Fitness cost of tet(A) type I variant-mediated tigecycline resistance in Klebsiella pneumoniae.

OBJECTIVE: The aim of the present study is to explore the impact of the tet(A) type I variant (tetA-v1) on its fitness effect in Klebsiella pneumoniae. METHODS: Clinical K. pneumoniae strains were utilized as parental strains to generate strains carrying only the plasmid vector (pBBR1MCS-5) or the tetA-v1 recombinant plasmid (ptetA-v1). Antimicrobial susceptibility testing was conducted to estimate the contribution of tetA-v1 to drug resistance. Plasmid stability was evaluated by serial passage over 10 consecutive days in the absence of tigecycline. Biological fitness was examined through growth curve analysis, in vitro competition assays and a neutropenic mouse thigh infection model. RESULTS: A 2-4-fold increase in tigecycline MIC was observed following the acquisition of tetA-v1. Without tigecycline treatment, the stability of ptetA-v1 plasmids has been decreasing since day 1. The ptetA-v1 plasmid in Kp89, Kp91, and Kp93 exhibited a decrease of about 20% compared to the pBBR1MCS-5 plasmid. The acquisition of the tetA-v1 gene could inhibit the growth ability of K. pneumoniae strains both in vitro and in vivo. tetA-v1 gene imposed a fitness cost in K. pneumoniae, particularly in the CRKP strain Kp51, with a W value of approximately 0.56. CONCLUSION: The presence of tetA-v1 is associated with a significant fitness cost in K. pneumoniae in the absence of tigecycline, both in vitro and in vivo.

Machine-learning-based risk assessment tool to rule out empirical use of ESBL-targeted therapy in endemic areas.

BACKGROUND: Antimicrobial stewardship focuses on identifying patients who require extended-spectrum beta-lactamase (ESBL)-targeted therapy. 'Rule-in' tools have been researched extensively in areas of low endemicity; however, such tools are inadequate for areas with high prevalence of ESBL-producing pathogens, as almost all patients will be selected. AIM: To develop a machine-learning-based 'rule-out' tool suitable for areas with high levels of resistance. METHODS: Gradient-boosted decision trees were used to train and validate a risk prediction model on data from 17,913 (45% ESBL) patients with Escherichia coli and Klebsiella pneumoniae in urine cultures. The predictive power of different sets of variables was evaluated using Shapley values to evaluate the contributions of variables. FINDINGS: The model successfully identified patients with low risk of ESBL resistance in ESBL-endemic areas (area under receiver operating characteristic curve 0.72). When used to select the 30% of patients with the lowest predicted risk, the model yielded a negative predictive value ≥0.74. A simplified model with seven input features was found to perform nearly as well as the full model. This simplified model is freely accessible as a web application. CONCLUSIONS: This study found that a risk calculator for antibiotic resistance can be a viable 'rule-out' strategy to reduce the use of ESBL-targeted therapy in ESBL-endemic areas. The robust performance of a version of the model with limited features makes the clinical use of such a tool feasible. This tool provides an important alternative in an era with growing rates of ESBL-producing pathogens, where some experts have called for empirical use of carbapenems as first-line therapy for all patients in areas with high prevalence of ESBL-producing pathogens.

Healthcare-associated carbapenem-resistant Klebsiella pneumoniae infections are associated with higher mortality compared to carbapenem-susceptible K. pneumoniae infections in the intensive care unit: a retrospective cohort study.

BACKGROUND: Klebsiella pneumoniae (KP) is an opportunistic pathogen causing severe pneumonia and sepsis. Carbapenem-resistant KP (CRKP) has become a major pathogen in many centres. AIM: To investigate the association between carbapenem resistance and the mortality rate, length of stay, and hospital cost in patients with Klebsiella pneumoniae infection. METHODS: The retrospective cohort study was conducted in the intensive care units of a large teaching tertiary hospital in southwest China between January 1st, 2020 and December 31st, 2022. To examine the impact of carbapenem resistance on mortality rates and economic burden, multivariate Cox regression and generalized linear models were constructed. FINDINGS: The study included 282 adult patients with KP infection (135 CSKP; 147 CRKP). CRKP-infected patients demonstrated higher mortality risk (unadjusted hazard ratio (aHR): 1.980; 95% confidence interval (CI): 1.206-3.248; P = 0.007; aHR: 1.767; 95% CI: 1.038-3.005; P = 0.036) compared to CSKP-infected patients. Stratified analysis, according to type of KP infection, revealed that patients with healthcare-associated CRKP infection had a significantly higher mortality risk compared to those with CSKP infection (log-rank P = 0.015). Patients with CRKP infection had longer hospital stays than those infected with CSKP (adjusted mean: 38.74 vs 29.71 days; P = 0.003), and hospital-related expenses were notably higher among CRKP patients than CSKP patients (adjusted cost: £40,126.73 vs 25,713.74; P < 0.001). CONCLUSION: CRKP infections increase mortality rates, prolong hospital stays, and raise healthcare costs. Healthcare facilities should adopt targeted strategies, including curtailing pre-infection hospitalization periods and managing medications more judiciously.

In vitro activity, pharmacodynamic profile and dose optimization of biapenem against NDM and OXA-48-like carbapenemase-producing Klebsiella pneumoniae: A multicentre study in Thailand.

BACKGROUND: Biapenem (BIPM) exhibited a less efficient substrate for various metallo-ß-lactamase (MBL) than other carbapenems. OBJECTIVE: We aimed to evaluate in vitro susceptibility data of BIPM and optimal dose based on Monte Carlo simulation to extend treatment options. METHODS: We collected 192 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients among multicentres in Thailand, from June 2019 to March 2023. BIPM disk diffusion and broth-microdilution testing were performed to obtain minimum inhibitory concentration (MIC). Each BIPM regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes among 192 CRKP isolates were blaOXA-48 (62.3%), blaOXA-48+blaNDM (22.6%) and blaNDM (15.1%). BIPM showed 22.4 and 28.6% susceptible rate when interpreted at clinical breakpoints of 1 and 2 mg/L. The MIC50 and MIC90 of BIPM against CRKP were 8 and 32 mg/L. The BIPM dosing regimens of 300 mg q 6 h infused 6 h and 600 mg q 8 h infused 8 h met the PTA target of %fTime >MIC at 50%, 75% and 100% against isolates MICs of ≤2 mg/L. Based on CFR ≥90%, no BIPM regimens were effective against all the studied CRKP isolates. CONCLUSION: BIPM exhibited a partially susceptible rate among the CRKP isolates in Thailand. The current suggested dose of BIPM with prolonged infusion appears appropriate regimen against CRKP MICs of ≤2 mg/L. However, the empirical use of BIPM for severe CRE infection is not recommended unless the susceptibility has been confirmed.

Extensively Drug-Resistant Klebsiella pneumoniae Counteracts Fitness and Virulence Costs That Accompanied Ceftazidime-Avibactam Resistance Acquisition.

The ability of extensively drug-resistant (XDR) Klebsiella pneumoniae to rapidly acquire resistance to novel antibiotics is a global concern. Moreover, Klebsiella clonal lineages that successfully combine resistance and hypervirulence have increasingly occurred during the last years. However, the underlying mechanisms of counteracting fitness costs that accompany antibiotic resistance acquisition remain largely unexplored. Here, we investigated whether and how an XDR sequence type (ST)307 K. pneumoniae strain developed resistance against the novel drug combination ceftazidime-avibactam (CAZ-AVI) using experimental evolution. In addition, we performed in vitro and in vivo assays, molecular modeling, and bioinformatics to identify resistance-conferring processes and explore the resulting decrease in fitness and virulence. The subsequent amelioration of the initial costs was also addressed. We demonstrate that distinct mutations of the major nonselective porin OmpK36 caused CAZ-AVI resistance that persists even upon following a second experimental evolution without antibiotic selection pressure and that the Klebsiella strain compensates the resulting fitness and virulence costs. Furthermore, the genomic and transcriptomic analyses suggest the envelope stress response regulator rpoE and associated RpoE-regulated genes as drivers of this compensation. This study verifies the crucial role of OmpK36 in CAZ-AVI resistance and shows the rapid adaptation of a bacterial pathogen to compensate fitness- and virulence-associated resistance costs, which possibly contributes to the emergence of successful clonal lineages. IMPORTANCE Extensively drug-resistant Klebsiella pneumoniae causing major outbreaks and severe infections has become a significant challenge for health care systems worldwide. Rapid resistance development against last-resort therapeutics like ceftazidime-avibactam is a significant driver for the accelerated emergence of such pathogens. Therefore, it is crucial to understand what exactly mediates rapid resistance acquisition and how bacterial pathogens counteract accompanying fitness and virulence costs. By combining bioinformatics with in vitro and in vivo phenotypic approaches, this study revealed the critical role of mutations in a particular porin channel in ceftazidime-avibactam resistance development and a major metabolic regulator for ameliorating fitness and virulence costs. These results highlight underlying mechanisms and contribute to the understanding of factors important for the emergence of successful bacterial pathogens.

Acquisition of a Stable and Transferable blaNDM-5-Positive Plasmid With Low Fitness Cost Leading to Ceftazidime/Avibactam Resistance in KPC-2-Producing Klebsiella pneumoniae During Treatment.

The emergence and prevalence of carbapenem-resistant Enterobacteriaceae (CRE) have drawn worldwide attention. Ceftazidime/avibactam (CAZ/AVI) gives us a valuable alternative strategy to treat CRE infections. Unfortunately, CAZ/AVI resistance could occur during CAZ/AVI treatment. The CAZ/AVI-resistant Carbapenem-resistant Klebsiella pneumoniae (CR-KP) (KP137060) and earlier CAZ/AVI-susceptible isolate (KP135194) from the same hospitalized patient were collected at Fujian Medical University Union Hospital between October and November 2019. In this study, CAZ/AVI MICs of CAZ/AVI-susceptible and -resistant isolates (KP135194 and KP137060) were 4 mg/L and 128 mg/L, respectively; and the two isolates had the same antibiotic resistance pattern to other carbapenems. Two strains were then submitted for whole-genome sequencing and bioinformatic analysis. ompK36 was not detected in two isolates. No mutation was observed in blaKPC-2, ompK35 and ompK37 in this study and there was no significant difference of the expression in blaKPC-2, ompK35 and ompK37 between the two isolates (p>0.05). Two isolates were sequence type 11 and harbored blaKPC-2, blaSHV-182 and blaTEM-1B. Compared with KP135194, KP137060 harbored an additional blaNDM-5 positive plasmid. blaNDM-5 gene could be successfully transferred into E. coli J53 at a conjugation frequency of 1.14×10-4. Plasmid stability testing showed that blaKPC-2- and blaNDM-5-harboring plasmids were still stably maintained in the hosts. Growth assay and growth competition experiments showed there was no significant difference in fitness cost between two CR-KP isolates. Our study described the acquisition of a blaNDM-5-harboring plasmid leading to resistance to ceftazidime/avibactam in KPC-2-producing Klebsiella pneumoniae during treatment. This phenomenon deserves further exploration.

The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital.

PURPOSE: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. PATIENTS AND METHODS: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes of CRKP were blaOXA-48 (53.1%) and blaOXA-48 +blaNDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. CONCLUSION: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying blaOXA-48 .

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Rapid visualized assessment of drug efficacy in live mice with a selectable marker-free autoluminescent Klebsiella pneumoniae.

Klebsiella pneumoniae is an opportunistic pathogen that is responsible for community acquired infections and nosocomial infections. Antibiotic-resistant K. pneumoniae and/or hypervirulent K. pneumoniae are emerging as a serious threat to public health. For the sake of alleviating and conquering current dilemma, discovery of effective new drugs against K. pneumoniae is a tough challenge. However, traditional anti-K. pneumoniae drug discovery methods cost considerable amount of time, animals, labor and so on. So an efficient technique for in vitro and in vivo drug screening with the least time duration, animals and labor cost is highly needed for the discovery of new effective compounds. Hence, in this study we constructed a selectable marker-free autoluminescent K. pneumoniae (SfAlKp) harboring luxCDABE by combining Tn7 transposon and Xer-dif system. SfAlKp can be used for discovery of new drugs via detecting luminescence intensity as a surrogate marker. The energy-consuming autoluminescent reaction catalyzed by the LuxAB enzymes which use the substrates produced by LuxCDE using the metabolites of the bacteria. Tn7 can insert exogenous genes into the bacterial genome and the DNA fragment in between dif sequences can be recognized and removed by endogenous XerCD recombinases of K. pneumoniae. The drug susceptibility and growth rate of SfAlKp are identical to its parent strain, meanwhile the luminescence intensity and stability are also significant characteristics of SfAlKp. Compared to conventional techniques, the autoluminescence-based measurement is more applicable to high throughput screening for compounds both in vitro as well as in vivo in animal model.

Clinical and Economic Impact of Third-Generation Cephalosporin-Resistant Infection or Colonization Caused by Escherichia coli and Klebsiella pneumoniae: A Multicenter Study in China.

Quantifying economic and clinical outcomes for interventions could help to reduce third-generation cephalosporin resistance and Escherichia coli or Klebsiella pneumoniae. We aimed to compare the differences in clinical and economic burden between third-generation cephalosporin-resistant E. coli (3GCREC) and third-generation cephalosporin-susceptible E. coli (3GCSEC) cases, and between third-generation cephalosporin-resistant K. pneumoniae (3GCRKP) and third-generation cephalosporin-susceptible K. pneumoniae (3GCSKP) cases. A retrospective and multicenter study was conducted. We collected data from electronic medical records for patients who had clinical samples positive for E. coli or K. pneumoniae isolates during 2013 and 2015. Propensity score matching (PSM) was conducted to minimize the impact of potential confounding variables, including age, sex, insurance, number of diagnoses, Charlson comorbidity index, admission to intensive care unit, surgery, and comorbidities. We also repeated the PSM including length of stay (LOS) before culture. The main indicators included economic costs, LOS and hospital mortality. The proportions of 3GCREC and 3GCRKP in the sampled hospitals were 44.3% and 32.5%, respectively. In the two PSM methods, 1804 pairs and 1521 pairs were generated, and 1815 pairs and 1617 pairs were obtained, respectively. Compared with susceptible cases, those with 3GCREC and 3GCRKP were associated with significantly increased total hospital cost and excess LOS. Inpatients with 3GCRKP were significantly associated with higher hospital mortality compared with 3GCSKP cases, however, there was no significant difference between 3GCREC and 3GCSEC cases. Cost reduction and outcome improvement could be achieved through a preventative approach in terms of both antimicrobial stewardship and preventing the transmission of organisms.

Cefuroxime pharmacokinetics and pharmacodynamics for intravenous dosage regimens with 750 mg or 1500 mg doses in healthy young volunteers.

Introduction. Cefuroxime is an important antibiotic to treat several serious infections. Rapid elimination through the kidneys and the variation in MICs of various susceptible pathogens such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae give rise to dosing issues, especially in otherwise healthy patients.Aim. To investigate the probability of target attainment (PTA) for obtaining the optimal dosage regimens for cefuroxime in healthy young people.Methodology. Two weeks apart 750 and 1500 mg cefuroxime were administered as an intravenous bolus to 20 healthy volunteers (mean age: 27 years). Population modelling and simulation studies were done based on the obtained data for cefuroxime plasma concentration.Results. With a target value of time above MIC (T >MIC) greater than 50 % the simulations revealed that a PTA of >99 % is obtained for S. pneumoniae with a dosage regimen of 750 mg q12h. For E. coli and K. pneumoniae the PTA was <90 % even with the highest, simulated dosage of 1500 mg q6h. For S. aureus a dosage of 1500 mg q8h gave a PTA above 97 %.Conclusions. S. pneumoniae is most likely treatable with a two-daily dose of 750 mg cefuroxime. Not treatable are K. pneumoniae and E. coli. For S. aureus 1500 mg q8h constitutes an optimal dosing schedule.

Econometric ARIMA methodology to elucidate the evolution of trends in nosocomial antimicrobial resistance rates in the European Union.

BACKGROUND: Infections with bacteria harbouring resistance to cephalosporins or fluoroquinolones (FQ) constitute a serious hazard to human health. OBJECTIVES: To establish a methodology based on econometric analysis and the largest European Union (EU) resistance database (EARS-Net), to model nosocomial antimicrobial resistance (AMR) in the EU and to detect tendency changes, steps or peaks. The contribution of legislation based on third-generation cephalosporin (3GC) and FQ class referrals to resistance rate patterns is evaluated. METHODS: Resistance to 3GC and FQ was examined in nosocomial Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in at least 25 out of 30 EU countries (> 94% population coverage), weighted by their mean annual population, between 2006 and 2016. Autoregressive integrated moving average (ARIMA) model analysis, inspired by Box-Jenkins methodology, was prepared to adjust series to a mathematical model to detect hypothetical changes in the general behaviour. To the best of the authors' knowledge, this is the first study to use ARIMA with interventions to model overall nosocomial AMR data compiled in EARS-Net. RESULTS AND CONCLUSIONS: Econometric ARIMA models statistically prove the occurence of slowdowns and reversions in the increasing trend of AMR prevalence in nosocomial E. coli and K. pneumoniae to 3GC and FQ, as well as resistance of P. aeruginosa to 3GC. The resistance of P. aeruginosa to FQ exhibited a descending slope. The presented decreasing trends constitute noteworthy milestones in tackling AMR in Europe.

Cost-effectiveness of antimicrobial treatment for inpatients with carbapenem-resistant Klebsiella pneumoniae infection: a systematic review of economic evidence.

OBJECTIVES: The objective of this review was to evaluate the cost-effectiveness of antimicrobial therapy for patients with carbapenem-resistant Klebsiella pneumoniae infection. INTRODUCTION: Among the main multi-resistant microorganisms, carbapenem-resistant K. pneumoniae is responsible for the mortality of 40% of patients following 30 days of infection. Treatment for carbapenem-resistant K. pneumoniae infection entails the use of high-cost antimicrobials. Inappropriate use of antimicrobials can increase the cost of treatment fourfold. This review aimed to evaluate the cost-effectiveness of antimicrobial therapy treatment for patients with carbapenem-resistant K. pneumoniae infection to better inform decision making in hospital services. INCLUSION CRITERIA: The review included studies on participants 18 years or over with carbapenem-resistant K. pneumoniae infection who had undergone antimicrobial therapy in hospital and acute care services. Studies that compared the cost-effectiveness of different antimicrobial therapy for carbapenem-resistant K. pneumoniae infection were included. Outcome measures were cost per unit of effect expressed in clinical outcome units; this included cost per avoided death, cost per prevention of sepsis and cost per duration of stay. Economic studies with a cost-effectiveness design were considered, as well as modeling studies. METHODS: A three-step search strategy was utilized to locate studies published in English, Spanish or Portuguese, with no date restrictions. Two independent reviewers screened titles and abstracts and the full texts of potentially relevant studies for eligibility. Methodological quality was assessed by two independent reviewers using the JBI critical appraisal checklist for economic evaluations. Data were extracted from included studies using the standardized JBI data extraction tool. Data were synthesized using narrative, tables and the JBI Dominance Ranking Matrix. RESULTS: This review identified eight studies that evaluated the cost-effectiveness of different treatments for carbapenem-resistant K. pneumoniae infection. The results of this study demonstrated that there was no gold standard treatment for carbapenem-resistant K. pneumoniae infection, hence treatment was generally directed by colonization pressure and resistance profiles. Furthermore, due to the moderate quality and limited number of studies, there was high uncertainty of the values of the cost-effectiveness ratio. CONCLUSIONS: Ofloxacin appears to be the most cost-effective treatment; however, conclusions are limited due to the small number and low quality of studies.

Decreasing and stabilising trends of antimicrobial consumption and resistance in Escherichia coli and Klebsiella pneumoniae in segmented regression analysis, European Union/European Economic Area, 2001 to 2018.

Investments to reduce the spread of antimicrobial resistance (AMR) in the European Union have been made, including efforts to strengthen prudent antimicrobial use. Using segmented regression, we report decreasing and stabilising trends in data reported to the European Surveillance of Antimicrobial Consumption Network and stabilising trends in data reported to the European Antimicrobial Resistance Surveillance Network. Our results could be an early indication of the effect of prioritising AMR on the public health agenda.

Economic burden of inpatients infected with Klebsiella pneumoniae carbapenemase.

OBJECTIVE: To estimate the direct medical costs of drug therapy of Klebsiella pneumoniae carbapenemase (KPC) infection patients in hospital-based context. METHODS: A cost-of-illness study conducted with a prospective cohort design with hospitalized adults infected by KPC. Data collection was performed using an instrument composed of sociodemographic data, clinical and prescription medication. Estimates of the direct costs associated to each treatment were derived from the payer's perspective, in the case of federal public hospitals from Brazil, and included only drug costs. These costs were based on the average price available at the Brazilian Price Database Health. No discount rate was used for the cost of drugs. The costs are calculate in American Dollar (US$). RESULTS: A total of 120 inpatients participated of this study. The total drug cost of these inpatients was US$ 367,680.85. The systemic antimicrobial group was responsible for 59.5% of total costs. The direct drug cost per patients infected by KPC was conservatively estimated at nearly US$ 4,100.00, and about of 60% of costs occurred during the period of infection. CONCLUSION: The findings of our study indicate a thoughtful economic hazard posed by KPC that all healthcare sectors have to face. The increasing worldwide incidence of these bacteria represents a growing burden that most health systems are unable to deal with. There is an imperative need to develop protocols and new antimicrobials to treatment of KPC, aiming to rearrange resources to increase the effectiveness of healthcare services.

Health and economic burden of antimicrobial-resistant infections in Australian hospitals: a population-based model.

OBJECTIVE: To estimate the additional health and economic burden of antimicrobial-resistant (AMR) infections in Australian hospitals. METHODS: A simulation model based on existing evidence was developed to assess the additional mortality and costs of healthcare-associated AMR Escherichia coli (E. coli), Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, and Staphylococcus aureus infections. SETTING: Australian public hospitals. FINDINGS: Australian hospitals spent an additional AUD$5.8 million (95% uncertainty interval [UI], $2.2-$11.2 million) per year treating ceftriaxone-resistant E.coli bloodstream infections (BSI), and an estimated AUD$5.5 million per year (95% UI, $339,633-$22.7 million) treating MRSA patients. There are no reliable estimates of excess morbidity and mortality from AMR infections in sites other than the blood and in particular for highly prevalent AMR E. coli causing urinary tract infections (UTIs). CONCLUSION: The limited evidence-base of the health impact of resistant infection in UTIs limits economic studies estimating the overall burden of AMR. Such data are increasingly important and are urgently needed to support local clinical practice as well as national and global efforts to curb the spread of AMR.

Características clínico-epidemiológicas y patrones de prescripción para quemaduras en tres hospitales de Lima, Perú / Clinical-epidemiological characteristics and prescribing patterns for burns in three hospitals in Lima, Peru

RESUMEN Con el objetivo de describir las características clínico-epidemiológicas y los patrones de prescripción médica de pacientes con quemaduras de primer y segundo grado que acudieron a tres hospitales de referencia de Lima, se realizó un estudio transversal donde se recogieron datos demográficos, antecedentes médicos, evaluación clínica y tratamiento recibido en 561 participantes. El uso de antibióticos y de agentes humectantes se dio en 64,7% y 4,2% en los centros de atención inmediata; y en 41,7% y 44,7% en los servicios de atención especializada en quemaduras. La sulfadiazina argéntica fue el antibiótico tópico más utilizado en los servicios de atención inmediata, en comparación con los servicios de quemados (80,2% vs 34,5%). El manejo de quemaduras fue más exhaustivo en los servicios de quemados que en los de atención inmediata. Asimismo, más de un cuarto de los pacientes que acudieron por emergencia lo hicieron luego de 24 horas de ocurrida la quemadura.

ABSTRACT In order to describe the clinical-epidemiological characteristics and medical prescription patterns of patients with first- and second-degree burns who visited three reference hospitals in Lima, a cross-sectional study was carried out to collect data on demographics, medical history, clinical evaluation, and treatment received by 561 participants. The use of antibiotics and moisturizing agents was 64.7% and 4.2% in immediate care centers; and 41.7% and 44.7% in specialized burn-care services. Argenic sulfadiazine was the most commonly used topical antibiotic in immediate care services compared to burned units (80.2% vs. 34.5%). Burn management was more comprehensive in burn services than in immediate care. Also, more than a quarter of the patients who sought emergency care did so within 24 hours of the burn.

Economic burden of inpatients infected with Klebsiella pneumoniae carbapenemase / Impacto econômico do tratamento de pacientes infectados com Klebsiella pneumoniae carbapenemase

ABSTRACT Objective: To estimate the direct medical costs of drug therapy of Klebsiella pneumoniae carbapenemase (KPC) infection patients in hospital-based context. Methods: A cost-of-illness study conducted with a prospective cohort design with hospitalized adults infected by KPC. Data collection was performed using an instrument composed of sociodemographic data, clinical and prescription medication. Estimates of the direct costs associated to each treatment were derived from the payer's perspective, in the case of federal public hospitals from Brazil, and included only drug costs. These costs were based on the average price available at the Brazilian Price Database Health. No discount rate was used for the cost of drugs. The costs are calculate in American Dollar (US$). Results: A total of 120 inpatients participated of this study. The total drug cost of these inpatients was US$ 367,680.85. The systemic antimicrobial group was responsible for 59.5% of total costs. The direct drug cost per patients infected by KPC was conservatively estimated at nearly US$ 4,100.00, and about of 60% of costs occurred during the period of infection. Conclusion: The findings of our study indicate a thoughtful economic hazard posed by KPC that all healthcare sectors have to face. The increasing worldwide incidence of these bacteria represents a growing burden that most health systems are unable to deal with. There is an imperative need to develop protocols and new antimicrobials to treatment of KPC, aiming to rearrange resources to increase the effectiveness of healthcare services.

RESUMO Objetivo: Estimar os custos médicos diretos da terapia medicamentosa de pacientes com infecção por carbapenemase por Klebsiella pneumoniae carbapenemase (KPC) em contexto hospitalar. Métodos: Estudo de custo de doença realizado com desenho de coorte prospectiva, com adultos hospitalizados infectados por KPC. A coleta de dados foi realizada usando instrumento composto por dados sociodemográficos, medicamentos clínicos e prescritos. As estimativas dos custos diretos associados a cada tratamento foram derivadas da perspectiva dos pagadores, no caso dos hospitais públicos federais do Brasil, e incluíram apenas custos de medicamentos, os quais basearam-se no preço médio disponível na Price Database Health do Brasil. Nenhuma taxa de desconto foi utilizada para o custo dos medicamentos. Os custos foram calculados em dólares norte-americanos (US$). Resultados: Um total de 120 pacientes hospitalizados participou do estudo. O custo total da droga desses pacientes internados foi de US$ 367,680.85. O grupo antimicrobianos de uso sistêmico foi responsável por 59,5% dos custos totais. O custo direto estimado de forma conservadora, por paciente, foi de aproximadamente US$ 4,100.00, e cerca de 60% destes se deram durante o período de infecção. Conclusão: Os achados deste estudo apontam um risco econômico importante relacionado a KPC, o qual todos os setores de saúde terão que enfrentar. A incidência mundial em elevação destas bactérias representa carga crescente, e a maioria dos sistemas de saúde é incapaz de resolvê-la. Há necessidade imperativa de se desenvolverem protocolos e novos antimicrobianos para o tratamento de KPC, com o objetivo de reorganizar os recursos para aumentar a efetividade dos serviços de saúde.

In-hospital Medical Costs of Infections Caused by Carbapenem-resistant Klebsiella pneumoniae.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major health threat, but the economic impact of carbapenem resistance in K. pneumoniae infections remains largely uninvestigated. Methods: We constructed a retrospective cohort of all patients hospitalized at West China Hospital in 2017 who had CRKP- or carbapenem-susceptible K. pneumoniae (CSKP)-positive clinical samples. Propensity score matching (PSM) was used to control the impact of potential confounding variables, including demographics, comorbidities, and treatment, and to observe the impact of factors other than length of stay (LOS). Patients who survived were subjected to subgroup analyses stratified by infection type. Results: There were 267 patients with CRKP and 1328 with CSKP. Patients with CRKP had a higher crude in-hospital mortality rate (14.61% vs 5.65%, P < .05) and longer LOS (median, 31 vs 19 days; P < .05). PSM for demographics, comorbidities, and treatment generated 237 pairs. Patients with CRKP had higher medical costs than those with CSKP during the entire hospitalization (median, in US dollars, $22962 vs $11755, respectively; P < .05) and during the period after infection (median, $9215 vs $6904, respectively; P < .05). When LOS was matched, patients with CRKP still had high excess costs compared to those with CSKP (median, $22917 vs $13851, respectively, for the entire hospitalization, P < .05; $9101 vs $7001, respectively, after infection, P < .05). For infection type, the sample size generated sufficient power to compare only the patients with pneumonia. For surviving patients, high excess costs were observed in those with pneumonia caused by CRKP as compared to CSKP ($21890 vs $11698, respectively, for the entire hospitalization, P < .05; $9773 vs $5298, respectively, after infection, P < .05). Medicines other than antibacterial agents and nonmedicinal therapies contributed most (57.8%) of the excess costs associated with CRKP. Conclusions: Carbapenem resistance in K. pneumoniae was associated with increased medical costs not accounted for by the cost of antimicrobial therapy.

Two for the price of one: emerging carbapenemases in a returning traveller to New York City.

We report a case of a complex orthopaedic infection in a patient returning to New York City from Bangladesh where he was involved in a serious motor vehicle accident. He developed extensive osteomyelitis with a carbapenem-resistant Klebsiella pneumoniae The isolate was unique due to the coexistence of New Delhi metallo-ß-lactamase-1 and Oxacillinase type-181 carbapenemases, which are relatively uncommon in North America and were presumably acquired in Bangladesh. Herein, we explore challenges associated with management of carbapenem-resistant Enterobacteriaceae infections, including limited available data on effective antimicrobial therapy. We also highlight the added value of rapid diagnostic technology in guiding clinical management. Ultimately, the patient required both aggressive surgical management and combination therapy with aztreonam and ceftazidime-avibactam for true source control and favourable clinical outcome.