Enterobacterales carrying chromosomal AmpC ß-lactamases in Europe (EuESCPM): Epidemiology and antimicrobial resistance burden from a cohort of 27 hospitals, 2020-2022.

INTRODUCTION: The ESCPM group (Enterobacter species including Klebsiella aerogenes - formerly Enterobacter aerogenes, Serratia species, Citrobacter freundii complex, Providencia species and Morganella morganii) has not yet been incorporated into systematic surveillance programs. METHODS: We conducted a multicentre retrospective observational study analysing all ESCPM strains isolated from blood cultures in 27 European hospitals over a 3-year period (2020-2022). Diagnostic approach, epidemiology, and antimicrobial susceptibility were investigated. RESULTS: Our study comprised 6,774 ESCPM isolates. MALDI-TOF coupled to mass spectrometry was the predominant technique for bacterial identification. Susceptibility to new ß-lactam/ß-lactamase inhibitor combinations and confirmation of AmpC overproduction were routinely tested in 33.3% and 29.6% of the centres, respectively. The most prevalent species were E. cloacae complex (44.8%) and S. marcescens (22.7%). Overall, third-generation cephalosporins (3GC), combined third- and fourth-generation cephalosporins (3GC + 4GC) and carbapenems resistance phenotypes were observed in 15.7%, 4.6%, and 9.5% of the isolates, respectively. AmpC overproduction was the most prevalent resistance mechanism detected (15.8%). Among carbapenemase-producers, carbapenemase type was provided in 44.4% of the isolates, VIM- (22.9%) and OXA-48-enzyme (16%) being the most frequently detected. E. cloacae complex, K. aerogenes and Providencia species exhibited the most notable cumulative antimicrobial resistance profiles, with the former displaying 3GC, combined 3GC + 4GC and carbapenems resistance phenotypes in 15.2%, 7.4%, and 12.8% of the isolates, respectively. K. aerogenes showed the highest rate of both 3GC resistant phenotype (29.8%) and AmpC overproduction (32.1%), while Providencia species those of both carbapenems resistance phenotype (42.7%) and carbapenemase production (29.4%). ESCPM isolates exhibiting both 3GC and combined 3GC + 4GC resistance phenotypes displayed high susceptibility to ceftazidime/avibactam (98.2% and 95.7%, respectively) and colistin (90.3% and 90.7%, respectively). Colistin emerged as the most active drug against ESCPM species (except those intrinsically resistant) displaying both carbapenems resistance phenotype (85.8%) and carbapenemase production (97.8%). CONCLUSIONS: This study presented a current analysis of ESCPM species epidemiology in Europe, providing insights to inform current antibiotic treatments and guide strategies for antimicrobial stewardship and diagnostics.

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study.

BACKGROUND: The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. METHODS: In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. FINDINGS: Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). INTERPRETATION: Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. FUNDING: Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

A Predictive Model of Mortality in Patients With Bloodstream Infections due to Carbapenemase-Producing Enterobacteriaceae.

OBJECTIVE: To develop a score to predict mortality in patients with bloodstream infections (BSIs) due to carbapenemase-producing Enterobacteriaceae (CPE). PATIENTS AND METHODS: A multinational retrospective cohort study (INCREMENT project) was performed from January 1, 2004, through December 31, 2013. Patients with clinically relevant monomicrobial BSIs due to CPE were included and randomly assigned to either a derivation cohort (DC) or a validation cohort (VC). The variables were assessed on the day the susceptibility results were available, and the predictive score was developed using hierarchical logistic regression. The main outcome variable was 14-day all-cause mortality. The predictive ability of the model and scores were measured by calculating the area under the receiver operating characteristic curve. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for different cutoffs of the score. RESULTS: The DC and VC included 314 and 154 patients, respectively. The final logistic regression model of the DC included the following variables: severe sepsis or shock at presentation (5 points); Pitt score of 6 or more (4 points); Charlson comorbidity index of 2 or more (3 points); source of BSI other than urinary or biliary tract (3 points); inappropriate empirical therapy and inappropriate early targeted therapy (2 points). The score exhibited an area under the receiver operating characteristic curve of 0.80 (95% CI, 0.74-0.85) in the DC and 0.80 (95% CI, 0.73-0.88) in the VC. The results for 30-day all-cause mortality were similar. CONCLUSION: A validated score predictive of early mortality in patients with BSIs due to CPE was developed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01 764490.

Emerging Escherichia coli O25b/ST131 clone predicts treatment failure in urinary tract infections.

BACKGROUND: We described the clinical predictive role of emerging Escherichia coli O25b/sequence type 131 (ST131) in treatment failure of urinary tract infection. METHODS: In this prospective observational cohort study, the outpatients with acute cystitis with isolation of E. coli in their urine cultures were assessed. All the patients were followed up for clinical cure after 10 days of treatment. Detection of the E. coli O25:H4/ST131 clone was performed by multiplex polymerase chain reaction (PCR) for phylogroup typing and using PCR with primers for O25b rfb and allele 3 of the pabB gene. RESULTS: In a cohort of patients with diagnosis of acute urinary cystitis, 294 patients whose urine cultures were positive with a growth of >10(4) colony-forming units/mL of E. coli were included in the study. In empiric therapy, ciprofloxacin was the first choice of drug (27%), followed by phosphomycin (23%), trimethoprim-sulfamethoxazole (TMP-SMX) (9%), and cefuroxime (7%). The resistance rate was 39% against ciprofloxacin, 44% against TMP-SMX, and 25% against cefuroxime. Thirty-five of 294 (12%) isolates were typed under the O25/ST131 clone. The clinical cure rate was 85% after the treatment. In multivariate analysis, detection of the O25/ST131 clone (odds ratio [OR], 4; 95% confidence interval [CI], 1.51-10.93; P = .005) and diabetes mellitus (OR, 2.1; 95% CI, .99-4.79; P = .05) were found to be significant risk factors for the treatment failure. In another multivariate analysis performed among quinolone-resistant isolates, treatment failure was 3 times more common among the patients who were infected with ST131 E. coli (OR, 3; 95% CI, 1.27-7.4; P = .012). CONCLUSIONS: In urinary tract infections, the E. coli ST131 clone seems to be a consistent predictor of treatment failure.

The prevalence, etiologic agents and risk factors for urinary tract infection among spinal cord injury patients.

BACKGROUND: Urinary tract infections (UTIs) are important causes of morbidity and mortality in patients with spinal cord injury and 22% of patients with acute spinal cord injury develop UTI during the first 50 days. OBJECTIVES: The aim of this study was to determine the prevalence, etiologic agents and risk factors for asymptomatic bacteriuria and symptomatic urinary tract infections in patients with spinal cord injury. PATIENTS AND METHODS: This was a prospective investigation of spinal cord injury patients with asymptomatic bacteriuria and symptomatic urinary tract infections in Baskent University Medical Faculty Ayas Rehabilitation Center and Ankara Physical Therapy and Rehabilitation Center between January 2008 and December 2010. The demographic status, clinical and laboratory findings of 93 patients with spinal cord injury were analyzed in order to determine the risk factors for asymptomatic or symptomatic bacteriuria. RESULTS: Sixty three (67.7%) of 93 patients had asymptomatic bacteriuria and 21 (22.6%) had symptomatic urinary tract infection. Assessment of the frequency of urinary bladder emptying methods revealed that 57 (61.3%) of 93 patients employed permanent catheters and 24 (25.8%) employed clean intermittent catheterization. One hundred and thirty-five (48.0%) of 281 strains isolated form asymptomatic bacteriuria attacks and 16 (66.6%) of 24 strains isolated from symptomatic urinary tract infection attacks, totaling 151 strains, had multidrug resistance (P > 0.05). One hundred (70.4%) of 142 Escherichia coli strains and 19 (34.5%) of 55 Klebsiella spp strains proliferated in patients with asymptomatic bacteriuria; 8 (80%) of 10 E. coli strains and 4 (80%) of 5 Klebsiella spp. strains were multidrug resistant. CONCLUSIONS: The most common infectious episode among spinal cord injury patients was found to be urinary tract infection. E. coli was the most common microorganism isolated from urine samples. Antibiotic use in the previous 2 weeks or 3 months, hospitalization during the last one-year and previous diagnosis of urinary tract infection were the risk factors identified for the development of infections with multi-drug resistant isolates. Urinary catheterization was found to be the only independent risk factor contributing to symptomatic urinary tract infection.

In vitro susceptibility of tigecycline against multidrug-resistant gram-negative strains: Etest versus agar dilution.

BACKGROUND AND AIM: Tigecycline is a semi-synthetic tetracycline with activity against most multidrug-resistant (MDR) bacteria. METHODS: We studied in vitro activity of tigecycline by agar dilution (AD) and Etest methods to evaluate their correlation. The study included 206 isolates of extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli, Klebsiella pneumoniae and MDR Acinetobacter baumannii recovered from blood cultures of patients of Baskent University between 2008 and 2010. RESULTS: ESBL-producing E. coli had MIC50/MIC90 values of 0.5/0.5 µg/ml by AD and 0.25/0.5 µg/ml by Etest. ESBL-producing K. pneumoniae had MIC50/MIC90 values of 1/2 µg/ml by AD and 0.75/2 µg/ml by Etest, whereas MDR A. baumannii had MIC50/MIC90 values of 4/4 µg/ml by AD and 2/4 µg/ml by Etest. The correlation between AD and Etest was weak for ESBL-producing E. coli and strong for ESBL-producing K. pneumoniae and MDR A. baumannii. Tigecycline MIC values for ESBL-producing E. coli were lower than the tigecycline concentration, while they were higher than the concentrations attainable by treatment doses for A. baumannii. CONCLUSION: Tigecycline is an appropriate agent in the treatment of E. coli bacteremia, but it is not for treating A. baumannii bacteremia. Tigecycline could be used for K. pneumoniae bacteremia treatment after determining its MIC value. Determining the MIC value by gold-standard methods is more appropriate due to the correlation between Etest and AD at high MIC values.

Assessment of the effectiveness of silver-coated dressing, chlorhexidine acetate (0.5%), citric acid (3%), and silver sulfadiazine (1%) for topical antibacterial effects against the multi-drug resistant Pseudomonas aeruginosa infecting full-skin thickness burn wounds on rats.

The aim of this study was to compare the effects of four different topical antimicrobial dressings on a multi-drug resistant Pseudomonas aeruginosa contaminated full-thickness burn wound rat model. A total of 40 adult male Wistar albino rats were used. The control group (group 1), silver sulfadiazine (1%) group 2, chlorhexidine acetate (0.5%) group 3, citric acid (3%) group 4, and silver-coated dressing group 5 were compared to assess the antibacterial effects of a daily application to a 30% full-skin thickness burn wound seeded 10 minutes earlier with 10(8) CFU (colony forming unit)/0.5 mL of a multi-drug resistant Pseudomonas aeruginosa strain. Five groups (1 control group and 4 treatment groups) were compared. The administration of third-degree burns to all rats was confirmed based on histopathologic data. The tissue cultures from groups 2 and 5 exhibited significant differences compared to those of the other 3 groups, whereas no significant differences were observed between groups 1, 3, and 4. The effectiveness of the treatments was as follows: 1% silver sulfadiazine > silver-coated dressing > 3% citric acid > 0.5% chlorhexidine acetate > control group. Our results supported the efficacy of topical therapy by silver sulfadiazine and silver-coated dressing on infections caused by multi-drug resistant Pseudomonas spp.

In vitro activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA 48-positive Klebsiella pneumoniae strains.

Carbapenem resistance due to OXA-48 enzymes in Klebsiella pneumoniae is increasing particularly in the Middle Eastern and European regions. Treatment options are limited. The aim of this study was to evaluate the in vitro synergistic activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA-48 producing K. pneumoniae strains. Twelve carbapenem-resistant OXA-48 producing K. pneumoniae isolates were enrolled in this study. Synergistic activity of fosfomycin combined with imipenem, meropenem, colistin, and tigecycline was assessed by chequerboard method. The combination of fosfomycin was synergistic with imipenem, meropenem and tigecycline with the ratios of 42%, 33%, and 33%, respectively. Whilst the combination of fosfomycin with colistin was fully antagonistic against all of the strains, there was no statistically significant difference between the in vitro synergistic activities of fosfomycin in combination with imipenem, meropenem and tigecycline combinations (P > 0.05). Fosfomycin in combination with other agents can be preferred against multidrug resistant K. pneumoniae strains.

Bloodstream Infections among Solid Organ Transplant Recipients: Eight Years' Experience from a Turkish University Hospital.

BACKGROUND: Bloodstream infections (BSI) are frequently seen after solid organ transplantation. The incidence of bloodstream infections differs among the types of transplantation. The microbiological features and antimicrobial resistance patterns change from centre to centre. AIMS: To evaluate the incidence and spectrum of aetiological agents of bloodstream infections among solid organ transplantation recipients. STUDY DESIGN: Retrospective descriptive study. METHODS: Medical records of solid organ transplant recipients in the period between January 1(st) 2004 and August 15(th) 2012 were assessed retrospectively. The study population comprised 927 (64 heart, 556 kidney, 307 liver) consecutive recipients. Bloodstream infections were divided into three groups according to the onset time of bloodstream infections after transplantation: early, mid-term and late. The incidence and microbiological features of bloodstream infections were evaluated. RESULTS: The number of bloodstream infection episodes was 317 in 191 recipients which was distributed as 228 (72%) in liver, 70 (22%) in kidney and 19 (6%) in heart transplantation. Ninety-eight 98 (30.9%) of the episodes were diagnosed within the early period, 134 (42.3%) within the mid-term and 85 (26.8%) in the late period. Early and mid-term bloodstream infections were seen statistically more often in liver than in kidney or heart transplantation (p=0.01 and p=0.031, respectively). Late bloodstream infections were also common in liver transplant recipients which was not statistically significant (p=0.229). CONCLUSION: Liver transplant recipients are at the highest risk for developing BSI after transplantation in early, mid-term and late periods.

A Rare Cause of Endocarditis: Streptococcus pyogenes.

Although group A ß-hemolytic streptococcus is an uncommon cause of infective endocarditis, an increase in the incidence of invasive group A streptococcus infections including bacteremia has been reported in the last two decades. Herein we report Streptococcus pyogenes endocarditis in a previously healthy adult patient who was hospitalized to investigate the etiology of fever. Because of a suspicion of a new vegetation appeared in the second (aortic) valve in the 14(th) day of high dose penicillin G treatment, the mitral and aortic valves were replaced by mechanical prosthesis on the 22(nd) day of treatment. He was discharged from hospital after the 6 week course of antibiotic treatment.

Double invasive fungal infection and typhlitis in children with acute lymphoblastic leukemia.

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.

Isolated Brucella peritonitis in a CAPD patient.

Peritonitis is the most common complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Brucellosis is a rare cause of bacterial peritonitis. Only 1 case was reported of a patient with brucella peritonitis during CAPD therapy. In that case, CAPD peritonitis was accompanied by acute brucellosis. We present the case of a patient with isolated brucella peritonitis receiving CAPD therapy without systemic manifestations of brucellosis who works as a farmer. Results of a serum agglutination test and blood cultures were negative; however, the patient's peritoneal fluid agglutination titer was 1:160 and samples inoculated into BACTEC (Becton Dickinson, NJ) bottles yielded Brucella melitensis. Because we were unable to isolate the organism in blood samples, transmission seems to be the result of direct inoculation, rather than hematogenous spreading. Therefore, our patient represents the first case of isolated brucella peritonitis during CAPD therapy. Successful treatment was obtained by using a treatment regimen of rifampin and doxycycline.

In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units.

The aim of this study was to assess the in vitro activity of a number of non-traditional antibiotics (colistin, azithromycin, doxycycline and rifampicin) against multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from Intensive Care Units (ICUs). We also used the checkerboard method to determine whether combinations of colistin with another non-traditional antibiotic or meropenem act synergistically against these strains. Thirty-five P. aeruginosa and 25 A. baumannii strains that were found to be MDR were included the study. Isolates were collected from the specimens of patients in ICUs from 2001 to 2003. All isolates were identified by standard methods and stored at -20 degrees C until use. Antibiotic powders of azithromycin, doxycycline, rifampicin, meropenem and colistin were obtained from their manufacturers. Minimum inhibitory concentrations (MICs) were determined by the agar dilution method on Mueller-Hinton agar. Five strains of A. baumannii and five strains of P. aeruginosa, all of which had different MIC values for colistin, were selected for the synergy study using the checkerboard titration method. The susceptibility results for doxycycline and meropenem were interpreted according to National Committee for Clinical Laboratory Standards guidelines. The susceptibility breakpoints for colistin and rifampicin were established as 4 mg/L and 2 mg/L, respectively, based on previous studies. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were used as control strains. Testing against the P. aeruginosa strains revealed high MIC50 values for all the drugs except colistin. Doxycycline and colistin were both effective against the A. baumannii strains, with high susceptibility rates of 92% and 100%, respectively. Azithromycin had a high MIC50 value against these strains, whilst rifampicin had a moderate effect (susceptibility rate 64%). The combination of colistin and rifampicin was fully synergistic against four A. baumannii and two P. aeruginosa strains. Combinations of colistin with meropenem and of colistin with azithromycin each showed synergistic activity against three A. baumannii isolates, whilst the same combinations resulted in generally additive or indifferent effects against P. aeruginosa strains. The colistin and doxycycline combination was generally partially synergistic or additive against all the isolates. MDR strains of P. aeruginosa and A. baumannii, which cause nosocomial infections with an increasing ratio in recent years, have limited treatment options. According to our in vitro study results, non-traditional antibiotics such as doxycycline and colistin can be an alternative for the treatment of infections caused by these strains. Combinations of colistin with non-traditional antibiotics or meropenem could be promising alternatives for the treatment of infections due to MDR strains of A. baumannii and P. aeruginosa.

Risk factors for ciprofloxacin resistance among Escherichia coli strains isolated from community-acquired urinary tract infections in Turkey.

OBJECTIVES: To determine the risk factors for community-acquired ciprofloxacin-resistant Escherichia coli urinary tract infection (UTI). METHODS: The study was performed with isolates from community-acquired UTIs collected from 15 centres representing six different geographic regions of Turkey. All microbiological procedures were carried out in a central laboratory. Multivariate analysis was performed for detection of risk factors for resistance. Use of quinolones more than once within the last year, living in a rural area, having a urinary catheter, age >50 and complicated infections were included in the model as variables and logistic regression was performed. RESULTS: A total of 611 gram-negative isolates were studied: 321 were isolated from uncomplicated UTI and 290 were isolated from complicated UTI. E. coli was the causative agent in 90% of the uncomplicated UTIs and in 78% of the complicated UTIs (P < 0.001). Seventeen percent of E. coli strains isolated from uncomplicated cases and 38% of E. coli strains isolated from complicated UTI were found to be resistant to ciprofloxacin. In multivariate analysis, age over 50 [odds ratio (OR): 1.6; confidence interval (CI): 1.08-2.47; P = 0.020], ciprofloxacin use more than once in the last year (OR: 2.8; CI: 1.38-5.47; P = 0.004) and the presence of complicated UTI (OR: 2.4; CI: 1.54-3.61; P < 0.001) were found to be associated with ciprofloxacin resistance. Detection of strains of E. coli producing extended-spectrum beta-lactamase (ESBL) enzymes was two times more common in the patients who received ciprofloxacin than those who did not (15% versus 7.4%). CONCLUSIONS: The increasing prevalence of infections caused by antibiotic-resistant bacteria makes the empirical treatment of UTIs more difficult. One of the important factors contributing to these high resistance rates might be high antibiotic use. Urine culture and antimicrobial susceptibility testing are essential in Turkey for patients with UTI who have risk factors for resistance, such as previous ciprofloxacin use. Fluoroquinolone-sparing agents such as nitrofurantoin and fosfomycin should be evaluated as alternative therapies by further clinical efficacy and safety studies.