused by a piperacillin/tazobactam (PIP/TAZ)-susceptible E. coli among three patient groups: BSI caused by ampicillin/sulbactam (AMP/SLB)-resistant isolates treated with PIP/TAZ, BSI caused by AMP/SLB-sensitive isolates treated with PIP/TAZ, and BSI caused by AMP/SLB-resistant isolates treated with another monotherapy. METHODS: This retrospective study was conducted in two academic centres in Europe. Adult patients with E. coli BSI were screened from 2014 to 2020. Inclusion criteria were non-ESBL BSI and initial monotherapy for ≥ 72 h. To reduce the expected bias between the patient groups, propensity score matching was performed. The primary outcome was early treatment response after 72 h and required absence of SOFA score increase in ICU/IMC patients, as well as resolution of fever, leukocytosis, and bacteraemia. RESULTS: Of the 1707 patients screened, 315 (18.5%) were included in the final analysis. Urinary tract infection was the most common source of BSI (54.9%). Monotherapies other than PIP/TAZ were cephalosporins (48.6%), carbapenems (34.3%), and quinolones (17.1%). Enhanced early treatment response rate was detected (p = 0.04) in patients with BSI caused by AMP/SLB-resistant isolates treated with another monotherapy (74.3%) compared to those treated with PIP/TAZ (57.1%), and was mainly driven by the use of cephalosporins and quinolones (p ≤ 0.03). Clinical success, 28-day mortality, and rate of relapsing BSI did not significantly differ between the groups. CONCLUSIONS: Our study suggests that initial use of PIP/TAZ may be associated with reduced early treatment response in E. coli BSI caused by AMP/SLB-resistant isolates compared to alternative monotherapies.

Impact of Piperacillin-Tazobactam Dosing in Septic Shock Patients Using Real-World Evidence: An Observational, Retrospective Cohort Study.

BACKGROUND: Sepsis and septic shock are associated with significant morbidity and mortality. Rapid initiation of appropriate antibiotic therapy is essential, as inadequate therapy early during septic shock has been shown to increase the risk of mortality. However, despite the importance of appropriate antibiotic initiation, in clinical practice, concerns for renal dysfunction frequently lead to antibiotic dose reduction, with scant evidence on the impact of this practice in septic shock patients. OBJECTIVE: The purpose if this article is to investigate the rate and impact of piperacillin-tazobactam dose adjustment in early phase septic shock patients using real-world electronic health record (EHR) data. METHODS: A multicenter, observational, retrospective cohort study was conducted of septic shock patients who received at least 48 hours of piperacillin-tazobactam therapy and concomitant receipt of norepinephrine. Subjects were stratified into 2 groups according to their cumulative 48-hour piperacillin-tazobactam dose: low piperacillin-tazobactam dosing (LOW; <27 g) group and normal piperacillin-tazobactam dosing (NORM; ≥27 g) group. To account for potential confounding variables, propensity score matching was used. The primary study outcome was 28-day norepinephrine-free days (NFD). RESULTS: In all, 1279 patients met study criteria. After propensity score matching (n = 608), the NORM group had more median NFD (23.9 days [interquartile range, IQR: 0-27] vs 13.6 days [IQR: 0-27], P = 0.021). The NORM group also had lower rates of in-hospital mortality/hospice disposition (25.9% [n = 79] vs 35.5% [n = 108]), P = 0.014). Other secondary outcomes were similar between the treatment groups. CONCLUSIONS AND RELEVANCE: In the propensity score-matched cohort, the NORM group had significantly more 28-day NFD. Piperacillin-tazobactam dose reduction in early phase septic shock is associated with worsened clinical outcomes. Clinicians should be vigilant to avoid piperacillin-tazobactam dose reduction in early phase septic shock.

Carbapenem alternatives for treatment of bloodstream infections due to AmpC producing enterobacterales.

INTRODUCTION: Carbapenems (CR) have traditionally been the first line treatment for bacteremia caused by AmpC-producing Enterobacterales. However, CR have a high ecological impact, and carbapenem-resistant strains continue rising. Thus, other treatment alternatives like Piperacillin-Tazobactam (P-T) or Cefepime (CEF) and oral sequential therapy (OST) are being evaluated. METHODS: We conducted a retrospective, single-centre observational study. All adult patients with AmpC-producing Enterobacterales bacteremia were included. The primary endpoint was clinical success defined as a composite of clinical cure, 14-day survival, and no adverse events. We evaluated the evolution of patients in whom OST was performed. RESULTS: Seventy-seven patients were included, 22 patients in the CR group and 55 in the P-T/CEF group (37 patients received CEF and 18 P-T). The mean age of the patients was higher in the P-T/CEF group (71 years in CR group vs. 76 years in P-T/CEF group, p = 0.053). In the multivariate analysis, age ≥ 70 years (OR 0.08, 95% CI [0.007-0.966], p = 0.047) and a Charlson index ≥ 3 (OR 0.16, 95% CI [0.026-0.984], p = 0.048), were associated with a lower clinical success. Treatment with P-T/CEF was associated with higher clinical success (OR 7.75, 95% CI [1.273-47.223], p = 0.026). OST was performed in 47% of patients. This was related with a shorter in-hospital stay (OST 14 days [7-22] vs. non-OST 18 days [13-38], p = 0.005) without difference in recurrence (OST 3% vs. non-OST 5%, p = 0.999). CONCLUSIONS: Targeted treatment with P-T/CEF and OST could be safe and effective treatments for patients with AmpC-producing Enterobacterales bacteremia.