MIC Breakpoints Research Articles

Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients.

Medical records of all patients admitted to ICU between January 2019 and December 2020 were retrospectively reviewed. Each patient received a 2/1 g ampicillin/sulbactam loading dose, followed by a continuous infusion of 8/4 g per 24 h. Ampicillin serum concentrations were measured. Main outcomes were reaching of plasma concentrations breakpoint defined by minimum inhibitory concentration (MIC at 8 ml/l) and 4-fold MIC (MIC at 32 ml/l) during steady state of CI. In 50 patients a total of 60 concentration measurements were performed. The first concentration was measured after a median of 29 h (IQR 21-61 h). Mean ampicillin concentration was 62.6 ± 39.1 mg/l. Furthermore, serum concentrations exceeded the defined MIC breakpoint in all measurements (100 %) and were above the 4-fold MIC in 43 analyses (71.1 %). However, patients suffering from acute kidney injury exhibited significant higher serum concentrations (81.1 ± 37.7 mg/l vs. 38.2 ± 24.8 mg/l; p < 0.001). Also, there was a negative correlation between ampicillin serum concentrations and GFR (r = -0.659; p < 0.001). The described dosing regimen for ampicillin/sulbactam is safe with respect to the defined MIC breakpoints for ampicillin, and continuous subtherapeutic concentration is unlikely. However, with impaired renal function drug accumulation occurs, and with increased renal clearance, drug levels can be below the 4-fold MIC breakpoint.

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Association between minimum inhibitory concentration values and mortality risk in patients with Stenotrophomonas maltophilia infections: a retrospective cohort study of electronic health records from 148 US hospitals.

Clinical data informing antimicrobial susceptibility breakpoints for Stenotrophomonas maltophilia infections are lacking. We sought to leverage real-world data to identify MIC values within the currently defined susceptible range that could discriminate mortality risk for patients with S. maltophilia infections and guide future breakpoint revisions. Inpatients with S. maltophilia infection who received single-agent targeted therapy with levofloxacin or trimethoprim/sulfamethoxazole were identified in the Cerner HealthFacts electronic health record database. Encounters were restricted to those with MIC values reported to be in the susceptible range for both agents. Curation for exact (non-range) MIC values yielded sequentially granular model populations. Logistic regression was used to calculate adjusted OR (aOR) of mortality or hospice discharge associated with different susceptible-range MICs, controlling for patient- and centre-related factors, and infection site, polymicrobial infection and receipt of empirical therapy. Seventy-three of 851 levofloxacin-treated patients had levofloxacin MIC of exactly 2 mg/L (current Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoint) and served as the reference category for levofloxacin breakpoint models. In breakpoint model I (n = 501), aOR of mortality associated with infection due to isolates with levofloxacin MIC of ≤1 versus 2 mg/L were similar [aOR = 1.79 (95% CI 0.88-3.62), P = 0.11]. In breakpoint model IIa (n = 358), aOR of mortality associated with MIC ≤0.5 versus 2 mg/L were also similar [aOR 0.1.36 (95% CI 0.65-2.83), P = 0.41]. However, breakpoint model IIb (n = 297) displayed higher aOR of mortality associated with an MIC of 1 versus 2 mg/L [aOR 2.36 (95% CI 1.14-4.88), P = 0.02]. Only 9/645 trimethoprim/sulfamethoxazole-treated patients had trimethoprim/sulfamethoxazole MIC of exactly 2/38 mg/L precluding informative models for this agent. In this retrospective study of real-world patients with S. maltophilia infection, risk-adjusted survival data do not appear to stratify patients clinically within current susceptible-range MIC breakpoint for levofloxacin (≤2 mg/L) by mortality.

Determination of MIC of Different Antibiotics against Intermediate Isolates of S. aureus at a Tertiary Care Hospital by E-test

Background: The E-test involves using a predefined antibiotic gradient on a strip, which is then placed on an agar plate containing the bacterial culture. The point at which the antibiotic concentration on the strip causes inhibition of bacterial growth is taken as the MIC. This method allows for the rapid and accurate determination of the MIC of antibiotics against specific bacterial strains and can aid in selecting appropriate antibiotics for treatment. Objectives: The aim of this study was also to include a comparison of the results with those of previous studies and an evaluation of the study's limitations. Method: A cross-sectional microbiological study was conducted at the Department of Microbiology, and the Department of ENT Rajshahi Medical College, Bangladesh, from January to December 2019. This section will provide a detailed description of the methods used in the study, including the study design, sampling methods, and procedures for collecting and analyzing the data. The methods section will also explain the E-test method used to determine MIC, including the procedure for performing the test and the criteria for interpreting the results. Results: A total of 96 samples, among 73 isolates from 68 culture-positive cases, 37 isolates showed intermediate susceptibility towards selected antibiotics such as beta-lactams, aminoglycosides and quinolones by disc diffusion method. Regarding MIC breakpoint in terms of susceptibility, out of 21 intermediate isolates of S. aureus, 16(76.2%) were susceptible, 01(4.8%) was intermediate, and 04(19%) were resistant to different antibiotics by E-test. Conclusion: In general, the conclusion of such an article would likely summarize the study's findings, such as the MIC values for the different antibiotics tested and how they compare to established MIC breakpoints, and any significant observations or trends noted. It may also discuss the clinical relevance of the results and provide recommendations for future research.

Pharmacokinetic/Pharmacodynamic Target Attainment of Ceftazidime in Adult Patients on General Wards with Different Degrees of Renal Function: A Prospective Observational Bicenter Cohort Study.

No prospective evidence exists on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime in adult patients on general wards. We aimed to investigate whether the PK/PD target of ceftazidime (50% T > MIC) is attained in adult patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime. In this observational, prospective, bicenter cohort study, adult patients admitted to a general ward receiving ceftazidime as part of standard care were included. Three blood samples per patient within 72 h after start of treatment were collected. Data were analyzed with nonlinear mixed effects modeling. The primary endpoint was target attainment of 50% T > MIC during the first 24 h of treatment (50% T0-24 > MIC). Forty patients were included from whom 121 blood samples were obtained. All 25/25 patients with adequate renal function, 9/10 patients with moderately impaired renal function (eGFR 30-50 mL/min/1.73 m2) and 5/5 patients with severe impaired renal function (eGFR < 30 mL/min/1.73 m2) attained 50% T0-24 > MIC when applying the clinical breakpoint MIC for Pseudomonas aeruginosa of 8 mg/L. The one patient not attaining the PK/PD target did not differ in any of the collected patients' characteristics, except that this patient was the oldest in the study population. However, age was not statistically significantly associated with clearance or volume of distribution in the population pharmacokinetic model and, therefore, not likely the cause for this patient not attaining the PK/PD target. Our results suggest ≥90% probability of the PK/PD target attainment of ceftazidime in patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime for treatment of infections with Pseudomonas aeruginosa and all bacteria with lower MIC-values.

Emergence of Clonally-Related South Asian Clade I Clinical Isolates of Candida auris in a Greek COVID-19 Intensive Care Unit.

Candida auris has recently emerged as a multidrug-resistant yeast implicated in various healthcare-associated invasive infections and hospital outbreaks. In the current study, we report the first five intensive care unit (ICU) cases affected by C. auris isolates in Greece, during October 2020-January 2022. The ICU of the hospital was converted to a COVID-19 unit on 25 February 2021, during the third wave of COVID-19 in Greece. Identification of the isolates was confirmed by Matrix Assisted Laser Desorption Ionization Time of Flight mass spectroscopy (MALDI-TOF]. Antifungal susceptibility testing was performed by the EUCAST broth microdilution method. Based on the tentative CDC MIC breakpoints, all five C. auris isolates were resistant to fluconazole (≥32 μg/mL), while three of them exhibited resistance to amphotericin B (≥2 μg/mL). The environmental screening also revealed the dissemination of C. auris in the ICU. Molecular characterization of C. auris clinical and environmental isolates was performed by MultiLocus Sequence Typing (MLST) of a set of four genetic loci, namely ITS, D1/D2, RPB1 and RPB2, encoding for the internal transcribed spacer region (ITS) of the ribosomal subunit, the large ribosomal subunit region and the RNA polymerase II largest subunit, respectively. MLST analysis showed that all isolates possessed identical sequences in the four genetic loci and clustered with the South Asian clade I strains. Additionally, PCR amplification and sequencing of the CJJ09_001802 genetic locus, encoding for the "nucleolar protein 58" that contains clade-specific repeats was performed. Sanger sequence analysis of the TCCTTCTTC repeats within CJJ09_001802 locus also assigned the C. auris isolates to the South Asian clade I. Our study confirms that C. auris is an emerging yeast pathogen in our region, especially in the setting of the ongoing COVID-19 worldwide pandemic. Adherence to strict infection control is needed to restrain further spread of the pathogen.

Pharmacokinetic/Pharmacodynamic Determination of Systemic MIC Breakpoints for Intermittent, Extended, and Continuous Infusion Dosage Regimens of Mecillinam.

Intravenous mecillinam has been used for the treatment of urosepsis at several dosing regimens, including a dose of 1,000 mg three times a day (TID). In the current pharmacokinetic/pharmacodynamic (PK/PD) study, we analyzed intermittent, extended, and continuous infusion regimens of mecillinam to provide dosage recommendations to treat infections caused by Enterobacterales exhibiting relatively higher mecillinam MICs than the wild-type strains. Monte Carlo simulation studies indicated that regimens of 1,000 mg TID and 1,000 to 1,200 mg four times a day (QID) are efficacious against wild-type and extended-spectrum β-lactamase-producing Enterobacterales, respectively. Prolonged infusion regimens (extended and continuous) could cover carbapenemase producers with a higher range of MICs (2 to 8 mg/L). IMPORTANCE Previous studies have shown that intravenous mecillinam might be suitable for treatment of urosepsis. Since multidrug-resistant Enterobacterales are common pathogens in such infections, an effort was made to delineate intermittent, extended, and continuous infusion regimens that could cover pathogens exhibiting relatively higher mecillinam MICs than the wild-type strains. Our PK/PD analysis has shown that mecillinam might be considered a valuable therapeutic option for the treatment of systemic infections caused by extended-spectrum β-lactamase- and carbapenemase-producing Enterobacterales exhibiting mecillinam MICs up to 8 mg/L.

Galaxy ASIST: A web-based platform for mapping and assessment of global standards of antimicrobial susceptibility: A case study in Acinetobacter baumannii genomes.

Antimicrobial susceptibility testing (AST) is used to determine the susceptibility of an organism to antibiotics. The determination of susceptibility is based on MIC breakpoints and is provided by EUCAST and CLSI. Likewise, phenotypic classification criteria developed by CDC/ECDC are used for the classification of pathogens into susceptible, multidrug-resistant, extremely drug-resistant, or totally drug-resistant categories. Whole-genome sequencing (WGS)-based diagnosis is now supplementing existing gold-standard microbiology methods for rapid and more precise AST, and therefore, EUCAST recommended quality criteria to assess whole-genome sequence for reporting the same. In this study, these three global standards, MIC breakpoints, phenotypic classification, and genome quality, are applied to the largest publicly available data for Acinetobacter baumannii (AB), the most critical priority pathogen identified by WHO. The drug sensitivity profile and genomes for isolates of AB were obtained from PATRIC and evaluated with respect to AST standards (CLSI and EUCAST). Whole genome quality assessment and antimicrobial resistance mapping is performed with QUAST and ABRicate, respectively. Four in-house methods are developed for mapping standards and are integrated into a Galaxy workflow based system, Galaxy-ASIST. Analysis of the extent of agreement between CLSI 2022 and EUCAST 2022 for antibiotics was carried out using Cohen's kappa statistics. An automated pipeline, Galaxy-ASIST, is designed and developed for the characterization of clinical isolates based on these standards. Evaluation of over 6,500 AB strains using Galaxy-ASIST indicated that only 10% of the publicly available datasets have metadata to implement these standards. Furthermore, given that CLSI and EUCAST have different MIC breakpoints, discrepancies are observed in the classification of resistant and susceptible isolates following these standards. It is, therefore, imperative that platforms are developed that allow the evaluation of ever increasing phenotypic and genome sequence datasets for AST. Galaxy-ASIST offers a centralized repository and a structured metadata architecture to provide a single globally acceptable framework for AST profiling of clinical isolates based on global standards. The platform also offers subsequent fine mapping of antimicrobial-resistant determinants. Galaxy-ASIST is freely available at https://ab-openlab.csir.res.in/asist.

Genotypically Confirmed Vancomycin-Resistant Staphylococcus aureus With vanB Gene Among Clinical Isolates in Kathmandu.

Methicillin-resistant Staphylococcus aureus, a common bacterial pathogen causes various infections. The acquisition of various antimicrobial-resistant genes in S. aureus has led to the transformation of this bacterium into a superbug. Vancomycin resistance among MRSA isolates is an emerging threat in empirical therapy of various infections. The study was hence aimed to find out the susceptibility status of S. aureus isolates toward vancomycin and detect mecA, vanA, and vanB genes among the isolates. A total of 1245 clinical samples from the participants attending a tertiary care hospital in Kathmandu were processed. S. aureus isolated from the samples were subjected to antibiotic susceptibility patterns using the modified Kirby-Bauer disk diffusion method. Agar dilution method was used to determine the minimum inhibitory concentration of vancomycin. The antibiotic-resistant genes such as mecA, vanA, and vanB among S. aureus isolates were screened by a conventional polymerase chain reaction. Of 1245 samples, 80 S. aureus were identified. Out of which, 47.5% (38/80) were phenotypically confirmed MRSA isolates. mecA gene was detected in 84.2% (32/38) of MRSA isolates. 10.5% (4/38) were confirmed as vancomycin-intermediate S. aureus (VISA) by MIC determination. None of the isolates was positive for the vanA gene; however, 2 isolates were found to possess the vanB gene. The 2 isolates have vancomycin MIC breakpoints of 4 to 8 μg/mL. There might be a spreading of vancomycin resistance among S. aureus, creating serious public health problems. Therefore, measures to limit vancomycin resistance should be considered in healthcare facilities as immediately as possible.

Comparison of the pharmacokinetics of continuous and intermittent infusions of ampicillin-sulbactam in dogs with septic peritonitis

To evaluate the time-course of ampicillin-sulbactam and percentage of time that its concentration is above a given MIC (T% > MIC) in dogs with septic peritonitis when delivered as either a continuous infusion (CI) or intermittent infusion (II). 11 dogs with septic peritonitis. Dogs were randomized to receive ampicillin-sulbactam as either CI or II. Continuous infusions were delivered as a 50 mg/kg bolus IV followed by a rate of 0.1 mg/kg/min. Intermittent infusions were administered as 50 mg/kg IV q8h. Serum ampicillin-sulbactam concentrations were measured at hours 0, 1, 6, and every 12 hours after until patients were transitioned to an oral antimicrobial equivalent. All other care was at the discretion of the attending clinician. Statistical analysis was used to determine each patient's percentage of time T% > MIC for 4 MIC breakpoints (0.25, 1.25, 8, and 16 µg/mL). No dogs experienced adverse events related to ampicillin-sulbactam administration. Both CI and II maintained a T% > MIC of 100% of MIC 0.25 µg/mL and MIC 1.25 µg/mL. The CI group maintained a higher T% > MIC for MIC 8 µg/mL and MIC 16 µg/mL; however, these differences did not reach statistical significance (P = .15 and P = .12, respectively). This study could not demonstrate that ampicillin-sulbactam CI maintains a greater T% > MIC in dogs with septic peritonitis than II; however, marginal differences were noted at higher antimicrobial breakpoints. While these data support the use of antimicrobial CI in septic and critically ill patients, additional prospective trials are needed to fully define the optimal doses and the associated clinical responses.

1673. In vitro Activities of Ceftaroline and Comparator Agents against Bacterial Pathogens Frequently Causing Community-Acquired Respiratory Tract Infections in Patients from a Global Population: ATLAS Surveillance Program 2017-2020

Abstract Background Community-acquired bacterial pneumonia (CABP) is a frequent cause of patient morbidity and mortality. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are frequent etiologic agents of CABP. Ceftaroline fosamil is a parenteral cephem approved for treatment of patients with CABP caused by S. pneumoniae (including cases with concurrent bacteremia), methicillin-susceptible Staphylococcus aureus (MSSA), H. influenzae, and some species of Enterobacterales. In this study we report the in vitro activity of ceftaroline and comparators against isolates from community-acquired respiratory tract infections (CARTI) collected through a global surveillance program. Methods Clinically relevant, non-duplicate, isolates cultured from respiratory specimens by clinical laboratories in 54 countries in 2017-2020 were collected by the ATLAS Surveillance Program central laboratory (IHMA, Schaumburg, IL, USA). In total, 2,284 isolates of S. pneumoniae, H. influenzae, M. catarrhalis, MSSA, and methicillin-resistant S. aureus (MRSA) were tested. The isolates (n/percent of total) originated from Asia/South Pacific (579/25.4%); Europe (1281/56.1%); Latin America (298/13.0%); Middle East/Africa (55/2.4%); and North America (Canada only) (71/3.1%). Ceftaroline and comparator agent MICs were determined by CLSI M07 broth microdilution methodology. MICs were interpreted using 2022 CLSI M100 MIC breakpoints. Results Ceftaroline and comparator agent in vitro activities are summarized in the table. Greater than 98% of S. pneumoniae and &amp;gt;99% of MSSA were susceptible to ceftaroline, including penicillin-nonsusceptible S. pneumoniae based on a dosage of 600 mg every 12h. Fifty-eight (31.4%) MRSA were ceftaroline-susceptible-dose-dependent (MIC 2-4 µg/mL) based on a dosage of 600 mg every 8h administered over 2h, with the majority from (n) China (18), S. Korea (8), and Japan (8). Three isolates, all from China, were resistant to CPT (MIC of 8 µg/mL). 99.3% of H. influenzae were susceptible to ceftaroline. Conclusion Ceftaroline demonstrated potent in vitro activity against current pathogens associated with CABP from a global collection. Disclosures All Authors: No reported disclosures.

Potassium penicillin and gentamicin pharmacokinetics in healthy conscious and anesthetized horses.

To determine the effects of general anesthesia on the safety and efficacy of co-administered potassium penicillin G (PEN) and gentamicin (GENT) in horses. Nonrandomized crossover. Six adult, Thoroughbred horses. Horses were administered PEN (22 000 IU/kg IV) and GENT (6.6 mg/kg IV). Plasma samples were collected over a 6 h period and synovial fluid was collected at 30 min and 6 h respectively. Drug administration and sample collection protocols were repeated after at least a 48 hour washout period and induction of anesthesia using xylazine/ketamine and maintenance with isoflurane gas. Drug concentrations were determined using ultrapressure liquid chromatography with mass spectrometry. A 2-compartment model was used to determine pharmacokinetics and differences were determined between conscious and anesthetized horses using paired t-tests (significance P< .05). Potassium penicillin g and GENT had higher minimum plasma concentrations (PEN 0.44 vs. 0.11 μg/mL, P= .002; GENT 3.0 vs. 1.9 μg/mL, P= .009), longer half lives (PEN 71 vs. 59 min, P= .018; GENT 149 vs. 109 min, P= .038), and slower clearances (PEN 3.41 vs. 5.1 mL/kg/min, P= .005; GENT 1.18 vs. 1.48 mL/kg/min, P= .028) in anesthetized horses vs. conscious horses. The PEN concentrations remained above the breakpoint minimum inhibitory concentration (MIC, 0.5 μg/mL) for 332 min in anesthetized vs. 199 min in conscious horses. The GENT concentrations reached 10 times higher than the breakpoint MIC (2 μg/mL) in all horses and were maintained for 58 vs. 59 min in anesthetized and conscious states, respectively. Synovial fluid concentrations were higher in conscious horses vs. anesthetized horses at 30 min for PEN (7.0 vs. 0.93 μg/mL, P< .001) and 30 (5.3 μg/mL vs. 0.79 μg/mL, P< .001) and 360 min (3.4 vs. 1.82 μg/mL, P < .003) for GENT. General anesthesia resulted in lower intrasynovial concentrations and delayed clearance of PEN/GENT in horses. Redosing healthy anesthetized horses with PEN prior to 4-5 h is not necessary. When administered to anesthetized horses, intravenous PEN/GENT may not reach adequate intrasynovial concentrations to treat or prevent common pathogens. The doses or dosing intervals of antimicrobials administered to horses undergoing anesthesia may need to be adjusted to ensure maintenance of safe and effective plasma concentrations.

Mupirocin susceptibility of staphylococci 2022: Is it time for a change in MRSA decolonization protocols?

Nasal decolonization with mupirocin has been a common strategy for the prevention of surgical site infections (SSIs) and recurrent skin and soft tissue infections due to Staphylococcus aureus (SA). We recently noted an increase in SSIs due to SA, including a case of post-operative mupirocin-resistant methicillin-resistant SA (MRSA) infection despite attempted preoperative decolonization with mupirocin. We therefore evaluated the mupirocin susceptibility of SA at our hospital to determine the optimal regimen for decolonization. SA isolates were recovered from clinical and screening samples received in the microbiology laboratory. Mupirocin susceptibility was determined using e-tests and isolates were categorized as susceptible or resistant using a breakpoint MIC value of 4mcg/ml. 223 unique SA isolates from 218 patients were tested. Twenty-four SA isolates (10.8%) were resistant to mupirocin (20 MRSA and 4 methicillin-sensitive SA [MSSA]). MRSA strains were more likely to be resistant to mupirocin than MSSA strains (22.5% vs 3.0%, P < .001). The emergence of drug resistance makes the policy of decolonization with nasal mupirocin a suboptimal strategy for the prevention of MRSA infections. In our study, less than 80% of MRSA strains were mupirocin susceptible. In patients colonized with MRSA at high risk for infection (eg, total joint replacement), other regimens such as intranasal povidone iodine may be preferable to mupirocin for patient decolonization.

Steering Away from Current Amoxicillin Dose Reductions in Hospitalized Patients with Impaired Kidney Function to Avoid Subtherapeutic Drug Exposure.

Current dose reductions recommended for amoxicillin in patients with impaired kidney function could lead to suboptimal treatments. In a prospective, observational study in hospitalized adults with varying kidney function treated with an IV or oral dose of amoxicillin, amoxicillin concentrations were measured in 1–2 samples on the second day of treatment. Pharmacometric modelling and simulations were performed to evaluate the probability of target attainment (PTA) for 40% of the time above MIC following standard (1000 mg q6h), reduced or increased IV dosing strategies. A total of 210 amoxicillin samples was collected from 155 patients with kidney function based on a CKD-EPI of between 12 and 165 mL/min/1.73 m2. Amoxicillin clearance could be well predicted with body weight and CKD-EPI. Recommended dose adjustments resulted in a clinically relevant reduction in the PTA for the nonspecies-related PK/PD breakpoint MIC of 8 mg/L (92%, 62% and 38% with a CKD-EPI of 10, 20 and 30 mL/min/1.73 m2, respectively, versus 100% for the standard dose). For MICs ≤ 2 mg/L, PTA > 90% was reached in these patients following both reduced and standard dose regimens. Our study showed that for amoxicillin, recommended dose reductions with impaired kidney function could lead to subtherapeutic amoxicillin concentrations in hospitalized patients, especially when targeting less susceptible pathogens.

In Vitro Activity of Sulbactam-Durlobactam against Global Isolates of Acinetobacter baumannii-calcoaceticus Complex Collected from 2016 to 2021.

ABSTRACTSulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii-calcoaceticus complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the in vitro activity of sulbactam-durlobactam against a collection of 5,032 ABC clinical isolates collected in 33 countries across the Asia/South Pacific region, Europe, Latin America, the Middle East, and North America from 2016 to 2021. The sulbactam-durlobactam MIC50 and MIC90 were 1 and 2 μg/mL, respectively, for all ABC isolates tested. The addition of durlobactam (at a fixed concentration of 4 μg/mL) to sulbactam decreased its MIC50 by 8-fold (from 8 to 1 μg/mL) and its MIC90 by 32-fold (from 64 to 2 μg/mL) for all ABC isolates. The in vitro activity of sulbactam-durlobactam was maintained across individual ABC species, years, global regions of collection, specimen sources, and resistance phenotypes, including MDR and extensively drug-resistant (XDR) isolates. At 4 μg/mL (preliminary sulbactam-durlobactam susceptible MIC breakpoint), sulbactam-durlobactam inhibited 98.3% of all ABC isolates and >96% of sulbactam-, imipenem-, ciprofloxacin-, amikacin-, and minocycline-non-susceptible isolates; as well as colistin-resistant, MDR, and XDR isolates. Most imipenem-non-susceptible ABC isolates (96.8%, 2,488/2,570) were carbapenem-resistant A. baumannii (CRAB); 96.9% (2,410/2,488) of CRAB isolates were sulbactam-durlobactam-susceptible. More than 80% of ABC isolates had sulbactam-durlobactam MIC values that were ≥2 doubling-dilutions (4-fold) lower than sulbactam alone. Only 1.7% (84/5,032) of ABC isolates from 2016 to 2021 had sulbactam-durlobactam MIC values of >4 μg/mL. Of the 84 isolates, 94.0% were A. baumannii, 4.8% were A. pittii, and 1.2% were A. nosocomialis. In summary, sulbactam-durlobactam demonstrated potent antibacterial activity against a 2016 to 2021 collection of geographically diverse clinical isolates of ABC isolates, including carbapenem-non-susceptible and MDR isolates.

10. Incomplete cefuroxime penetration to the anterior and posterior column of the lumbar spine: an experimental porcine study

BACKGROUND CONTEXT Surgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. PURPOSE The objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. STUDY DESIGN/SETTING In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. OUTCOME MEASURES The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary end-point was tissue penetration (AUCtissue/AUCplasma). METHODS The lumbar vertebral column was exposed from L1 to L5 in eight female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continously obtained over eight hours. Cefuroxime concentration were quantified by ultra high-performance liquid chromatography tandem mass spectrometry. RESULTS Mean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105-141) in plasma, 97 min (79-115) in the anterior column and 93 min (75-111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40-0.56) and posterior column 0.40 (0.33-0.48). CONCLUSIONS T>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint MIC for S. aureus of 4 µg/mL after 123 min (plasma), 97 min (anterior column) and 93 min (posterior column). Open lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebrae of the lumber spine for up to 1.5 hours. This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours. FDA DEVICE/DRUG STATUS cefuroxime (Approved for this indication). Surgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. The objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary end-point was tissue penetration (AUCtissue/AUCplasma). The lumbar vertebral column was exposed from L1 to L5 in eight female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continously obtained over eight hours. Cefuroxime concentration were quantified by ultra high-performance liquid chromatography tandem mass spectrometry. Mean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105-141) in plasma, 97 min (79-115) in the anterior column and 93 min (75-111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40-0.56) and posterior column 0.40 (0.33-0.48). T>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint MIC for S. aureus of 4 µg/mL after 123 min (plasma), 97 min (anterior column) and 93 min (posterior column). Open lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebrae of the lumber spine for up to 1.5 hours. This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours.

In vitro activity of fosfomycin against bacterial pathogens isolated from urine specimens in Canada from 2007 to 2020: CANWARD surveillance study.

Multiple susceptible breakpoints are published to interpret fosfomycin MICs: ≤64 mg/L for Escherichia coli and Enterococcus faecalis grown from urine (CLSI M100); ≤32 mg/L for Enterobacterales and staphylococci when parenteral fosfomycin is prescribed (EUCAST); and ≤8 mg/L for uncomplicated urinary tract infection with E. coli when oral fosfomycin is used (EUCAST). Clinical laboratories are frequently requested to test fosfomycin against antimicrobial-resistant urinary isolates not included in standard documents. The in vitro activity of fosfomycin was determined using the CLSI agar dilution method for a 2007-20 collection of clinically significant Gram-negative (3656 Enterobacterales; 140 Pseudomonas aeruginosa) and Gram-positive (346 E. faecalis; 94 Staphylococcus aureus) urinary isolates from the CANWARD surveillance study. Comparator agents were tested using CLSI broth microdilution. Using the CLSI MIC breakpoint (≤64 mg/L), 99.2% of E. coli (n = 2871; MIC90, 4 mg/L), including 96.7% of ESBL-positive isolates, were fosfomycin susceptible. Similarly, 95.8% of E. coli, including 95.2% of ESBL-positive isolates, were fosfomycin susceptible at ≤8 mg/L (EUCAST oral susceptible MIC breakpoint). All other species of Enterobacterales (except Citrobacter freundii) and P. aeruginosa had higher fosfomycin MICs (MIC90s, 64 to &gt;512 mg/L) than E. coli. Using published breakpoints, 88.4% of E. faecalis (MIC ≤64 mg/L) and 97.9% of S. aureus (MIC ≤32 mg/L) isolates were fosfomycin susceptible. Fosfomycin demonstrated in vitro activity against frequently encountered Gram-positive and Gram-negative urinary pathogens; however, the extrapolation of current CLSI and EUCAST MIC breakpoints to pathogens not specified by standard methods requires further study and is currently not recommended.

Mortality risks associated with empirical antibiotic activity in Escherichia coli bacteraemia: an analysis of electronic health records.

BackgroundReported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy.MethodsWe investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests.ResultsA total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83–1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99–3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07–3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40–3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40–1.89); P = 0.72].ConclusionsWe found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints.

Penicillin plus Ceftriaxone versus Ampicillin plus Ceftriaxone Synergistic Potential against Clinical Enterococcus faecalis Blood Isolates.

ABSTRACTPenicillin plus ceftriaxone is a promising alternative to ampicillin plus ceftriaxone for the treatment of Enterococcus faecalis infective endocarditis. Limited data is available supporting the utilization of penicillin plus ceftriaxone. A total of 20 E. faecalis isolates; one wild-type strain (JH2-2) and 19 clinical blood strains were assessed for penicillin plus ceftriaxone and ampicillin plus ceftriaxone synergy using a 24-h time-kill experiment. Susceptibility was determined by broth microdilution. Differences in bactericidal, bacteriostatic, or inactivity, as well as synergy between treatments were assessed by chi-square or Fisher exact test. All E. faecalis isolates were considered susceptible to ampicillin and penicillin. Ampicillin plus ceftriaxone versus penicillin plus ceftriaxone similarly demonstrated synergy. Bactericidal activity was more commonly observed for ampicillin plus ceftriaxone versus penicillin plus ceftriaxone. Among isolates with a penicillin MIC of 4 μg/mL (n = 7), synergistic activity for both combinations was less common compared to isolates with a penicillin MIC ≤ 2 μg/mL (n = 13). Ampicillin plus ceftriaxone and penicillin plus ceftriaxone demonstrate similar synergistic potential against E. faecalis clinical blood isolates, but strains with higher penicillin and ceftriaxone MICs less frequently demonstrated synergy. Further research is warranted to determine the role of the penicillin plus ceftriaxone therapy and the penicillin MIC in clinical practice.IMPORTANCE Penicillin plus ceftriaxone demonstrates similar synergistic activity against Enterococcus faecalis to ampicillin plus ceftriaxone. Isolates with a penicillin MIC of 4 mg/L and a ceftriaxone MIC of 512 or higher, lack penicillin plus ceftriaxone synergy despite the penicillin susceptibility MIC breakpoint of 8 mg/L.

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

ObjectivesTo describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling.MethodsPatients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L.ResultsThirty-six patients (0.2–12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function.ConclusionsDosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.