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Whole genome and transcriptome analysis of 213 Pseudomonas aeruginosa isolates resistant to antipseudomonal β-lactams collected in 30 countries was performed to evaluate resistance mechanisms against these agents.Isolates were susceptibility tested by reference broth microdilution. Whole genome and transcriptome sequencing were performed, and data were analysed using open-source tools. A statistical analysis of changes in the expression of5500 genes was compared to the expression of PAO1.The high-risk clones ST235 and ST111 were the most prevalent among90 sequence types (STs). Metallo-β-lactamase (MBLs) genes were detected in 40 isolates. AmpC and MexXY were the most common genes overexpressed in approximately 50% of the 173 isolates that did not carry MBLs. Isolates overexpressing pmrA and pmrB, the norspermidine production genes speD2 and speE2, and the operon arnBCADTEF-ugd were noted among strains resistant to ceftolozane-tazobactam and ceftazidime-avibactam, despite the lack of polymyxin resistance often associated to increased expression of these genes. Overexpression of MuxABC-OpmB, OprG, and OprE proteins were associated with resistance to ceftolozane-tazobactam in addition to the usual genes involved in cephalosporin, monobactam, and carbapenem resistance. Statistical analysis identified discrete mutations in ArmZ, OprD, and AmpC that correlated to antipseudomonal β-lactam resistance.P. aeruginosa resistance mechanisms are complex. This analysis suggests the role of multiple genes in resistance to antipseudomonal β-lactams, including some not commonly described.

Objectives To evaluate the genotypic and ceftazidime/avibactam-susceptibility profiles amongst ceftolozane/tazobactam-non-susceptible (NS), MBL-negative Pseudomonas aeruginosa in a global surveillance programme. Methods Isolates were collected as part of the ERACE-PA Global Surveillance programme. Carbapenem-resistant P. aeruginosa deemed clinically relevant by the submitting laboratories were included. Broth microdilution MICs were conducted per CLSI standards to ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime and cefepime. Genotypic carbapenemases were detected using CarbaR and CarbaR NxG (research use only). Isolates negative for carbapenemases by PCR were assessed via WGS. Isolates were included in the analysis if they were ceftolozane/tazobactam-NS and lacked detection of known MBLs. Results Of the 807 isolates collected in the ERACE-PA programme, 126 (16%) were ceftolozane/tazobactam-NS and lacked MBLs. Cross-resistance to ceftazidime and cefepime was common, with only 5% and 16% testing susceptible, respectively. Ceftazidime/avibactam retained in vitro activity, with 65% of isolates testing susceptible. GES was the most common enzymology, detected in 57 (45%) isolates, and 89% remained susceptible to ceftazidime/avibactam. Seven isolates harboured KPC and all tested susceptible to ceftazidime/avibactam. In the remaining 62 isolates, WGS revealed various ESBLs or OXA β-lactamases. While 39% remained susceptible to ceftazidime/avibactam, marked variability was observed among the diverse resistance mechanisms. Conclusions Ceftazidime/avibactam remained active in vitro against the majority of ceftolozane/tazobactam-NS, MBL-negative P. aeruginosa. Ceftazidime/avibactam was highly active against isolates harbouring GES and KPC β-lactamases. These data highlight the potential clinical utility of genotypic profiling as well as the need to test multiple novel agents when carbapenem-resistant P. aeruginosa are encountered.

Background : Narrow-spectrum antibiotics have been found to be equivalent to anti-Pseudomonal agents in preventing organ space infections (OSI) in children with uncomplicated appendicitis. Comparative effectiveness data for children with complicated appendicitis remains limited. This investigation aimed to compare outcomes between the most common narrow-spectrum regimen (ceftriaxone with metronidazole: CM) and anti-Pseudomonal regimen (piperacillin/tazobactam: PT) used perioperatively in children with complicated appendicitis. Methods : Multicenter retrospective cohort study using clinical data from the NSQIP-Pediatric Appendectomy Collaborative database merged with antibiotic utilization data from the Pediatric Health Information System database. Mixed-effects multivariate regression was used to compare NSQIP-defined outcomes and resource utilization between treatment groups after adjusting for patient characteristics, disease severity, and clustering of outcomes within hospitals. Results : 654 patients from 14 hospitals were included, of which 37.9% received CM and 62.1% received PT. Following adjustment, patients in both groups had similar rates of OSI (CM: 13.3% vs. PT: 18.0%, OR 0.88 [95%CI 0.38, 2.03]), drainage procedures (CM: 8.9% vs. PT: 14.9%, OR 0.76 [95%CI 0.30, 1.92]), and postoperative imaging (CM: 19.8% vs. PT: 22.5%, OR 1.17 [95%CI 0.65, 2.12]). Treatment groups also had similar rates of 30-day cumulative post-operative length of stay (CM: 6.1 vs. PT: 6.0 days, RR 1.01 [95%CI 0.81, 1.25]) and hospital cost (CM: $19,235 vs. PT: $20,552, RR 0.92 [95%CI 0.69, 1.23]). Conclusions : Rates of organ space infection and resource utilization were similar in children with complicated appendicitis treated with ceftriaxone plus metronidazole and piperacillin/tazobactam.

Objectives To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants. Methods The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies. Results For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes. Conclusions Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Background Zidebactam, a bicyclo-acyl hydrazide β-lactam ‘enhancer’ antibiotic, in combination with cefepime (WCK 5222) is under clinical development for the treatment of resistant Gram-negative infections. Objectives To evaluate the in vitro activity of cefepime/zidebactam and comparators against 24 220 Gram-negative bacteria. Methods Organisms were consecutively collected in 2018–19 from 137 medical centres located in the USA (n = 9140), Western Europe (W-EU; n = 5929), Eastern Europe (E-EU; n = 3036), the Asia-Pacific region (APAC; n = 3791) and Latin America (LATAM; n = 2324). The isolates were susceptibility tested using the broth microdilution method as part of the SENTRY Program. Cefepime/zidebactam was tested at a 1:1 ratio. Results Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; 99.9% inhibited at ≤8 mg/L) and retained potent activity against carbapenem-resistant Enterobacterales (CRE) isolates (97.8% inhibited at ≤8 mg/L). CRE rates varied widely from 1.1% in the USA to 1.9% in W-EU, 3.6% in APAC and 14.6% in E-EU (3.9% overall). The most common carbapenemase genes observed overall were blaKPC (37.6% of CRE), blaOXA-48-like (30.0%) and blaNDM (23.8%). Resistance to ceftazidime/avibactam among CRE was elevated in APAC (64.8%), E-EU (25.5%) and LATAM (20.7%). Against Pseudomonas aeruginosa, cefepime/zidebactam inhibited 99.2% of isolates at ≤8 mg/L and susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was lowest in E-EU (83.9% and 82.0%, respectively). Cefepime/zidebactam exhibited good activity against Stenotrophomonas maltophilia (80.0% inhibited at ≤8 mg/L) and Burkholderia cepacia (89.4% inhibited at ≤8 mg/L). Conclusions Cefepime/zidebactam demonstrated potent in vitro activity against a large worldwide collection of contemporary clinical isolates of Gram-negative bacteria.

Antimicrobial resistance is one of the top 10 global public-health threats. Especially high rates of resistance have been reported for isolates from ICU patients, requiring expanded treatment options in this setting. We evaluated the activity of ceftolozane/tazobactam and comparators against Gram-negative isolates collected from patients with lower respiratory tract infections (LRTIs) in ICUs in seven Asian countries.In 2017-2019, up to 100 consecutive, aerobic Gram-negative LRTI isolates were collected per year at each of 37 hospitals. MICs were determined using the Clinical and Laboratory Standards Institute reference broth microdilution method.Overall, ceftolozane/tazobactam was active against 72% of 1408 Enterobacterales and 86% of 761 Pseudomonas aeruginosa isolates. Susceptibility to the non-carbapenem β-lactam comparators, including piperacillin/tazobactam, was 52-67% among Enterobacterales isolates, and the activity of all β-lactam comparators, including meropenem, was 57-70% among P. aeruginosa. Ceftolozane/tazobactam maintained activity against 61% of meropenem-nonsusceptible and 64% of piperacillin/tazobactam-nonsusceptible P. aeruginosa. At the country-level, ceftolozane/tazobactam activity ranged from90% against Enterobacterales from Hong Kong and South Korea to64% in Thailand and Vietnam, and from90% against P. aeruginosa from South Korea, Malaysia, Philippines and Taiwan to75% in Thailand and Vietnam. Correspondingly, the proportions of carbapenemase-positive isolates among Enterobacterales and P. aeruginosa isolates were highest in Thailand and Vietnam.Ceftolozane/tazobactam provides a potential treatment option for ICU patients in Asia, which is especially important considering the reduced activity of commonly used β-lactams against the studied ICU isolates. Knowledge of local resistance patterns should inform empirical therapy decision-making.

Objectives To explore the in vitro antimicrobial susceptibility among clinically important Gram-negative bacteria (GNB) in Taiwan. Methods From 2016 through 2018, a total of 5458 GNB isolates, including Escherichia coli (n = 1545), Klebsiella pneumoniae (n = 1255), Enterobacter species (n = 259), Pseudomonas aeruginosa (n = 1127), Acinetobacter baumannii complex (n = 368), and Stenotrophomonas maltophilia (n = 179), were collected. The susceptibility results were summarized by the breakpoints of minimum inhibitory concentration (MIC) of CLSI 2020, EUCAST 2020 (for colistin), or published articles (for ceftolozane/tazobactam). The resistance genes among multidrug-resistant (MDR) or extensively drug-resistant (XDR)-GNB were investigated by multiplex PCR. Results Significantly higher rates of non-susceptibility (NS) to ertapenem and carbapenemase production, predominantly KPC and OXA-48-like beta-lactamase, were observed in Enterobacterales isolates causing respiratory tract infection than those causing complicated urinary tract or intra-abdominal infection (12.7%/3.44% vs. 5.7%/0.76% or 7.7%/0.97%, respectively). Isolates of Enterobacter species showed higher rates of phenotypic extended-spectrum β-lactamase and NS to ertapenem than E. coli or K. pneumoniae isolates. Although moderate activity (54–83%) was observed against most potential AmpC-producing Enterobacterales isolates, ceftolozane/tazobactam exhibited poor in vitro (44.7–47.4%) activity against phenotypic AmpC Enterobacter cloacae isolates. Additionally, 251 (22.3%) P. aeruginosa isolates exhibited the carbapenem-NS phenotype, and their MDR and XDR rate was 63.3% and 33.5%, respectively. Fifteen (75%) of twenty Burkholderia cenocepacia complex isolates were inhibited by ceftolozane/tazobactam at MICs of ≤4 μg/mL. Conclusions With the increase in antibiotic resistance in Taiwan, it is imperative to periodically monitor the susceptibility profiles of clinically important GNB.

Implant-associated osteomyelitis is one of the most feared complications following orthopedic surgery. Although the risk is low, sufficient antibiotic protection of the implant surface is important. The aim of this study was to assess steady-state piperacillin concentrations in the proximity of an orthopedic implant. Time above the minimal inhibitory concentration (fT>MIC) was evaluated for MIC of 8 (low target) and 16 μg/mL (high target). Six female pigs received an intravenous bolus infusion of 4 g/0.5 g piperacillin/tazobactam over 30 min every 6 h. Steady state was assumed achieved in the third dosing interval (12–18 h). Microdialysis catheters were placed in a cannulated screw in the proximal tibial cancellous bone, in cancellous bone next to the screw, and in cancellous bone on the contralateral tibia. Dialysates were collected from time 12 to 18 h and plasma samples were collected as reference. For the low piperacillin target (8 µg/mL), comparable mean fT>MIC across all the investigated compartments (mean range: 54–74%) was found. For the high target (16 µg/mL), fT>MIC was shorter inside the cannulated screw (mean: 16%) than in the cancellous bone next to the screw and plasma (mean range: 49–54%), and similar between the two cancellous bone compartments. To reach more aggressive piperacillin fT>MIC targets in relation to the implant, alternative dosing regimens such as continuous infusion may be considered.

Background: Gram-negative rods are one of the most commonly isolated bacteria within human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to the possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate ceftolozane–tazobactam in vitro activity against carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae clinical strains. Information on the antimicrobial activity of this antimicrobial against Gram-negative rods was also supplemented with a brief review of the relevant literature. Methods: The research involved 316 strains of Gram-negative rods: P. aeruginosa—206 and K. pneumoniae—110. Results: Of the tested strains, 86.0% P. aeruginosa and 30.0% K. pneumoniae remained susceptible to ceftolozane–tazobactam. Conclusions: Therefore, ceftolozane–tazobactam might be a good option in the treatment of infections caused by carbapenem-resistant P. aeruginosa strains, including those in ICU patients. Meanwhile, due to dissemination of ESBLs among K. pneumoniae strains, infections with this etiology should not be treated with the ceftolozane–tazobactam combination.

Ceftolozane/tazobactam, ceftazidime/avibactam and cefiderocol belong to a novel generation of antibiotics that correspond with the β-lactam family. It is necessary to having new options in treating infections caused by Gram-negative, non-fermenting multidrug-resistant bacilli due to the significant increase in multidrug resistance in the last decades. Knowing the main characteristics of each drug is key for correct use.

Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) are new possibilities of antimicrobial treatment that combined a β-lactam with a β-lactamase inhibitor. The United States (US) and European regulatory agencies approved their clinical use in adults with complicated intra-abdominal infections. This study aims to know if one of the two antibiotics obtain better efficacy in adults with complicated intra-abdominal infections and by specific pathogens such as

Contains fulltext : 252053.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T(>1×MIC) (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T(>5×MIC) with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases. GOV IDENTIFIER: NCT03738683.

To evaluate the real-world clinical efficacy of ceftolozane/tazobactam (C/T) in difficult-to-treat infections caused by multi-drug resistant Gram-negative microorganisms, including carbapenem-resistant Pseudomonas aeruginosa.Retrospective cohort study of adult patients treated with C/T for at least 48 hours for infections caused by multi-drug resistant Gram-negative bacteria in a tertiary hospital from May 2016 until August 2019. The primary outcome analysed was clinical failure, defined as a composite of symptomatology persistence after 7 days of C/T treatment, infection recurrence, and/or all-cause mortality within 30 days of follow-up.96 episodes of C/T treatment were included, mostly consisting of targeted treatments (83.9%) for the following sources of infection: intra-abdominal (22.6%), urinary tract (25.8%), skin and soft tissue (19.4%), hospital-acquired pneumonia (14%), and other (6.4%). The most frequently isolated bacteria were carbapenem-resistant (88, 94.6%). Clinical failure rate was 30.1%, due to persistent infection at day 7 (4.3%), recurrence of the initial infection (16.1%), or 30-day all-cause mortality (8.6%). Adverse events most frequently reported were Clostridium difficile infection (9%) and cholestasis (8%).C/T showed a favourable clinical profile for difficult-to-treat multidrug-resistant and carbapenem-resistant Gram-negative infections, regardless of the source of infection.

Widespread antimicrobial resistance in Gram-negative bacteria (GNB), particularly carbapenem resistance, represents a major clinical challenge. Cefiderocol is a novel siderophore cephalosporin active against all carbapenemase classes.We evaluated the in vitro activity of cefiderocol and other antibacterial agents (ceftazidime/avibactam, ceftolozane/tazobactam, colistin and meropenem) against GNB isolates collected in Germany (2013-2018) as part of two multinational studies. Antimicrobial susceptibility testing was performed by broth microdilution. Minimum inhibitory concentrations were interpreted according to EUCAST breakpoints.Cefiderocol had high activity against GNB isolates (N = 2298), encompassing both Enterobacterales (n = 1562) and non-fermenter species (n = 736), and maintained high activity against carbapenem-resistant strains (n = 211). The activity of cefiderocol against Enterobacterales was equivalent to that of ceftazidime/avibactam and colistin, while ceftolozane/tazobactam was somewhat less active. Against non-fermenter species, cefiderocol displayed equivalent activity to colistin; both of these agents were more active than ceftazidime/avibactam and ceftolozane/tazobactam. Colistin had similar activity to cefiderocol against the majority of species. These patterns of activity were echoed in carbapenem-resistant isolates. The high activity of cefiderocol was independent of infection site, whereas other antibacterial agents demonstrated slightly lower activity against isolates causing pneumonia compared with those from other key infection sites.Cefiderocol exhibited consistently high in vitro activity against a variety of GNB isolates collected in Germany, including resistant phenotypes, across multiple infection sites. These data suggest that cefiderocol is an effective choice of antibacterial agent in patients with GNB infection, regardless of species and resistance phenotype to other agents.

Objectives: Treatment options are limited for melioidosis patients who develop nosocomial infections due to extensively drug-resistant (XDR) Gram-negative bacilli. Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA), which have activity against XDR Gram-negative bacteria, are two potential options. Data regarding the susceptibility of Burkholderia pseudomallei to these agents are limited, especially from Thailand, which is an endemic area for melioidosis. Methods: A total of 28 B. pseudomallei isolates from melioidosis patients in northeast Thailand were tested for susceptibility to C/T and CZA by Etest and the disk diffusion method. Minimum inhibitory concentrations (MICs) for other antibiotics commonly used in melioidosis, including trimethoprim/sulfamethoxazole (SXT), ceftazidime (CAZ), imipenem (IPM) and meropenem, were also determined. Results: The MIC of C/T was very low for all isolates, ranging from 0.75 μg/mL to 1.0 μg/mL. For CZA, wide inhibitory zones ranging from 34–35 mm and MICs at 0.5 μg/mL were found. All isolates were also susceptible to SXT, CAZ and IPM based on Clinical and Laboratory Standards Institute (CLSI) breakpoints. Conclusion: C/T and CZA exhibited excellent in vitro activity against B. pseudomallei. Further studies are required to prove efficacy in human subjects.

Objectives To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients. Methods Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24 h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation. Results A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16 g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130–170 mL/min/1.73 m2. Conclusions ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8 mg/L or when patients have an eGFR of 130–170 mL/min/1.73 m2.

BACKGROUND This article provides baseline epidemiological data on Pseudomonas spp. BSI in England for comparison against future findings from the mandatory surveillance of this infection, beginning April 2017. AIM We report trends in incidence, thirty-day all-cause mortality and antimicrobial resistance of Pseudomonas spp. BSI in England between 2009 and 2018. METHODS Patients and antibiotic susceptibility data were obtained from Public Health England's voluntary surveillance database. Mortality information was linked from a central data repository. FINDINGS There were 39,322 Pseudomonas spp. BSI between 2009 and 2018. Regression analysis found that the incidence rate was greater by 18.5% (p< 0.01) in the summer (June to August) and by 16.2% (p< 0.01) in the autumn (September to November), compared with spring (March to May). The thirty-day all-cause case fatality rate (CFR) declined from 32.0% in 2009 to 23.8% in 2018 (p

Purpose The risk of acute kidney injury (AKI) associated with concomitant vancomycin and piperacillin/tazobactam in the intensive care unit (ICU) remains controversial. The aim of this study was to compare the AKI incidence associated with concomitant vancomycin and piperacillin/tazobactam compared to either cefepime or meropenem with vancomycin in the ICU. Materials and methods A multicenter, retrospective, propensity score-matched cohort study was conducted in adult ICU patients administered vancomycin in combination with either piperacillin/tazobactam, cefepime, or meropenem were included. Patients developing AKI ≤48 h following combination therapy initiation were excluded. The primary endpoint was to compare the incidence of AKI associated with concomitant antimicrobial therapy. Multivariable Cox regression modeling in predicting AKI was also conducted. Results A total of 1044 patients were matched. The AKI incidence in vancomycin- piperacillin/tazobactam and vancomycin-cefepime/meropenem groups were 21.9% and 16.8%, respectively (p = 0.068). Multivariable prediction models showed concomitant vancomycin-piperacillin/tazobactam was an independent risk factor of AKI using serum creatinine only (HR 1.52, 1.10–2.10, p = 0.011) and serum creatinine with urine output-based KDIGO criteria (HR 1.77, 1.18–2.67, p = 0.006). No significant differences between groups were observed for AKI recovery patterns or mortality. Conclusion Concomitant vancomycin and piperacillin/tazobactam administration in adult ICU patients was independently associated with an increased risk of AKI.

Background: Irish and European antimicrobial resistance (AMR) surveillance data have highlighted increasing AMR in Enterobacterales and vancomycin resistance in Enterococcus faecium (VRE). Antimicrobial consumption (AC) in Irish hospital settings is also increasing. Methods: A retrospective time series analysis (TSA) was conducted to evaluate the trends and possible relationship between AC of selected antimicrobials and AMR in Enterobacterales and vancomycin resistance in E. faecium, from January 2017 to December 2020. Results: Increased AC was seen with ceftriaxone (P = 0.0006), piperacillin/tazobactam (P = 0.03) and meropenem (P = 0.054), while ciprofloxacin and gentamicin use trended downwards. AMR rates in Escherichia coli, Klebsiella pneumoniae and other Enterobacterales were largely stable or decreasing, an increase in ertapenem resistance in the latter from 0.58% in 2017 to 5.19% in 2020 (P = 0.003) being the main concern. The proportion of E. faecium that was VRE did not changed significantly (64% in 2017; 53% in 2020, P = 0.1). TSA identified a correlation between piperacillin/tazobactam use and the decreasing rate of ceftriaxone resistance in E. coli. Conclusion: Our data suggest that the hospital antimicrobial stewardship programme is largely containing, but not reducing AMR in key nosocomial pathogens. An increase in AC following the COVID-19 pandemic appears as yet to have had no impact on AMR rates.

[Background] Antimicrobial resistance is a threat to global public health. The use of prolonged infusions in the hospital setting for certain antimicrobials is widely increasing in order to improve their efficacy and safety, including resistance development. Due to limited vascular access, it is important to clarify whether they can be infused through the same line with other drugs during Y-site administration., [Aim] The aim of this review is to update and summarize the evidence on Y-site compatibility of antibacterial agents administered as prolonged infusions in intensive care units (ICUs). Study Design A literature review of PubMed, EMBASE and Trissel's Handbook on Injectable Drugs databases was conducted on the compatibility of selected antimicrobials administered simultaneously at a Y-site connection with parenteral nutrition and other widely used drugs in ICUs. All articles published up to October 30, 2021, in English or Spanish were included, regardless of the type of publication (original articles, case reports, letters, etc.). Eligible antimicrobials were those that can be administered as prolonged infusions: ceftazidime, cefepime, piperacillin/tazobactam, meropenem, ceftolozane/tazobactam, ceftaroline, cloxacillin, ceftobiprole, vancomycin and fosfomycin., [Results] A total of 1302 drug-to-drug potential combinations were explored, 196 (15.05%) were found to be incompatible, and in 541 (41.55%), data were not available. The results were presented in a simple 2-dimensional consultation chart as a quick reference for health care professionals., [Conclusions] This review provides useful and reliable information on the compatibility of antimicrobials administered as Y-site infusion with other drugs commonly used in the critical setting. This review contributes to patient safety in nursing practice. Relevance to Clinical Practice To our knowledge, this is the first review on Y-site compatibility of antimicrobials used as prolonged infusions with other commonly used drugs, including anti-emetics, analgesics and anti-epileptic and parenteral nutrition. The results of the current review need to be addressed to promote the knowledge sharing between health professionals and improve the quality and safety of patients. We believe that this review may serve as a simple and effective 2-dimensional updated drug-to-drug compatibility reference chart for critical care nurses.

Objectives To analyse the dynamics and mechanisms of stepwise resistance development to ceftolozane/tazobactam and imipenem/relebactam in XDR Pseudomonas aeruginosa clinical strains. Methods XDR clinical isolates belonging to ST111 (main resistance mechanisms: oprD−, dacB−, CARB-2), ST175 (oprD−, ampR-G154R) and ST235 (oprD−, OXA-2) high-risk clones were incubated for 24 h in Müeller-Hinton Broth with 0.125–64 mg/L of ceftolozane + tazobactam 4 mg/L or imipenem + relebactam 4 mg/L. Tubes from the highest antibiotic concentration showing growth were reinoculated into fresh medium containing concentrations up to 64 mg/L for 7 consecutive days. Two colonies per strain from each of the triplicate experiments were characterized by determining the susceptibility profiles, whole genome sequencing (WGS), and in vitro fitness through competitive growth assays. Results Resistance development occurred more slowly and reached a lower level for imipenem/relebactam than for ceftolozane/tazobactam in all tested XDR strains. Moreover, resistance development to imipenem/relebactam remained low even for ST175 isolates that had developed ceftolozane/tazobactam resistance during therapy. Lineages evolved in the presence of ceftolozane/tazobactam showed high-level resistance, imipenem/relebactam hypersusceptibility and low fitness cost, whereas lineages evolved in the presence of imipenem/relebactam showed moderate (borderline) resistance, no cross-resistance to ceftolozane/tazobactam and high fitness cost. WGS evidenced that ceftolozane/tazobactam resistance was mainly caused by mutations in the catalytic centres of intrinsic (AmpC) or acquired (OXA) β-lactamases, whereas lineages evolved in imipenem/relebactam frequently showed structural mutations in MexB or in ParS, along with some strain-specific mutations. Conclusions Imipenem/relebactam could be a useful alternative for the treatment of XDR P. aeruginosa infections, potentially reducing resistance development during therapy.

Objectives In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. Methods Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7–14 days after the end of therapy) in the microbiological ITT (mITT) population. Results The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: −4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: −18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: −4.51 to 19.38], respectively, were also comparable. Conclusions In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

Objectives: To investigate the clinical distribution and drug resistance of Klebsiella pneumoniae pulmonary infection in patients with hypertensive intracerebral hemorrhage after minimally invasive surgery. Methods: A total of 658 patients with hypertensive intracerebral hemorrhage who underwent minimally invasive surgery admitted to the intensive care unit (ICU) and the Department of Neurology of Affiliated Hospital of Hebei University from January 2015 to January 2020 were enrolled and divided into two groups: the observation group and the control group. Three hundred and thirty-three cases with postoperative pulmonary infection were included into the observation group, and 325 cases without postoperative pulmonary infection were divided into the control group. The intubation time, neurological deficiency score and Glasgow coma scale (GCS) of the two groups were analyzed and compared. Automatic microbial identification system was utilized to isolate bacteria from patients in the observation group, identify Klebsiella pneumoniae, and analyze Klebsiella pneumoniae infection, clinical department distribution, and age distribution. The Kirby-Bauer method was adopted to carry out the drug susceptibility test of Klebsiella pneumoniae infection. Results: The intubation time and neurological deficiency score of patients with hypertensive cerebral hemorrhage in the observation group were significantly higher than those in the control group (p

Published data demonstrate that management of uncomplicated pediatric appendicitis with antibiotics-alone is safe and frequently successful. Randomized controlled trials (RCT) comparing antibiotics-alone to appendectomy are lacking, alongside insight into drivers of failure. We sought to validate the antibiotics-alone approach and identify barriers to success using an RCT design.Patients aged 6-17 years with uncomplicated appendicitis were randomized to appendectomy or intravenous piperacillin/tazobactam for 24-48 h followed by 10 days of oral ciprofloxacin/metronidazole. Enrollment required symptoms48 h, WBC18, appendiceal diameter11 mm, and radiographic absence of perforation. Lack of clinical improvement or persistently elevated WBC resulted in appendectomy. Primary outcomes were 1-year success rate of antibiotics-alone and quality-of-life measures.Among 39 children enrolled over 31 months, 20 were randomized to antibiotics-alone and 19 to surgery. At 1 year, 6 nonoperative patients underwent appendectomy (70% success). Four cases were not true antibiotic failures but instead reflected "pragmatic" challenges to executing nonoperative algorithms. Only 2 cases represented recurrent/refractory appendicitis, suggesting a 90% adjusted 1-year success rate. Parental PedsQL™ scores were similar between treatment cohorts (91.3 vs 90.2, P = 0.32). Children treated with antibiotics-alone had faster return to activity (2.0 vs 12 days, P = 0.001) and fewer parental missed work days (0.0 vs 2.5, P = 0.03).These data corroborate findings from non-randomized studies suggesting 70-90% of uncomplicated pediatric appendicitis can be treated with antibiotics-alone, with fewer disability days. Failures appear multifactorial, often reflecting practical hurdles and not antibiotic limitations. As surgeons consider nonoperative protocols for uncomplicated appendicitis, these data further inform the variability of treatment success.1; randomized controlled trial.

Background The rate of surgical site infection (SSI) after appendectomy for complicated appendicitis (CA) was high at our children's hospital. We hypothesized that practice standardization, including obtaining intra-operative cultures of abdominal fluid in patients with CA, would improve outcomes and reduce healthcare utilization after appendectomy. Methods A quality improvement team designed and implemented a clinical practice guideline for CA that included obtaining intra-operative culture of purulent fluid, administering piperacillin/tazobactam for at least 72 h post-operatively, and transitioning to oral antibiotics based on intraoperative culture data. We compared outcomes before and after guideline implementation. Results From July 2018-October 2019, 63 children underwent appendectomy for CA compared to 41 children from January-December 2020. Compliance with our process measures are as follows: Intra-operative culture was obtained in 98% of patients post-implementation; 95% received at least 72 h of piperacillin-tazobactam; and culture results were checked on all patients. Culture results altered the choice of discharge antibiotics in 12 (29%) of patients. All-cause morbidity (SSI, emergency department visit, readmission to hospital, percutaneous drain, unplanned return to operating room) decreased significantly from 35% to 15% (p=0.02). Surgical site infections became less frequent, occurring on average every 27 days pre-implementation and every 60 days after care pathway implementation (p=0.03). Conclusions Utilization of a clinical practice guideline was associated with reduced morbidity after appendectomy for CA. Intra-operative fluid culture during appendectomy for CA appears to facilitate the selection of appropriate post-operative antibiotics and, thus, minimize SSIs and overall morbidity.

La pipéracilline-tazobactam est une combinaison d’un antibiotique bêta-lactamine et d’un inhibiteur des bêta-lactamases fréquemment prescrite aux soins intensifs. Les patients admis aux soins intensifs présentent souvent une réponse très variable au traitement en raison des multiples changements pathophysiologiques présents dans cette population qui modifient le profil pharmacocinétique du médicament. La modélisation pharmacocinétique de population est une approche qui permet d’expliquer une partie de cette variabilité au moyen d’équations mathématiques. À l’aide d’un modèle pharmacocinétique, il est possible de décrire le devenir systémique du médicament à l’aide de paramètres clés comme la clairance et le volume de distribution. Également, ce type de modèle offre la possibilité d’effectuer des simulations de régimes posologiques pour faciliter l’atteinte des cibles thérapeutiques, dans une optique d’individualisation de la pharmacothérapie. Ce projet de maîtrise avait trois objectifs. Le premier était de documenter la variabilité associée à la pharmacocinétique de la pipéracilline-tazobactam aux soins intensifs en réalisant une revue de la littérature. Cette revue a pu relever certaines covariables significatives dans les modèles qui expliquaient une partie de la variabilité observée, comme la clairance de la créatinine et le poids. Le second avait pour but d’évaluer la performance prédictive des modèles pharmacocinétiques déjà disponibles dans la littérature pour la pipéracilline-tazobactam à l’aide d’une base de données indépendante. Parmi les modèles évalués, le meilleur a été retenu afin d’optimiser les régimes posologiques aux soins intensifs. Ainsi, grâce à ce modèle, un nomogramme prenant en considération la fonction rénale du patient a été développé pour faciliter l’atteinte des cibles thérapeutiques lors de l’administration de la pipéracilline-tazobactam. Finalement, le troisième objectif était d’évaluer l’impact d’une variation de la fraction libre de la pipéracilline-tazobactam sur la performance prédictive du modèle ainsi que son impact sur la pharmacocinétique du médicament. Cette évaluation a fait ressortir l’importance d’utiliser la concentration libre plutôt que d’utiliser la concentration totale de la pipéracilline-tazobactam pour le suivi thérapeutique, car l’assomption d’une fraction libre théorique unique pour tous les patients peut nuire à la prédiction adéquate des concentrations par un modèle pharmacocinétique en milieu clinique., Piperacillin-tazobactam is a beta-lactam/beta-lactamase inhibitor antibiotic combination frequently prescribed in intensive care units. Admitted patients often show a large variability in treatment response due to multiple pathophysiological changes that alter the pharmacokinetic profile of the drug. Population pharmacokinetic modeling is an approach that can explain some of this variability using mathematical equations. Using a pharmacokinetic model, key parameters such as clearance and volume of distribution can be retrieved to describe the systemic exposure of the drug. Also, this type of model offers the possibility to perform simulations to find optimized dosing regimens that may facilitate the achievement of target concentrations to individualize drug therapy. This master's project had three objectives. The first was to document the variability in the pharmacokinetics of piperacillin-tazobactam in the intensive care unit by conducting a literature review. This review was able to highlight key covariates, such as creatinine clearance and body weight, that could explain the variability observed in this population. The second was to evaluate the predictive performance of pharmacokinetic models available in the literature for piperacillin-tazobactam using an independent database. Among the models evaluated, the best one was selected to offer optimized dosing regimens for critically ill patients. Thus, with this model, a nomogram that accounts for the patient's renal function was developed to facilitate the achievement of therapeutic targets of piperacillin-tazobactam. Finally, the third objective was to evaluate the impact of fluctuations in the unbound fraction of piperacillin-tazobactam on the predictive performance of the model as well as its impact on the pharmacokinetics of the drug. This evaluation highlighted the importance of using unbound piperacillin concentrations for drug monitoring over total concentrations, as applying a theoretical unbound fraction to every individual may hinder the predictive performance of pharmacokinetic model if it is used in a clinical setting.

The management of infections caused by carbapenem-resistant organisms has been a challenge. We report a rare emergence of resistance to the novel beta-lactam/ beta-lactamase combination ceftolozane/tazobactam by Klebsiella pneumoniae, causing urinary tract infection. The K. pneumoniae, in this case, was reported to be sensitive to the other novel beta-lactam/ beta-lactamase combination of ceftazidime/avibactam. The timely administration of ceftazidime/avibactam resulted in prompt clinical resolution of the urinary tract infection caused by an extensively drug-resistant K. pneumoniae.

Background: Piperacillin (Pip)/tazobactam (Taz) is a broad-spectrum antimicrobial agent that has been commonly used in the intensive care unit for severe and life-threatening infections. Recent evidence suggests that therapeutic drug monitoring (TDM) for Pip could be beneficial in clinical practice to facilitate dose optimization and increase the odds of treatment success. The aim was to develop and validate a sensitive and simple high-performance liquid chromatography (HPLC) method for the simultaneous quantification of Pip and Taz in human plasma. Methods: Samples (0.3 mL) were deproteinized with acetonitrile. The supernatant was evaporated and then reconstituted and injected into the HPLC. The chromatographic analysis was carried out by using the C18 column and gradient elution with the acetonitrile:water mobile phase mixture with 0.1% trifluoracetic acid at a flow rate of 0.8 mL/min using a UV detector at 218 nm. Results: The method had acceptable linearity (r2 > 0.99) over the concentration ranges of 0.5–400 μg/mL and 1–100 μg/mL for Pip and Taz, respectively. The method demonstrated acceptable inter- and intra-day precision and accuracy within ±20% with adequate stability results. Conclusion: The developed method is sensitive and simple and utilizes simple sample preparation and elution steps, making it suitable and practical for Pip/Taz TDM.

Die bakterielle Sepsis und der septische Schock stellen in der operativen Intensivmedizin nach wie vor die häufigste Todesursache dar. Eine frühzeitige und adäquate Antibiotikatherapie ist essentiell wichtig, um dieses Krankheitsbild zu beherrschen. Trotz therapeutischem Drug Monitoring und kontinuierlicher Infusion von β-Lactamen stellt sich die korrekte Dosisfindung beim kritisch Kranken als sehr komplex dar. Dies liegt vor allem in der veränderten Physiologie intensivmedizinscher Patienten begründet: variierte Verteilungsvolumina sowie Funktionseinschränkungen verschiedener Organsysteme haben eine schwer vorhersagbare Veränderung der Pharmakokinetik zur Folge. Aus diesem Grund etabliert sich auf Intensivstationen zunehmend das Therapeutische Drug Monitoring, Über- und Unterdosierungen können so rechtzeitig erkannt und rasch korrigiert werden. Zudem wird auf Basis zahlreicher Studien die kontinuierliche Gabe von β-Lactamen präferiert, da so möglichst lange die gewünschte Serumkonzentration oberhalb der vierfachen minimalen Hemmkonzentration erreicht werden kann. Ein Rückschluss auf entsprechend hohe Gewebekonzentrationen lässt sich weiterhin nicht sinnvoll ziehen, ebenso wenig auf das klinische Outcome. In dieser Beobachtungsstudie wurden 109 Fälle von Patienten retrospektiv analysiert, welche im Zeitraum von August 2014 bis April 2015 auf der operativen Intensivstation der Universitätsklinik Ulm eine antibiotische Therapie mit Piperacillin/Tazobactam erhielten. Trotz kontinuierlicher Infusion und therapeutischem Drug Monitoring wurde in knapp 80 % der Fälle nicht die gewünschte Zielkonzentration von 64 mg/L +/- 10 % erreicht. Fast 45 % der Patienten hatten zu niedrige Medikamentenkonzentrationen. Als wichtigste Einflussgröße auf das Erreichen der festgelegten Zielkonzentration konnte die Nierenfunktion herausgearbeitet werden. Sowohl eine augmented renal clearance als auch eine Niereninsuffizienz oder eine Nierenersatztherapie beim Patienten hatten relevante Veränderungen der Serumkonzentration zur Folge. In Zukunft ist die Festlegung einer Standardprozedur bezüglich der Dosisanpassung sicherlich sinnvoll. Zudem sollten neuere Erkenntnisse bezüglich möglicher geringerer Zielkonzentrationen Berücksichtigung finden.

The treatment of K. pneumoniae infections has become more difficult due to the emergence of multidrug-resistant strains. This study aimed to evaluate antimicrobial resistance patterns and detect different types of beta-lactamase genes among MDR and non-MDR Klebsiella pneumoniae in various clinical samples. A total of 150 Klebsiella pneumoniae were identified from different clinical samples by conventional microbiological procedures. Antibiotic sensitivity was detected by the Kirby-Bauer disc diffusion method. Extended-spectrum beta-lactamase, Metallo-β-lactamase, and carbapenemase were phenotypically detected by double-disk synergy test, combined disk assay, and modified Hodge test. PCR also detected different β lactamase genes and virulence genes. The majority of Klebsiella pneumoniae were multi-drug resistant (82%). The bacteria were found resistant to most β-lactam antibiotics, aminoglycosides, ciprofloxacin, cotrimoxazole, carbapenem, piperacillin, and tazobactam. However, only about 0.7% colistin resistance was observed. A double-disk synergy test was performed among the isolates for phenotypic detection of ESBL producing Klebsiella pneumoniae. Only 16.6% of isolates were found to be ESBL producers. Among β-lactamase genes, NDM (23.34%), OXA-48(8%), and KPC (7.3%) were detected. Other prevalent β lactamase genes VIM and IMP were not detected. In summary, the prevalence of MDR Klebsiella pneumoniae is high in Bangladesh, which may complicate the treatment of hospitalized patients.

Background: Antibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia. Procedure: We analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery. Results: Recurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0–27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics

Objectives: The prevalence of Gram-negative bacteria (GNB) demonstrating extensive, multiple antimicrobial resistance is increasing in England, leaving few treatment choices. Cefiderocol is a novel siderophore cephalosporin approved in Europe for the treatment of aerobic GNB infections in adults with limited treatment options. We report pooled data for a clinical isolate set collected in England between 2014–2018. Methods: MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol susceptibility was tested using iron-depleted cation-adjusted Muller–Hinton broth. Susceptibility rates were based on EUCAST breakpoints. In the absence of a species-specific breakpoint, pharmacokinetic/pharmacodynamic breakpoints were used. Results: Of 1886 isolates from England [74.1% Enterobacterales (18.7% Escherichia coli, 17.2% Klebsiella pneumoniae), 25.9% non-fermenters (18.4% Pseudomonas aeruginosa, 3.7% Acinetobacter baumannii)], 98.7% were cefiderocol-susceptible. Cefiderocol susceptibility in Enterobacterales (99.0%) was significantly (P < 0.01) greater than ceftolozane/tazobactam (94.3%), but similar to meropenem (99.3%) and ceftazidime/avibactam (99.4%). Overall, cefiderocol susceptibility (98.0%) in non-fermenters was significantly (P < 0.01) higher than comparators (range, 84.5–92.4%). Susceptibility to cefiderocol was 98.3–99.6% by infection source and was significantly (P < 0.01) greater than comparators for isolates from patients with nosocomial pneumonia (cefiderocol, 98.3%; comparators range, 79.8–93.8%). Excluding intrinsically meropenem-resistant Stenotrophomonas maltophilia, 47/1846 isolates (2.5%) were meropenem-resistant. A high proportion of meropenem-resistant P. aeruginosa were susceptible to cefiderocol (95.0%). All S. maltophilia isolates (40/40) were cefiderocol-susceptible. Conclusion: A substantial proportion of clinical isolates from England, representing a wide range of pathogens across multiple infection sources, was cefiderocol-susceptible. Cefiderocol retained activity against meropenem-resistant strains.

Background Very limited studies, so far, have been conducted to identify the pharmacodynamic targets of cefepime, a well-established fourth-generation cephalosporin. As a result, conventional targets representing the cephalosporin class are used for cefepime target attainment analysis. Objectives We employed both a neutropenic murine lung infection model and an in vitro pharmacokinetic model (IVPM) to determine cefepime’s pharmacodynamic target [percentage of the dosing interval during which unbound drug concentrations remain higher than the MIC (%fT>MIC)] for bacteriostatic and 1 log10 kill effects. Methods Ten strains with cefepime MICs ranging from 0.03 to 16 mg/L were studied in the lung infection. In the IVPM, five cefepime-resistant strains with cefepime/tazobactam (fixed 8 mg/L) MICs ranging from 0.25 to 8 mg/L were included. Through 24 h dose fractionation, both in lung infection and IVPM (in the latter case, tazobactam 8 mg/L continuous infusion was used to protect cefepime), varying cefepime exposures and corresponding pharmacodynamic effect scenarios were generated to identify the pharmacodynamic targets. Results Using a non-linear sigmoidal maximum-effect (Emax) model, the cefepime’s plasma fT>MIC for 1 log10 kill in lung infection ranged from 17% to 53.7% and a combined exposure–response plot yielded 30%. In the case of IVPM, T>MIC ranged from 6.9% to 75.4% with a mean value of 34.2% for 1 log10 kill. Conclusions Both in vivo and in vitro studies showed that cefepime’s pharmacodynamic requirements are lower than generally reported for cephalosporins (50%–70% fT>MIC). The lower requirement for cefepime could be linked with factors such as cefepime’s better permeation properties and multiple PBP affinity-driven enhanced bactericidal action.

In India, the most common complication of lower limb amputated stump is infection, and it accounts 53.5% of total amputation. The published studies on prevention and management of such infection are very few. All the patients presenting with infection of amputated lower limb stump between 2010 and 2015 were included in this descriptive study. Diagnosis was confirmed by clinical, hematological, radiological, and microbiological test, i.e., culture and sensitivity of wound. Based on sensitivity report, treatment was started. There were 62 patients with 80 amputated lower limb stump infections. The most common presentation was sinus tract (54.8%). The most common cultured pathogen was Pseudomonas aeruginosa (39%). The most sensitive antibiotic was Piperacillin + Tazobactam (82.25%), followed by imipenem (75%), and levofloxacin (58.75%). More than 60% of Indian population lives in rural area. The primary mode of healthcare services in India is peripheral health centers. The first choice of drug therapy in management of amputated lower limb stump infection can be levofloxacin. Mishra S, Kumar DK, Gupta AK, et al. Lower Limb Stump Infection Management among Rural North Indian Population. Indian J Phys Med Rehab 2019;30(3):66–68.

WHAT IS KNOWN AND OBJECTIVE Betalactam antibiotics are the most frequent cause of hypersensitivity reactions. Rapid drug desensitization (RDD) is a technique that induces temporary tolerance to a drug allowing a patient to receive the optimal agent. The increased use of RDD and the lack of standardization among available protocols in terms of formulation, starting dose, number of steps and dosing frequency make it essential to determine the safety and appropriate management of these protocols, especially regarding reconstitution, diluents, stability and drug administration in order to guarantee reproducibility. We reviewed betalactam desensitization protocols in a tertiary hospital, in accordance with currently published practices and evaluated its use on patients over a period of three years. METHODS (a) We performed a literature search in PubMed, MEDLINE and Google Scholar databases for case reports and/or systematic reviews describing desensitization protocols for betalactam antibiotics. Pharmacokinetic parameters and physicochemical stability were checked for each antibiotic. (b) We retrospectively reviewed inpatients undergoing our antibiotic desensitization protocols from February 2018 to January 2021. Data and outcomes of desensitization procedures were analysed. RESULTS We developed nine RDD protocols: meropenem, ceftriaxone, ceftazidime, ampicillin, ceftolozane/tazobactam, cloxacillin, piperacillin/tazobactam, amoxicillin/clavulanate and penicillin G sodium. Five antibiotics have RDD protocols for two different doses, adjusted to patients with impaired renal function. Detailed data (diluent, total dose, volume, concentrations, duration and stability) of the protocol of each antibiotic used are provided. 28 desensitizations were performed in 17 patients, three of them with confirmed allergies by skin test. 26 out of 28 (92.9%) of them were successfully completed, including those three with positive skin results. The pathogens most frequently involved were E. faecalis and P. aeruginosa; both frequently associated with bacterial resistance. Meropenem, ceftriaxone and ceftazidime were the antibiotics most desensitized. 25 out of 26 (96.1%) procedures were successful in resolving the infection. WHAT IS NEW AND CONCLUSIONS Detailed information about compounding, dilution and stability is crucial to ensure safe and successful desensitization processes, as well as good coordination between the Allergy and Pharmacy departments. The increase in bacterial resistance to many of the commercially available antibiotics limits the therapeutic options for treating multidrug-resistant infections; in those situations, antibiotic desensitization may be a key therapeutic option. Although there is a broad consensus in limiting the use of RDD to patients with confirmed allergy, in usual clinical practice its application in those strongly suspected of having type I hypersensitivity is still observed. Our betalactam desensitization protocols have shown themselves to be safe and effective, as evidenced by data from the 17 patients on whom they have been tested.

β-Lactams are the most commonly used antibiotics in intensive care units (ICUs). As critically ill patients often experience pharmacokinetic aberrations, and rates of antimicrobial resistance vary between hospital settings, reliance on tertiary sources or package labeling to guide empiric dosing often results in suboptimal β-lactam exposure. The primary objective was to identify β-lactam regimens capable of achieving ≥90% cumulative fraction of response (CFR) against 7 Gram-negative pathogens within 4 ICUs at our institution. Unit-specific minimal inhibitory concentration (MIC) distribution data was used in combination with published pharmacokinetic parameters in critically ill patients to perform Monte Carlo simulations. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (%ƒT > MIC) was used as the pharmacodynamic target: 70%ƒT >MIC for cefepime, 40%ƒT > MIC for meropenem, and 50%ƒT > MIC for piperacillin/tazobactam. Regimens were modeled to determine the likelihood of achieving ≥90% CFR. Overall, intermittently dosed cefepime, meropenem, and piperacillin/tazobactam failed to achieve ≥90% CFR for every organism. Cefepime 2 g intermittent bolus every 8 hours failed to achieve ≥90% CFR for Klebsiella pneumoniae or Enterobacter cloacae despite susceptibility rates exceeding 90%. Piperacillin/tazobactam 4.5 g prolonged infusion (PI) every 6 hours achieved

Introduction Combined use of vancomycin (VCM) and piperacillin/tazobactam (PIPC/TAZ) has been reported to increase the incidence of acute kidney injury (AKI). However, the risk factors associated with AKI after VCM and PIPC/TAZ (VPT) administration have not yet been identified. Therefore, we retrospectively assessed patients treated with VPT to investigate the risk factors for AKI development. Methods The study involved patients who were treated with VPT from January 1, 2016 to March 31, 2020. The patients were divided into the AKI or non-AKI group. The clinical characteristics of patients and antimicrobial therapy were compared between the groups. Their association with AKI risk was evaluated using multivariate logistic regression analysis. Results In total, 182 patients were included, with 118 in the non-AKI group and 64 in the AKI group. Therefore, the incidence of AKI was 35.2 %. The initiation of VPT combination therapy on the same day and concomitant use of vasopressors were associated with an increased risk of AKI (odds ratio [OR] 2.55, 95 % confidential interval [CI] 1.20–5.44 and OR 3.22, 95 % CI 1.31–7.89, respectively). Conclusion Our findings suggest that the concomitant use of vasopressors and initiating VPT combination therapy on the same day are likely risk factors for AKI development.

Introduction Colistin is used to treat severe antibiotic-resistant Gram-negative infections (GNIs). With the rise of antibiotic resistance, colistin has been used increasingly as a ‘last-line’ therapy for multidrug-resistant GNIs. We evaluated the incidence of acute kidney injury (AKI) and mortality among patients receiving colistin or one of the new β-lactam/β-lactamase inhibitors (βL + βLI) (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam). Methods This retrospective cohort study used data from the Premier Healthcare Database. The cohort included propensity score-matched adults with an inpatient stay between January 2016 and December 2018. Patients given both colistin and BL + BLI as treatment for ≥ 72 h were excluded. AKI was defined as acute renal failure or dialysis during hospitalization with antibiotic administration. Propensity score matching was used to control for selection bias and confounding. Logistic regression evaluated associations between treatment, AKI, and in-hospital mortality. Results The total number of patients in the matched cohorts were 256 in each. Overall, 23.8% and 13.3% of patients receiving colistin or new βL + βLI agents, respectively, experienced AKI during hospitalization (p = 0.002); odds of AKI for colistin were 3.0 (95% CI 1.71, 5.21). Following propensity score-matching, patients without baseline renal disease experienced AKI during hospitalization to a higher degree in the colistin group compared to the βL + βLI group (17.1% vs. 6.8%); colistin use was associated with 3.7 times higher odds (95% CI 1.84, 7.42) of AKI compared to βL + βLI agents. The odds of mortality in patients on colistin developing AKI were more than three times that of patients receiving a BL + BLI agent who developed AKI. Among patients receiving colistin, incident AKI was associated with 6.1 times higher odds (95% CI 2.53, 14.71) of mortality. Conclusions Patients receiving colistin for GNIs had significantly higher odds of AKI and mortality than those receiving βL + βLI. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00556-x.

Purpose Consensus is lacking regarding the optimal antibiotic treatment for pediatric complicated appendicitis. This study determined the optimal first-line antibiotic treatment for pediatric patients with complicated appendicitis based on peritoneal fluid cultures. Methods This retrospective study examined the cases of pediatric patients who underwent appendectomy for complicated appendicitis at our institution between 2013 and 2019. Peritoneal fluid specimens obtained during appendectomy were cultured for the presence of bacteria. Results Eighty-six pediatric patients were diagnosed with complicated appendicitis. Of them, bacteria were identified in 54 peritoneal fluid samples. The major identified bacteria were Escherichia coli (n=36 [66.7%]), Bacteroides fragilis (n=28 [51.9%]), α-Streptococcus (n=25 [46.3%]), Pseudomonas aeruginosa (n=10 [18.5%]), Enterococcus avium (n=9 [16.7%]), γ-Streptococcus (n=9 [16.7%]), and Klebsiella oxytoca (n=6 [11.1%]). An antibiotic susceptibility analysis showed E. coli was inhibited by sulbactam/ampicillin in 43.8% of cases versus cefmetazole in 100% of cases. Tazobactam/piperacillin and meropenem inhibited the growth of 96.9-100% of the major identified bacteria. E. coli (100% vs. 84.6%) and P. aeruginosa (100% vs. 80.0%) were more susceptible to amikacin than gentamicin. Conclusion Tazobactam/piperacillin or meropenem is a reasonable first-line antibiotic treatment for pediatric complicated appendicitis. In the case of aminoglycoside use, amikacin is recommended.

Streptococcus suis (S. suis) infection, a zoonotic infection with a global distribution, is clinically manifested by meningitis, followed by sepsis, infective endocarditis and arthritis. S. suis infection is not uncommon, but acute myocardial infarction (AMI), as an initial symptom, has not yet been reported. We report a case of S. suis infection with AMI as an initial symptom. The patient, a previously healthy butcher with no known risk factors for AMI, was admitted to hospital with a sudden onset of AMI. Then, thrombolytic therapy, anticoagulation therapy with nadroparin calcium and antiplatelet therapy with aspirin and ticagrelor were adopted. Two days later, blood cultures in aerobic and anaerobic bottles were positive for S. suis and he received antibiotic therapy with piperacillin/tazobactam. Then, his symptoms improved and he was transferred to a special infectious disease hospital for further treatment and was discharged upon complete recovery. To the best of our knowledge, this is the first reported case of AMI as the initial symptom of S. suis infection, which illustrates a possible new symptom of this important pathogen. For AMI patients with unexplained infections, and who are in close frequent contact with pigs and/or pork products, clinicians should be alert to the possibility of S. suis infections.

In the phase III RESTORE‐IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all‐cause mortality at day 28 and favorable clinical response at the early follow‐up visit in adult participants with gram‐negative hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE‐IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to

INTRODUCTION The duration of perioperative antibiotic prophylaxis following live liver donor hepatectomy (LDH) is not known. METHODS This is a double-blind equivalence trial. All consecutive LDH were randomized into: group A (three doses) and group B (nine doses) of perioperative antibiotics (piperacillin + tazobactam - 4.5 g intravenous) at fixed 8 hourly intervals. Primary end point was incidence of infective complications as per CDC (Centers for Disease Control and Prevention) criteria. Secondary end points were liver function tests, total leukocyte count, international normalized ratio, hospital stay, morbidity, and cost analysis. RESULTS One hundred and twenty-six LDHs were enrolled. A total of 19.8% (n = 25) experienced postoperative complications, 11 (17.7%) in group A and 14 (21.9%) in group B (P = .561). Infective complications were seen in 11 donors (8.1%), five in group A and six in group B (P = .79). A total of 8.1% of donors required continuation/up-gradation of antibiotics in group A and 9.4% in group B. Return to soft diet was delayed in group B (P = .039). Median hospital stay and cost were similar. CONCLUSION Three doses of perioperative antibiotic are equally effective in preventing infective complications.

Introduction Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. Methods We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. Results Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). Conclusions Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the β-lactam/β-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

OBJECTIVES: The aim of this study was to determine the prevalent aerobic vaginal bacteria and their antibiogram to commonly prescribed antibiotics for the treatment of aerobic vaginitis (AV). METHODOLOGY: A total of 200 high vaginal swabs (HVS) samples were collected from different AV suspected patients visiting Khyber Teaching Hospital (KTH) and processed for identification of bacterial isolates followed by antibiotic susceptibility patterns as per CLSI protocols. RESULTS: Out of 200 clinical samples, 70 (35%) HVS isolates yielded bacterial growth. Of the isolates, E.coli was the common pathogen 36 (51.4%) followed by S.aureus 20 (28.5%), Enterobacter spp 08 (11.4%), Pseudomonas spp 04 (5.7%) and Citrobacter spp 02 (2.8%). The highest prevalence was observed in the age group of 21-35 years (31.4%) followed by age groups 16-20 years (25.7%) and 26-30 years. S.aureus isolates (n=20) were resistant to ciprofloxacin (90%), cephradine (70%), erythromycin (70%), gentamicin (50%) and cefotaxime (40%) while 1 (5%) of each isolate was resistant to methicillin and vancomycin. Majority of the gram-negative isolates (n=50) were resistant to cotrimoxazole, cephalosporins, quinolones, aminoglycosides and susceptible to carbapenems, tigecycline, sulbactam and tazobactam. CONCLUSION: Aerobic vaginitis should be treated very selectively in order not to kill the beneficial bacteria. Before treating AV, the causative agents should be accurately identified and tested for drug susceptibility patterns and empirical antibiotic therapy should be avoided.

Objetivo: Avaliar a importância do farmacêutico clí­nico tanto na utilização dos antimicrobianos, quanto na redução de custo desses medicamentos.Método: O estudo caracterizado como descritivo, com abordagem quantitativa foi realizado no perí­odo de outubro a dezembro de 2016 em uma Unidade de Terapia Intensiva de um hospital público na cidade de Caruaru-PE. A coleta de dado ocorreu por meio de análise documental utilizando como ferramenta o sistema operacional padrão MV200.Resultados: Verificou-se uma maior utilização de piperacilina+tazobactam e meropenem, ambos antibióticos com amplo espectro de ação, evidenciando a escolha de terapias por parte dos protocolos do hospital com essa caracterí­stica. Entretanto, não se observa uma redução de gastos significativos em decorrência de um alto consumo ainda prevalente de antimicrobianos por pacientes de UTI. Conclusão: Diante dos resultados, infere-se que a ação de um farmacêutico clí­nico na Unidade de Terapia Intensiva auxiliaria com um maior controle dessas prescrições, evitando interações medicamentosas e atendendo í s necessidades de cada paciente.

Background The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. Methods Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. Results A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]). Conclusions C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Purpose The combination of vancomycin and piperacillin/tazobactam (VAN + PTZ) provides a broad spectrum of activity against multiple pathogens. However, a major issue in previous research concerned significant nephrotoxicity associated with this drug combination, and most studies have been conducted in American and European countries, with no similar data available from China. Therefore, this study evaluated the nephrotoxic effects of VAN + PTZ in a large-scale Chinese cohort to determine the prevalence of acute kidney injury (AKI) in this population by comparing PTZ and vancomycin monotherapies and the combined use of vancomycin and β-lactam antibiotics. Methods This retrospective cohort study identified adult patients who received vancomycin either as monotherapy or in combination with PTZ or carbapenem (VAN + CAR) for at least 48 hours at Jiangsu Province Hospital from January 1, 2017, to December 31, 2018. Patients were also evaluated for the development of AKI, defined according to the Kidney Disease Improving Global Outcome criteria. Duration of vancomycin exposure, steady-state trough vancomycin concentrations, and other risk factors for AKI were assessed. A Bayesian network meta-analysis was conducted to validate our results and comparatively evaluate the nephrotoxicity of β-lactam antibiotics in combination with vancomycin. Findings In all, 752 patients were included in the present study. The prevalence of AKI was higher in the VAN + PTZ group than in the VAN and VAN + CAR groups (15.2% vs 4.0% and 6.0%, respectively). After adjustment for confounding factors, VAN + PTZ was still related to AKI (odds ratio [OR] = 4.37; 95% CI, 1.65–11.59; P = 0.003). The network meta-analysis indicated that VAN + PTZ was associated with a significantly higher risk for AKI than was VAN (OR = 3.23; 95% CI, 2.50–4.35), PTZ (OR = 2.86; 95% CI, 1.92–4.12), VAN + cefepime (FEP) (OR = 2.37; 95% CI, 1.80–3.19), or VAN + CAR (OR = 2.28; 95% CI, 1.64–3.21). However, there was no significant difference with respect to AKI prevalence among the VAN, PTZ, VAN + FEP, and VAN + CAR groups. Implications The prevalence of AKI was higher with VAN + PTZ therapy than with VAN or PTZ monotherapy or with the concurrent use of VAN and FEP or CAR in our study. Clinicians should adequately assess renal function and consider this differential risk for nephrotoxicity when choosing empiric antibiotics in hospitalized patients to minimize the rates of AKI.

Background Several viral, bacterial and fungal co-infections have been associated with increased morbidity and mortality among patients with COVID-19. We report a fatal case of severe COVID-19 pneumonia in a patient with a recent diagnosis of advanced HIV disease complicated by cryptococcal meningitis, disseminated tuberculosis and acute ischemic stroke. Case presentation A 37-year-old Ugandan woman was diagnosed with HIV infection 8 days prior to her referral to our center. She was antiretroviral naive. Her chief complaints were worsening cough, difficulty in breathing, fever and altered mental status for 3 days with a background of a 1-month history of coughing with associated drenching night sweats and weight loss. The reverse transcriptase-polymerase chain reaction for SARS-CoV-2 of her nasopharyngeal swab sample was positive. Chest radiograph demonstrated military pattern involvement of both lungs. The serum and cerebrospinal fluid cryptococcal antigen tests were positive. Urine lipoarabinomannan and sputum GeneXpert were positive for Mycobacterium tuberculosis. Computed tomography of the brain showed a large acute ischemic infarct in the territory of the right middle cerebral artery. Regardless of the initiation of treatment, that is, fluconazole 1200 mg once daily, enoxaparin 60 mg, intravenous (IV) dexamethasone 6 mg once daily, oral fluconazole 1200 mg once daily, IV piperacillin/tazobactam 4.5 g three times daily and oxygen therapy, the patient passed on within 36 hours of admission. Conclusion Co-infections worsen COVID-19 outcomes.