Treatment Failure Of Infections Research Articles

P-281. Risk Factors for Treatment Failure in Infections Caused by Carbapenem-Resistant Enterobacterales (CRE)

Abstract Background Multi-drug resistant organisms (MDROs) are a rising global public health threat. During the COVID-19 pandemic, there was a surge in New Delhi Metallo-Beta-Lactamases (NDM) amidst increasing prevalence of Carbapenem-Resistant Enterobacterales (CRE) infections in Maricopa County, Arizona. The objective of this study was to investigate risk factors associated with CRE treatment failure by measuring the composite of 30-day mortality and 30-day microbiologic recurrence.Table 1.Patient Characteristics Methods A multicenter observational retrospective chart review of a large health system’s 31 acute care facilities was performed for adult patients with infections caused by an organism in the Enterobacterales group with resistance to at least one carbapenem between January 1st, 2023 and July 31st, 2023. Key exclusion criteria were pregnancy and any patients with prior positive cultures with CRE within 60 days (only the first instance was included). Data was obtained via reports provided by pharmacy analytics.Table 1.Multivariable Logistic Regression, Predictors of Clinical Failure Results Of 169 included patients, 21% faced 30-day mortality, while 18% encountered microbiologic recurrence within 30 days. The majority (53%) of patients were admitted from assisted living facilities. The most common organism was Klebsiella pneumoniae occurring in 82% of cases and NDMs were the most prevalent carbapenemase, occurring in 76% of patients; urine was the source of infection in 60% of patients. Our multivariable logistic regression identified several significant risk factors associated with CRE treatment failure, including receipt of renal replacement therapy (RRT), prior diagnosis of peripheral vascular disease (PVD), and prior hospitalization within 90 days of index culture. Patients infected with an MBL producer and those not being seen by ID consult also trended towards worse outcomes. Conclusion Our study highlights the concerning prevalence of Klebsiella pneumoniae infections with metallo-beta lactamases in Maricopa County Arizona, along with clinically significant risk factors contributing to treatment failure against CREs. Notably, the majority of patients arrived from a healthcare related facility, underscoring the importance of implementing best infection prevention and antimicrobial stewardship practices in these settings. Disclosures Emir Kobic, BCIDP, Shionogi: Grant/Research Support|Shionogi: Speaker Bureau

P-1476. Cefiderocol Treatment Outcomes and Risk Factors for Gram-negative Bacterial Infection Treatment Failure

Abstract Background The IDSA 2023 guidance lacks strong evidence about cefiderocol (FDC) efficacy and real-world data are limited. The aim of this study was to evaluate effectiveness, safety, and risk factors for clinical failure (ClinF) associated with FDC use in hospitalized patients. Methods This was a retrospective, observational study. Adults treated with an initial course of FDC for ≥ 48 hours from Feb 2020 - Aug 2023 were included. Primary outcome was clinical success (ClinS) defined as a composite of survival, resolution of signs and symptoms, and absence of both recurrent infection or microbiological failure. Factors associated with success and failure were compared on univariable analysis and those with a p-value < 0.2 and FDC monotherapy were considered for inclusion in a multivariable model for ClinF. Results 87 patients were included. Most common pathogens: Pseudomonas spp (49%), Acinetobacter spp (29%), and Klebsiella spp 16%. Carbapenem-resistance was reported for 93% of isolates and majority of cases were from a respiratory source (72%). At FDC initiation, 39 patients (45%) were admitted to the ICU and the median PITT bacteremia score was 3 (IQR, 1.5-4). ClinS was achieved in 32 patients (37%). Within this composite, 70% survived, 59% resolved their signs/symptoms, 62% had absence of microbiologic failure, and 63% did not recur within 30 days. 16 patients (18%) developed FDC non-susceptibility (NS) within 90 days. ClinS was associated with urine and intra-abdominal sources, while ClinF was associated with COPD, mechanical ventilation, respiratory sources, and higher PITT bacteremia scores. No significant differences found between age, Charlson comorbidity index score, or monotherapy and combination therapy. COPD was found to be an independent factor associated with ClinF [OR 11.5 (95% CI 1.63-82.28, p=0.014)]. Comparing patients who developed FDC NS to those that did not, solid organ transplant [7(44) vs 14(20); p=0.088], longer antibiotic days prior to FDC [14.5 d vs 7 d; p=0.079], and longer FDC duration [14 d vs 10 d; p=0.023] were more common in those that developed NS. Conclusion In this single center experience with mostly respiratory infections, FDC was successfully used with ClinF being associated with underlying illness. The potential development of NS should be further explored. Disclosures All Authors: No reported disclosures

Identification of Multiple Drug-Resistance Genes in Clinical Isolates of Acinetobacter baumannii

Around the world, Acinetobacter baumannii is a nosocomial pathogen that accounts for 80% of hospitalized patient infections. This opportunistic bacterium can cause a wide range of infections, including skin and soft tissue infections, meningitis, pneumonia acquired on a ventilator, urinary tract infections, and bacteremia, all of which have a high death rate of almost 63.3%. Finding multidrug-resistant genes in the clinical isolates of A. baumannii was the goal of this study. Twenty-four (24) A. baumannii clinical isolates were obtained from the Federal Teaching Hospital in Gombe, Nigeria, and subcultured on MacConkey agar for eighteen to twenty-four hours at 37 ˚C. The isolates were identified using traditional biochemical testing, morphology, and cultural traits. The VITEK was then used to validate the identification. Twenty of the 24 isolates had been identified as A. baumannii. The Kirby Bauer method and CLSI recommendations were utilized to determine the antibiotic susceptibility of the A. baumannii isolates. Polymerase Chain Reaction was used to identify the genes that were resistant to many drugs. According to the data, fifteen (15) A. baummanii isolates, or 75% of the total, were likely multidrug resistant. The presence of the BlaNDM-1 gene in eight isolates, the BlaOXA23 gene in six isolates, and the BlaVIM gene in just four isolates was confirmed by molecular detection of the MDR genes from these isolates. These results show that a significant portion of the isolates of A. baumannii carried genes resistant to many drugs, which could be the root cause of any infection treatment failure caused by this organism.

A Process Evaluation of the Isfahan Antibiotic Awareness Campaign: Developing Engagement on Antimicrobial Resistance.

One of the most prominent global health threats is antibiotic resistance, leading to infection treatment failure. The first Iranian antibiotic awareness week campaign was initiated to improve the prudent use and wise prescription of antibiotics. The Isfahan antibiotic awareness campaign was held from November 30 to December 6, 2019, among two targeted populations; the general population and health-care workers by Isfahan University of Medical Sciences. In this campaign held in the main squares, streets, and a city's referral hospital, various educational methods were used to aware and sensitize the general population and medical staff about antibiotics and microbial resistance. These methods include face-to-face training, brochures, advertisement posters and billboards around the city, educational videos, social media messages, retraining for medical doctors and medical specialists, and interviewing in the Islamic Republic of Iran Broadcast. Two hundred and twenty general practitioners, medical specialists, and residents participated in two retraining educational conferences in Al-Zahra Hospital, Isfahan, Iran. The mean score satisfaction of the two conferences was three from four. Nearly 2000 of the general population were under face-to-face educational programs whom after that, 83.6% had the correct answer to the questions around antimicrobial awareness. This campaign was an excellent experience as a pilot study with appealing issues. Further, activities are required to improve engagement with the target population and determine the impact of this campaign on antibiotic consumption and prescription behavior among the public and health-care professionals.

341. Evaluation of Antimicrobial Use and Prescribing Patterns During the COVID-19 Pandemic in Patients Receiving Tocilizumab

BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients experience systemic inflammation and respiratory distress, which appears to be associated with increased cytokine release. During the peak of coronavirus disease 2019 (COVID-19), tocilizumab was used to treat critically ill patients with potential cytokine storm. However, tocilizumab has an increased risk of developing serious infections.MethodsThis retrospective observational chart review was approved by Institutional Review Board and evaluated patients admitted from March to November 2020, who were SARS-CoV-2 positive and received tocilizumab for the treatment group and no tocilizumab for the control group. The primary endpoint is usage of antimicrobials. The secondary endpoints are development and outcomes of secondary infections and hospital length of stay and mortality. Chi-square test was used for categorical data and Mann-Whitney test was used for continuous data.ResultsA total of 160 patients were included in analysis, with 80 in each arm. 60% of patients in the treatment group required antibiotics compared to 35% in the control group (p = 0.0015), with the highest usage of anti-MRSA coverage, beta-lactams, cephalosporins, and carbapenems in both groups. Antifungal therapy was required in 21.3% of patients in the tocilizumab group compared to 6.3% in the control group (p = 0.0059), with echinocandins being the most used class in both groups. The median days of antimicrobial use in the tocilizumab group was 14 (IQR 7, 24.5) compared to 9 (IQR 6.5, 19) in the control group (p = 0.3346). In the treatment group, 60% of patients developed a secondary infection compared to 35% of patients in the control group (p < 0.0017). Secondary infection treatment failure was observed in 75% of tocilizumab patients compared to 60.7% of control patients (p = 0.1910). In hospital mortality was 50% in patients who received tocilizumab compared to 27.5% in the control group (p < 0.0039).ConclusionPatients on tocilizumab received more antimicrobials, but with a similar spectrum of antimicrobial coverage. Patients who received tocilizumab had higher odds of developing secondary infections and expiring during their hospital stay. There were similar durations of antimicrobial therapy and treatment outcomes.Disclosures All Authors: No reported disclosures

The Prediction and Prognosis of Fungal Infection in Lung Transplant Recipients-A Retrospective Cohort Study in South Korea.

(1) Background: Lung transplant recipients (LTRs) are at substantial risk of invasive fungal disease (IFD), although no consensus has been reached on the use of antifungal agents (AFAs) after lung transplantation (LTx). This study aimed to assess the risk factors and prognosis of fungal infection after LTx in a single tertiary center in South Korea. (2) Methods: The study population included all patients who underwent LTx between January 2012 and July 2019 at a tertiary hospital. It was a retrospective cohort study. Culture, bronchoscopy, and laboratory findings were reviewed during episodes of infection. (3) Results: Fungus-positive respiratory samples were predominant in the first 90 days and the overall cumulative incidence of Candida spp. was approximately three times higher than that of Aspergillus spp. In the setting of itraconazole administration for 6 months post-LTx, C. glabrata accounted for 36.5% of all Candida-positive respiratory samples. Underlying connective tissue disease-associated interstitial lung disease, use of AFAs before LTx, a longer length of hospital stay after LTx, and old age were associated with developing a fungal infection after LTx. IFD and fungal infection treatment failure significantly increased overall mortality. Host factors, antifungal drug resistance, and misdiagnosis of non-Aspergillus molds could attribute to the breakthrough fungal infections. (4) Conclusions: Careful bronchoscopy, prompt fungus culture, and appropriate use of antifungal therapies are recommended during the first year after LTx.

Shooting yourself in the foot: How immune cells induce antibiotic tolerance in microbial pathogens.

Antibiotic treatment failure of infection is common and frequently occurs in the absence of genetically encoded antibiotic resistance mechanisms. In such scenarios, the ability of bacteria to enter a phenotypic state that renders them tolerant to the killing activity of multiple antibiotic classes is thought to contribute to antibiotic failure. Phagocytic cells, which specialize in engulfing and destroying invading pathogens, may paradoxically contribute to antibiotic tolerance and treatment failure. Macrophages act as reservoirs for some pathogens and impede penetration of certain classes of antibiotics. In addition, increasing evidence suggests that subpopulations of bacteria can survive inside these cells and are coerced into an antibiotic-tolerant state by host cell activity. Uncovering the mechanisms that drive immune-mediated antibiotic tolerance may present novel strategies to improving antibiotic therapy.

Implant-associated osteomyelitis: Development, characterisation, and application of a porcine model.

Implant-associated osteomyelitis: Development, characterisation, and application of a porcine model.

Risk Factors, Molecular Epidemiology, and Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Infection for Hospital-Acquired Pneumonia: A Matched Case-Control Study in Eastern China During 2015-2017.

This study was conducted to acknowledge microbiological and clinical characteristics of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). A retrospective, 1:1 matched (age, gender, specimen source, and ward) case-control study was conducted during 2015-2017 in a tertiary teaching hospital in Anhui, China. Multivariate logistic regression analysis demonstrated that prior central venous catheter use, sputum suction, continuous renal replacement therapy, and exposure to fluroquinolones were independent risk factors for the morbidity of CRKP infection for HAP. Treatment failure for infection was an independent risk factor for crude in-hospital mortality, while the use of fluroquinolones may improve the effective treatment for infection (p = 0.040). Among 74 CRKP strains, 85.1% of them were positive for the production of KPC-2, and one of them was detected for co-harboring blaKPC-2 and blaIMP-38-like. Separately, sequence type (ST) 11 (81.1%) was the predominant ST in this study, and ST11 CRKP isolates were related with higher detection rate of blaKPC-2 and lower resistance rate to trimethoprim/sulfamethoxazole when compared with non-ST11 ones. Moreover, resistance to carbapenem was associated with higher mortality (35.1%) and hospitalization costs for HAP patients with K. pneumoniae infection. Invasive procedures may increase the morbidity of CRKP infection for HAP. Prior exposure to fluroquinolones is associated with the development of resistance, but as a targeted treatment it may be effective.

The Stringent Response Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection Through the Purine Biosynthetic Pathway.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a significant clinical-therapeutic challenge. Of particular concern is antibiotic treatment failure in infections caused by MRSA that are "susceptible" to antibiotic in vitro. In the current study, we investigate specific purine biosynthetic pathways and stringent response mechanism(s) related to this life-threatening syndrome using genetic matched persistent and resolving MRSA clinical bacteremia isolates (PB and RB, respectively), and isogenic MRSA strain sets. We demonstrate that PB isolates (vs RB isolates) have significantly higher (p)ppGpp production, phenol-soluble-modulin expression, polymorphonuclear leukocyte lysis and survival, fibronectin/endothelial cell (EC) adherence, and EC damage. Importantly, an isogenic strain set, including JE2 parental, relP-mutant and relP-complemented strains, translated the above findings into significant outcome differences in an experimental endocarditis model. These observations indicate a significant regulation of purine biosynthesis on stringent response, and suggest the existence of a previously unknown adaptive genetic mechanism in persistent MRSA infection.

Factors Associated With Latent Tuberculosis Infection Treatment Failure Among Patients With Commercial Health Insurance-United States, 2005-2016.

Approximately 80% of US tuberculosis (TB) cases verified during 2015-2016 were attributed to untreated latent TB infection (LTBI). Identifying factors associated with LTBI treatment failure might improve treatment effectiveness. To identify patients with indicators of isoniazid (INH) LTBI treatment initiation, completion, and failure. We searched inpatient and outpatient claims for International Classification of Diseases (Ninth and Tenth Revisions), National Drug, and Current Procedural Terminology codes. We defined treatment completion as 180 days or more of INH therapy during a 9-month period. We defined LTBI treatment failure as an active TB disease diagnosis more than 1 year after starting LTBI treatment among completers and used exact logistic regression to model possible differences between groups. Among treatment completers, we matched 1 patient who failed treatment with 2 control subjects and fit regression models with covariates documented on medical claims paid 6 months or less before INH treatment initiation. Commercially insured US patients in a large commercial database with insurance claims paid during 2005-2016. (1) Trends in treatment completion; (2) odds ratios (ORs) for factors associated with treatment completion and treatment failure. Of 21 510 persons who began LTBI therapy during 2005-2016, 10 725 (49.9%) completed therapy. Treatment noncompletion is associated with those younger than 45 years, living in the Northeast or South Census regions, and women. Among persons who completed treatment, 30 (0.3%) progressed to TB disease. Diagnoses of rheumatoid arthritis during the 6 months before treatment initiation and being aged 65 years or older (reference: ages 0-24 years) were significantly associated with INH LTBI treatment failure (adjusted exact OR = 5.1; 95% CI, 1.2-28.2; and adjusted exact OR = 5.1; 95% CI, 1.2-25.3, respectively). Approximately 50% of persons completed INH LTBI therapy, and of those, treatment failure was associated with rheumatoid arthritis and persons 65 years or older among a cohort of US LTBI patients with commercial health insurance.

Prevalence of macrolide- and fluoroquinolone-resistant Mycoplasma genitalium strains in clinical specimens from men who have sex with men of two sexually transmitted infection practices in Berlin, Germany.

The cell-wall-less Mollicutes species Mycoplasma genitalium is a sexually transmitted micro-organism that causes different male and female genital tract infections. In recent years, resistance of the pathogen to macrolides and fluoroquinolones has been increasingly reported worldwide and is more frequent in risk groups. To determine the rates of antimicrobial resistance, M. genitalium strains in 195 specimens from 154 outpatients (154 first and 41 follow-up samples) treated in two specialised practices between September 2017 and December 2018 in Berlin, Germany, were analysed. The included patients were predominantly men who have sex with men (MSM) (91.6%) and were HIV-positive in many cases (49.4%). Only 27.3% of M. genitalium-positive patients reported symptoms. Among the first samples (mainly rectal swabs) (57.8%), mutations associated with macrolide (23S rRNA) and quinolone (parC gene) resistance were detected in 79.9% and 13.0% of strains, respectively. Resistance to both classes of antibiotics was found in 11.7% of specimens. Changes of A→G at position 2072 of 23S rRNA and of serine at position 83 of ParC were the most frequent alterations. Although azithromycin is recommended as a first-line antibiotic to treat infections with M. genitalium in MSM, according to these data its use must be highly limited in Berlin. Besides the need for resistance studies regarding strains circulating in other locations and among different patient groups in Germany, the results emphasise the importance of intensified antibiotic resistance testing of M. genitalium to avoid a further increase in treatment failures in infections with this emerging human pathogen.

Helicobacter pylori: Multiple resistance in patients from Bogotá, Colombia

Introduction: The main cause for Helicobacter pylori infection treatment failure is antibiotic resistance, where clarithromycin and metronidazole play the main role. In Colombia, primary resistance as a consequence of the use of these two antibiotics and excessive levofloxacin use is above the accepted limit (13.6%, 83%, and 16%, respectively). Despite this fact, empirical therapies that include the combination of these antibiotics are used in patients with previous therapeutic failure. Objective: To determine antibiotic resistance in patients previously treated for H. pylori in Bogotá, Colombia. Materials and methods: We conducted a descriptive study that included ten isolates obtained from five patients with three or four previous failed treatments for H. pylori. Antibiotic resistance to amoxicillin, clarithromycin, levofloxacin, and metronidazole was investigated by agar dilution and confirmed by DNA sequencing (Magrogen, Korea). Results: Eight isolates were resistant to two or more antibiotics. All isolates were resistant to levofloxacin. Susceptibility patterns in isolates from the gastric antrum and the body of the stomach were different in three patients. Conclusion: As far as we know, this is the first evidence of multiple H. pylori resistance in Colombia in previously treated patients. Results demonstrated the consequences of using an ineffective antibiotic scheme and the need to assess antibiotic susceptibility in different anatomical sites of the stomach. The consequences of multiple resistance decrease possible antibiotic effectiveness to eradicate H. pylori in the future.

Adaptation of Pseudomonas aeruginosa clinical isolates to benzalkonium chloride retards its growth and enhances biofilm production.

The increasing percentage of Pseudomonas aeruginosa strains that are resistant to multiple antibiotics is a global problem. The exposure of P. aeruginosa isolates to repeated sub lethal concentrations of biocides in hospitals and communities may be one of the causes leading to increased antibiotic resistance. Benzalkonium chloride (BAC) is widely used as disinfectant and preservative. This study investigated the effect of exposure of P. aeruginosa clinical isolates to sub lethal concentrations of BAC on their antibiotic resistance, growth process and biofilm formation. The collected 43 P. aeruginosa clinical isolates were daily subjected to increasing sub lethal concentrations of BAC. The effect of adaptation on antibiotic resistance, growth process, cell surface hydrophobicity and biofilm formation of P. aeruginosa isolates were examined. Interestingly, Most P. aeruginosa isolates adapted to BAC showed an increase in antibiotic resistance and 66% of the isolates showed retardation of growth, 63% showed increased cell surface hydrophobicity and 23.5% exhibited enhanced biofilm formation by crystal violet assay. To define whether the effect of BAC adaptation on biofilm production was manifested at the transcriptional level, quantitative RT-PCR was used. We found that 60% of the tested isolates showed overexpression of ndvB biofilm gene. More efforts are required to diminish the increasing use of BAC to avoid bacterial adaptation to this biocide with subsequent retardation of growth and enhanced biofilm formation which could lead to antibiotic resistance and treatment failure of infections caused by this opportunistic pathogen.

Invitro antibacterial activity of Cassia fistula Linn methanolic leaf extracts

Background: Cassia fistula Linn is a plant which is widely grown in India and is used for medicinal purposes. The study was carried out with an objective to demonstrate the antimicrobial activity of leaves of Cassia fistula Linn. The aim of the study is to assess antibacterial and antifungal activity of methanolic leaf extract of Cassia fistula Linn against selected clinical isolates.Methods: The antimicrobial activity of methanolic extract of Cassia fistula was evaluated using agar well diffusion method and to zone of inhibition of extract was determined. Clinical isolates of Staphyloccocus aureus, MRSA, Pseudomonas aeruginosa, E. coli and Proteus were screened.Results: The methanolic extracts exhibited antibacterial activity against Staphylococcus aureus. The extract was not active against E. coli, Proteus, MRSA, Pseudomonas aeruginosa. The extract also failed to demonstrate antifungal activity against Candida albicans and Aspergillus niger.Conclusions: The global emergence of multidrug resistant bacterial strains is increasing, limiting the effectiveness of current drugs and treatment failure of infections. A novel approach to the prevention of antibiotic resistance of pathogenic species is the use of new compounds that are not based on existing synthetic antimicrobial agents.

An Overview of New Delhi Metallo-Beta Lactamase-1 and Extended Spectrum Beta Lactamase Producing Bacteria: Need for an Alternate

Resistance to antibiotics is increasing dangerously worldwide. The emergence of antibiotic resistant bacteria is no more a local problem and calls for global action. It has become a leading challenge in infectious diseases management. The effectiveness of current drugs is restricted by emergence of multi-drug resistant bacterial strains and they have become the major reason for treatment failure of infections. Antimicrobial agents were initially highly successful in treating infections; however, their unsound use leads to rise in antimicrobial resistance frighteningly, especially in the developing countries. With the emergence of New Delhi Metallo-beta lactamase-1 and Extended Spectrum Beta Lactamase producing bacteria the clinicians are left with a very limited choice of treating the common infections. The recent situation calls for an urgent need for search of alternatives like herbal medicine which has shown potential in treating various other ailments. Because herbs are plants, they are often perceived as “natural” and therefore safe. Development of plant based compounds and combinational therapies using compounds may provide safer options for the community. Research should focus on scrutinizing compounds from plants for a target and bioactivity based drug discovery. However, the safety of using most herbs with drugs is not well established. Some herbs are known to interact with pharmaceutical drugs, although most of this information comes from case reports rather than systematic investigations. Because many herbs contain pharmacologically active compounds, some herbs may cause side effects through excessive biological effects. Unfortunately, the true frequency of side effects for most herbs is not known because most have not been tested in large clinical trials and because surveillance systems are much less extensive than those in place for pharmaceutical products. There is also a need for a strict regulations and policy in place for the use of herbal drugs or compounds of herbal origin in treatment of various common bacterial infections.

Characterization of ST258 Colistin-Resistant, blaKPC-Producing Klebsiella pneumoniae in a Greek Hospital.

The emergence of colistin resistance may further contribute to treatment failure of infection caused by multidrug-resistant (MDR) Klebsiella pneumoniae. The colistin resistance rates were determined and colistin-resistant carbapenemase-producing K. pneumoniae (COL-R CP-Kp) were characterized over an 18-month period in a Greek hospital. Out of 135 carbapenemase producers, 19 isolates (14%) were categorized as resistant to colistin. Phenotypic and molecular characterization of the COL-R CP-Kp isolates revealed that all were MDR blaKPC producers and, excluding one isolate of MLST ST383, belonged to the international clonal lineage ST258. Furthermore, PCR amplification and sequencing of the mgrB locus revealed nucleotide sequences of different sizes and insertions of IS1- and IS5-like mobile elements. The majority (63%) of the COL-R blaKPC producers was recovered from patients in the intensive care unit (ICU) and clinical data indicated that all patients should have acquired these isolates in the ICU. The findings of the present study underscore a concerning evolution of colistin resistance in a setting of high K. pneumoniae carbapenemase (KPC)-Kp endemicity, such as Greece. Thus, continuous surveillance, molecular characterization, prudent use of antibiotics, and implementation of infection control measures for K. pneumoniae are urgent.

Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis.

BackgroundA target AUC0-24/MIC ratio of 400 has been associated with its clinical success when treating Staphylococcus aureus infections but is not currently supported by state-of-the-art evidence-based research.ObjectiveThis current systematic review aimed to evaluate the available evidence for the association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness on hospitalized patients and to confirm the existing target value of 400.MethodsPubMed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were systematically searched. Manual searching was also applied. Both RCTs and observational studies comparing the clinical outcomes of high AUC0-24/MIC groups versus low AUC0-24/MIC groups were eligible. Two reviewers independently extracted the data. The primary outcomes were mortality and infection treatment failure. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated.ResultsNo RCTs were retrieved. Nine cohort studies were included in the meta-analysis. Mortality rates were significantly lower in high AUC0-24/MIC groups (RR = 0.47, 95%CI = 0.31–0.70, p<0.001). The rates of infection treatment failure were also significantly lower in high AUC/MIC groups and were consistent after correcting for heterogeneity (RR = 0.39, 95%CI = 0.28–0.55, p = 0.001). Subgroup analyses showed that results were consistent whether MIC values were determined by broth microdilution (BMD) method or Etest method. In studies using the BMD method, breakpoints of AUC0-24/MIC all fell within 85% to 115% of 400.ConclusionsThis meta-analysis demonstrated that achieving a high AUC0-24/MIC of vancomycin could significantly decrease mortality rates by 53% and rates of infection treatment failure by 61%, with 400 being a reasonable target.

Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.

BackgroundAlthough methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes.MethodsRetrospective cohort study (2001–2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression.ResultsSixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9–71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as “difficult-to-treat” in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9–36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7–103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166–24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013–1.271).ConclusionsThe important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-443) contains supplementary material, which is available to authorized users.

A putative de-N-acetylase of the PIG-L superfamily affects fluoroquinolone tolerance inPseudomonas aeruginosa

A major cause of treatment failure of infections caused by Pseudomonas aeruginosa is the presence of antibiotic-insensitive persister cells. The mechanism of persister formation in P. aeruginosa is largely unknown, and so far, only few genetic determinants have been linked to P. aeruginosa persistence. Based on a previous high-throughput screening, we here present dnpA (de-N-acetylase involved in persistence; gene locus PA14_66140/PA5002) as a new gene involved in noninherited fluoroquinolone tolerance in P. aeruginosa. Fluoroquinolone tolerance of a dnpA mutant is strongly reduced both in planktonic culture and in a biofilm model, whereas overexpression of dnpA in the wild-type strain increases the persister fraction. In addition, the susceptibility of the dnpA mutant to different classes of antibiotics is not affected. dnpA is part of the conserved LPS core oligosaccharide biosynthesis gene cluster. Based on primary sequence analysis, we predict that DnpA is a de-N-acetylase, acting on an unidentified substrate. Site-directed mutagenesis suggests that this enzymatic activity is essential for DnpA-mediated persistence. A transcriptome analysis indicates that DnpA primarily affects the expression of genes involved in surface-associated processes. We discuss the implications of these findings for future antipersister therapies targeted at chronic P. aeruginosa infections.