Therapy of invasive infections due to multidrug-resistant
(MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC ...producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producing
(CPE), only some "second-line" drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.
Background There is little clinical information about community-onset bloodstream infections (COBSIs) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC). We ...investigated the prevalence and risk factors for COBSI due to ESBLEC, and described their clinical features and the impact of COBSI caused by ESBLEC on 14-day mortality. Methods Risk factors were assessed using a multicenter case-control-control study. Influence of ESBL production on mortality was studied in all patients with COBSI due to E. coli. Isolates and ESBLs were microbiologically characterized. Statistical analysis was performed using multivariate logistic regression. Thirteen tertiary care Spanish hospitals participated in the study. Results We included 95 case patients with COBSI due to ESBLEC, which accounted for 7.3% of all COBSI due to E. coli. The ESBL in 83 of these (87%) belonged to the CTX-M family of ESBL, and most were clonally unrelated. Comparison with both control groups disclosed association with health care (odds ratio OR, 2.1; 95% confidence interval CI, 1.2–3.8), urinary catheter use (OR, 3.1; 95% CI, 1.5–6.5), and previous antimicrobial use (OR, 2.7; 95% CI, 1.5–4.9) as independent risk factors for COBSI due to ESBLEC. Mortality among patients with COBSI due to ESBLEC was lower among patients who received empirical therapy with β-lactam/β-lactam inhibitor combinations or carbapenems (8%–12%) than among those receiving cephalosporins or fluoroquinolones (24% and 29%, respectively). Mortality among patients with COBSI due to E. coli was associated with inappropriate empirical therapy irrespective of ESBL production. Conclusions ESBLEC is an important cause of COBSI due to E. coli. Clinicians should consider adequate empirical therapy with coverage of these pathogens for patients with risk factors.
Escherichia coli sequence type 131 (ST131) is a globally disseminated, multidrug resistant (MDR) clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid ...emergence and successful spread of E. coli ST131 is strongly associated with several factors, including resistance to fluoroquinolones, high virulence gene content, the possession of the type 1 fimbriae FimH30 allele, and the production of the CTX-M-15 extended spectrum β-lactamase (ESBL). Here, we used genome sequencing to examine the molecular epidemiology of a collection of E. coli ST131 strains isolated from six distinct geographical locations across the world spanning 2000–2011. The global phylogeny of E. coli ST131, determined from whole-genome sequence data, revealed a single lineage of E. coli ST131 distinct from other extraintestinal E. coli strains within the B2 phylogroup. Three closely related E. coli ST131 sublineages were identified, with little association to geographic origin. The majority of single-nucleotide variants associated with each of the sublineages were due to recombination in regions adjacent to mobile genetic elements (MGEs). The most prevalent sublineage of ST131 strains was characterized by fluoroquinolone resistance, and a distinct virulence factor and MGE profile. Four different variants of the CTX-M ESBL–resistance gene were identified in our ST131 strains, with acquisition of CTX-M-15 representing a defining feature of a discrete but geographically dispersed ST131 sublineage. This study confirms the global dispersal of a single E. coli ST131 clone and demonstrates the role of MGEs and recombination in the evolution of this important MDR pathogen.
There is paucity of data describing the impact of COVID-19 pandemic on antimicrobial resistance. This review evaluated the changes in the rate of multidrug resistant gram negative and gram positive ...bacteria during the COVID-19 pandemic.
A search was conducted in PubMed, Science Direct, and Google Scholar databases to identify eligible studies. Studies that reported the impact of COVID-19 pandemic on carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase inhibitor (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Pseudomonas aeruginosa (CPE) were selected. Studies published in English language from the start of COVID-19 pandemic to July 2022 were considered for inclusion.
Thirty eligible studies were selected and most of them were from Italy (n = 8), Turkey (n = 3) and Brazil (n = 3). The results indicated changes in the rate of multidrug resistant bacteria, and the changes varied between the studies. Most studies (54.5%) reported increase in MRSA infection/colonization during the pandemic, and the increase ranged from 4.6 to 170.6%. Five studies (55.6%) reported a 6.8–65.1% increase in VRE infection/colonization during the pandemic. A 2.4–58.2% decrease in ESBL E. coli and a 1.8–13.3% reduction in ESBL Klebsiella pneumoniae was observed during the pandemic. For CRAB, most studies (58.3%) reported 1.5–621.6% increase in infection/colonization during the pandemic. Overall, studies showed increase in the rate of CRE infection/colonization during the pandemic. There was a reduction in carbapenem-resistant E. coli during COVID-19 pandemic, and an increase in carbapenem-resistant K. pneumoniae. Most studies (55.6%) showed 10.4 – 40.9% reduction in the rate of CRPA infection during the pandemic.
There is an increase in the rate of multidrug resistant gram positive and gram negative bacteria during the COVID-19 pandemic. However, the rate of ESBL-producing Enterobacteriaceae and CRPA has decrease during the pandemic. Both infection prevention and control strategies and antimicrobial stewardship should be strengthen to address the increasing rate of multidrug resistant gram positive and gram negative bacteria.
Background. Empirical combination therapy is recommended for patients with known or suspected Pseudomonas aeruginosa (PA) infection as a means to decrease the likelihood of administering inadequate ...antimicrobial treatment, to prevent the emergence of resistance, and to achieve a possible additive or even synergistic effect. Methods. We performed a post hoc analysis of patients with PA bloodstream infections from a published prospective cohort. Mortality was compared in patients treated with adequate empirical and definitive combination therapy (AECT, ADCT), and adequate empirical and definitive single-drug therapy (AESD, ADSD). Confounding was controlled by Cox regression analysis, and a propensity score for receiving AECT or ADCT was also used. Results. The final cohort comprised 593 patients with a single episode of PA bacteremia. The 30-day mortality was 30% (176 patients); 76 patients (13%) died during the first 48 hours. The unadjusted probabilities of survival until day 30 were 69.4% (95% confidence interval CI, 59.1–81.6) for the patients receiving AECT, 73.5% (95% CI, 68.4%–79.0%) for the AESD group, and 66.7% (95% CI, 61.2%–72.7%) for patients who received inadequate empirical therapy (P = .17, log-rank test). After adjustment for confounders, the AESD group (adjusted hazard ratio AHR, 1.17; 95% CI, .70–1.96; P = .54) and patients who received ADSD (AHR, 1.34; 95% CI, .73–2.47; P = .35) showed no association with 30-day mortality compared with the AECT and ADCT groups, respectively. Conclusions. These results suggests that treatment with combination antimicrobial therapy did not reduce the mortality risk compared with single-drug therapy in PA bloodstream infections.
Background. Infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are increasing in frequency and are associated with high mortality rates. Circulation of CTX-M-type ...ESBLs in the community is of particular concern, because it may confound standard infection-control measures. Methods. We analyzed the results of epidemiologic studies of infection caused by ESBL-producing Enterobacteriaceae in nonhospitalized patients from 6 centers in Europe, Asia, and North America. Risk factors for infection with an ESBL-producing organism were identified by univariate and multivariate analyses. Results. A total of 983 patient-specific isolates were reviewed (890 90.5% of which were Escherichia coli, 68 6.9% of which were Klebsiella species, and 25 2.5% of which were Proteus mirabilis ); 339 34.5% of the isolates produced ESBLs. CTX-M types were the most frequent ESBLs (accounting for 65%). Rates of co-resistance to ciprofloxacin among ESBL-producing isolates were high (>70%), but significant variation was seen among centers with respect to rates of resistance to gentamicin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Similar risk factors for infection with an ESBL-producing organism were found in the different participating centers. Significant risk factors, identified by multivariate analysis, were recent antibiotic use, residence in a long-term care facility, recent hospitalization, age ⩾65 years, and male sex (area under the receiver-operator characteristic ROC curve, 0.80). However, 34% of ESBL-producing isolates (115 of 336 isolates) were obtained from patients with no recent health care contact; the area under the ROC curve for the multivariate model for this group of patients was only 0.70, which indicated poorer predictive value. Conclusions. Community-acquired ESBL-producing Enterobacteriaceae are now prevalent worldwide, necessitating international collaboration. Novel approaches are required to adequately address issues such as empirical treatment for severe community-acquired infection and infection control.
These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on ...the effectiveness of individual antibiotics and on combination versus monotherapy.
An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak).
The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
Summary 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.
Extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli (ESBLEC) is an increasing cause of community and nosocomial infections worldwide. However, there is scarce clinical information about ...nosocomial bloodstream infections (BSIs) caused by these pathogens. We performed a study to investigate the risk factors for and prognosis of nosocomial BSIs due to ESBLEC in 13 Spanish hospitals. Risk factors were assessed by using a case-control-control study; 96 cases (2 to 16% of all nosocomial BSIs due to E. coli in the participating centers) were included; the most frequent ESBL was CTX-M-14 (48% of the isolates). We found CTX-M-15 in 10% of the isolates, which means that this enzyme is emerging as a cause of invasive infections in Spain. By repetitive extragenic palindromic sequence-PCR, most isolates were found to be clonally unrelated. By multivariate analysis, the risk factors for nosocomial BSIs due to ESBLEC were found to be organ transplant (odds ratio OR = 4.8; 95% confidence interval CI = 1.4 to 15.7), the previous use of oxyimino-β-lactams (OR = 6.0; 95% CI = 3.0 to 11.8), and unknown BSI source (protective; OR = 0.4; 95% CI = 0.2 to 0.9), and duration of hospital stay (OR = 1.02; 95% CI = 1.00 to 1.03). The variables independently associated with mortality were a Pitt score of >1 (OR = 3.9; 95% CI = 1.2 to 12.9), a high-risk source (OR = 5.5; 95% CI = 1.4 to 21.9), and resistance to more than three antibiotics, apart from penicillins and cephalosporins (OR = 6.5; 95% CI = 1.4 to 30.0). Inappropriate empirical therapy was not associated with mortality. We conclude that ESBLEC is an important cause of nosocomial BSIs. The previous use of oxyimino-β-lactams was the only modifiable risk factor found. Resistance to drugs other than penicillins and cephalosporins was associated with increased mortality.
There is limited data to describe the point-prevalence of healthcare-associated infections (HAIs) among patients at a regional level in Africa. This study estimated the pooled prevalence of HAIs and ...described the distribution of HAIs as well as the pathogens identified from African studies.
PubMed, Scopus and Google Scholar databases were searched to find point-prevalence studies of HAIs in Africa. Studies conducted in Humans that reported the prevalence of HAIs among hospitalized patients and published in English language from January 2010 to March 2022 were selected. Longitudinal studies of HAIs and unpublished studies were excluded. The reference list of the selected studies was checked to find additional studies. A meta-analysis was conducted using RevMan 5.4 and the pooled prevalence of HAIs was determined using a random effect model.
Of the 6094 articles identified from the databases, fifteen eligible articles were selected. The studies were conducted in the North, South, East and West African regions with Tunisia (n = 4) and South Africa (n = 2) having the highest number of studies. Most of the studies (n = 12, 80.0%) had good quality. The pooled prevalence of HAIs was 12.76% (95% confidence interval CI 10.30-15.23) with a high degree of heterogeneity (I
= 90.0%). The prevalence of HAIs varied between wards with the highest rate found in the ICU (25.2%-100%), followed by neonatal ICU/ward (7.0%-53.6%) and paediatric medical ward (2.7%-33.0%). Surgical site infection was the most common HAIs and accounted for 41.6% of all HAIs (95% CI 23.55-59.80), followed by bloodstream infection (17.07%, 95% CI 11.80-22.33) and respiratory tract infections/pneumonia (17.04%, 95% CI 13.21-20.87). Recent hospitalization (adjusted odds ratio AOR: 4.17, 95% CI 1.85-9.41), presence of peripheral vascular catheter (AOR: 2.87, 95% CI 1.54-5.36) and having diabetes mellitus (AOR: 2.46, 95% CI 1.45-4.17) were the strongest predictors of HAIs in Africa. Only 37.9% of HAIs had documented positive microbiological culture result with gram negative bacteria including Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii and Citrobacter been the most common microorganisms and accounted for 40%-100% of the pathogens.
The pooled point-prevalence of HAIs in Africa is more than two times higher than the rate reported in developed countries. The prevalence varied between the countries and was highest in the ICU and neonatal ICU/ward. Surgical site infection and bloodstream infection were the most common HAIs reported in African studies. Recent hospitalization, presence of peripheral vascular catheter and having diabetes mellitus were the strongest predictors of HAIs in African studies. Most of the HAIs are preventable with appropriate infection control measures and antimicrobial stewardship. Additional studies are needed especially in the Central African region. Future studies should be designed using standardized protocol and standardized definition to reduce heterogeneity among the studies.
PDF
