BACKGROUND: Cefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-β-lactamase-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important.
OBJECTIVE: To systematically collate and examine studies investigating in vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens.
METHODS: PubMed and Scopus, up to May 2023.
METHODS: Eligible were studies reporting CFDC-NS in Enterobacterales, P. aeruginosa, A. baumannii, or Stenotrophomonas maltophilia clinical isolates.
UNASSIGNED: Two independent reviewers extracted study data and assessed the risk of bias on the population, setting, and measurement (susceptibility testing) domains.
RESULTS: Binomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, coresistance phenotype, and breakpoint definition (EUCAST, CLSI, and FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses.
RESULTS: In all, 78 studies reporting 82 035 clinical isolates were analysed (87% published between 2020 and 2023). CFDC-NS prevalence (EUCAST breakpoints) was low overall but varied by species (S. maltophilia 0.4% [95% CI 0.2-0.7%], Enterobacterales 3.0% [95% CI 1.5-6.0%], P. aeruginosa 1.4% [95% CI 0.5-4.0%]) and was highest for A. baumannii (8.8%, 95% CI 4.9-15.2%). CFDC-NS was much higher in CR Enterobacterales (12.4%, 95% CI 7.3-20.0%) and CR A. baumannii (13.2%, 95% CI 7.8-21.5%), but relatively low for CR P. aeruginosa (3.5%, 95% CI 1.6-7.8%). CFDC-NS was exceedingly high in New Delhi metallo-β-lactamase-producing Enterobacterales (38.8%, 95% CI 22.6-58.0%), New Delhi metallo-β-lactamase-producing A. baumannii (44.7%, 95% CI 34.5-55.4%), and ceftazidime/avibactam-resistant Enterobacterales (36.6%, 95% CI 22.7-53.1%). CFDC-NS varied considerably with breakpoint definition, predominantly among CR bacteria. Additional sources of heterogeneity were single-centre investigations and geographical regions.
CONCLUSIONS: CFDC-NS prevalence is low overall, but alarmingly high for specific CR phenotypes circulating in some institutions or regions. Continuous surveillance and updating of global CFDC-NS estimates are imperative while cefiderocol is increasingly introduced into clinical practice. The need to harmonize EUCAST and CLSI breakpoints was evident.

To analyze the mortality rate of patients with Klebsiella pneumoniae bacteremia (KPB) and the impact of extended spectrum beta-lactamase (ESBL) producing or carbapenem-resistance (CR) KP on the mortality rate among patients with bacteremia.
EMbase, Web of Science, PubMed, and The Cochrane Library were searched up to September 18th, 2022. Two reviewers independently extracted data and evaluated risk of bias of included studies by ROBINS-I tool. A meta-regression analysis was conducted using a mixed-effects model to explore possible sources of heterogeneity. A random-effects model was used for pooled analysis in case of significant heterogeneity (I2>50%). Otherwise, the fixed-effects model was performed.
A total of 157 studies (37,915 enrolled patients) were included in the meta-analysis. The pooled death proportions of KPB were 17% (95% CI=0.14-0.20) at 7-day, 24% (95% CI=0.21-0.28) at 14-day, 29% (95% CI=0.26-0.31) at 30-day, 34% (95% CI=0.26-0.42) at 90-day, and 29% (95% CI=0.26-0.33) in hospital, respectively. Heterogeneity was found from the intensive care unit (ICU), hospital-acquired (HA), CRKP, and ESBL-KP in the meta-regression analysis. More than 50% of ICU, HA, CRKP, and ESBL-KP were associated with a significant higher 30-day mortality rates. The pooled mortality odds ratios (ORs) of CRKP vs. non-CRKP were 3.22 (95% CI 1.18-8.76) at 7-day, 5.66 (95% CI 4.31-7.42) at 14-day, 3.87 (95% CI 3.01-3.49) at 28- or 30-day, and 4.05 (95% CI 3.38-4.85) in hospital, respectively.
This meta-analysis indicated that patients with KPB in ICU, HA-KPB, CRKP, and ESBL-KP bacteremia were associated with a higher mortality rate. The high mortality rate caused by CRKP bacteremia has increased over time, challenging the public health.

[This corrects the article DOI: 10.3389/fphar.2022.896971.].

Cefiderocol is a novel synthetic siderophore-conjugated antibiotic that hijacks the bacterial iron transport systems facilitating drug entry into cells, achieving high periplasmic concentrations. This systematic review analyzed the currently available literature on cefiderocol. It summarized in vitro susceptibility data, in vivo antimicrobial activity, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety and resistance mechanisms of cefiderocol. Cefiderocol has potent in vitro and in vivo activity against multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant isolates. But New Delhi Metallo-β-lactamase (NDM)- positive isolates showed significantly higher MICs than other carbapenemase-producing Enterobacterales, with a susceptible rate of 83.4% for cefiderocol. Cefiderocol is well-tolerated, and the PK/PD target values can be achieved using a standard dose regimen or adjusted doses according to renal function. Clinical trials demonstrated that cefiderocol was non-inferiority to the comparator drugs in treating complicated urinary tract infection and nosocomial pneumonia. Case reports and series showed that cefiderocol was a promising therapeutic agent in carbapenem-resistant infections. However, resistant isolates and reduced susceptibility during treatment to cefiderocol have already been reported. In conclusion, cefiderocol is a promising powerful weapon for treating MDR recalcitrant infections.

BACKGROUND: Carbapenems are β-lactam antibiotics which are used to treat severe infections caused by multidrug resistant Enterobacteriacea. The recent emergence and rapid spread of Enterobacteriaceae resistant to carbapenems is a global concern. We undertook a systematic review of the antibiotic susceptibility and genotypic characteristics of carbapenem-resistant Enterobacteriaceae in Chinese neonates.
METHODS: Systematic literature reviews were conducted (PubMed/Medline, Embase, Wanfang medical online databases, China National Knowledge Infrastructure (CNKI) database) regarding sepsis caused by carbapenem-resistant Enterobacteriaceae in Chinese neonates aged 0-30 days.
RESULTS: 17 studies were identified. Eleven patients in the six studies reported the source of infection. Ten patients (10/11, 90.9%) were hospital-acquired infections. Genotypic data were available for 21 isolates in 11 studies (20 K. pneumoniae, 1 E. coli). NDM-1 was the most frequently reported carbapenem-resistant genotype (81.0%, 17/21). Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli were resistant to many antibiotic classes with the exception of colistin and fosfomycin. Sequence type 105 (ST105) was the most commonly reported K. pneumoniae ST type (30.8%; 4/13), which was from the same hospital in Western China. ST17 and ST20 were the second and third most common K. pneumoniae ST type, 23.1% (3/13) and 15.4% (2/13) respectively. The three strains of ST17 are all from the same hospital in central China. The two strains of ST20, although not from the same hospital, belong to the eastern part of China.
CONCLUSIONS: Klebsiella pneumoniae with the NDM-1 genotype was the leading cause of neonatal carbapenem resistant sepsis in China. Hospital acquired infection is the main source of carbapenem resistant sepsis. There is currently no licenced antibiotic regimen available to treat such an infection in China. Improved surveillance, controlling nosocomial infection and the rational use of antibiotics are the key factors to prevent and reduce its spread.

The objective of this works was to assess the global prevalence of multidrug-resistance among A. baumannii causing hospital-acquired (HAP) and ventilator-associated pneumonia (VAP), and describe its associated mortality.
We performed a systematic search of four databases for relevant studies. Meta-analysis was done based on United Nations geoscheme regions, individual countries and study period. We used a random-effects model to calculate pooled prevalence and mortality estimates with 95% confidence intervals (CIs), weighted by study size.
Among 6445 reports screened, we identified 126 relevant studies, comprising data from 29 countries. The overall prevalence of multidrug-resistance among A. baumannii causing HAP and VAP pooled from 114 studies was 79.9% (95% CI 73.9-85.4%). Central America (100%) and Latin America and the Caribbean (100%) had the highest prevalence, whereas Eastern Asia had the lowest (64.6%; 95% CI, 50.2-77.6%). The overall mortality estimate pooled from 27 studies was 42.6% (95% CI, 37.2-48.1%).
We observed large amounts of variation in the prevalence of multidrug-resistance among A. baumannii causing HAP and VAP and its mortality rate among regions and lack of data from many countries. Data from this review can be used in the development of customized strategies for infection control and antimicrobial stewardship.

Multi-drug resistant organisms are an increasingly important cause of neonatal sepsis.
This study aimed to review neonatal sepsis caused by multi-drug resistant Enterobacteriaceae (MDRE) in neonates in Johannesburg, South Africa.
This was a cross sectional retrospective review of MDRE in neonates admitted to a tertiary neonatal unit between 1 January 2013 and 31 December 2015.
There were 465 infections in 291 neonates. 68.6% were very low birth weight (< 1500 g). The median age of infection was 14.0 days. Risk factors for MDRE included prematurity (p = 0.01), lower birth weight (p = 0.04), maternal HIV infection (p = 0.02) and oxygen on day 28 (p < 0.001). The most common isolate was Klebsiella pneumoniae (66.2%). Total MDRE isolates increased from 0.39 per 1000 neonatal admissions in 2013 to 1.4 per 1000 neonatal admissions in 2015 (p < 0.001). There was an increase in carbapenem-resistant Enterobacteriaceae (CRE) from 2.6% in 2013 to 8.9% in 2015 (p = 0.06). Most of the CRE were New Delhi metallo-β lactamase- (NDM) producers. The all-cause mortality rate was 33.3%. Birth weight (p = 0.003), necrotising enterocolitis (p < 0.001) and mechanical ventilation (p = 0.007) were significantly associated with mortality. Serratia marcescens was isolated in 55.2% of neonates that died.
There was a significant increase in MDRE in neonatal sepsis during the study period, with the emergence of CRE. This confirms the urgent need to intensify antimicrobial stewardship efforts and address infection control and prevention in neonatal units in LMICs. Overuse of broad- spectrum antibiotics should be prevented.

Providencia species are Gram-negative bacteria that belong to the Enterobacteriaceae family. They have intrinsic resistance to colistin and tigecycline, which makes treatment of the multidrug-resistant strains of Providencia challenging. Carbapenem-resistant Providencia species are increasingly reported. In this review, patients\' characteristics, resistance mechanisms, treatment and infection control measures of carbapenem-resistant Providencia species in the literature are described.

OBJECTIVE: Carbapenem resistant K. pneumoniae (CRKP) has aroused widespread attention owing to its very limited therapeutic options, and this strain has increased rapidly in recent years. Although it is accepted that drug resistance is associated with increased mortality in general, but some other studies found no such relationship. To estimate mortality of patients infected with CRKP in general and analyze factors for mortality of this infection, thus, we conducted this systematic review and meta-analysis.
METHODS: A systematic literature review of relevant studies published until December 2015 was conducted. We selected and assessed articles reporting mortality of patients infected with CRKP.
RESULTS: Pooled mortality was 42.14% among 2462 patients infected with CRKP versus 21.16% in those infected with carbapenem-susceptible K. pneumoniae (CSKP). The mortality of patients with bloodstream infection (BSI) or urinary tract infection was 54.30 and 13.52%, respectively, and 48.9 and 43.13% in patients admitted to the intensive care unit (ICU) or who underwent solid organ transplantation (SOT). Mortality was 47.66% in patients infected with K. pneumoniae carbapenemase-producing K. pneumoniae and 46.71% in those infected with VIM-producing K. pneumoniae. Geographically, mortality reported in studies from North America, South America, Europe, and Asia was 33.24, 46.71, 50.06, and 44.82%, respectively.
CONCLUSIONS: Our study suggests that patients infected with CRKP have higher mortality than those infected with CSKP, especially in association with BSI, ICU admission, or SOT. We also considered that patients\' survival has a close relationship with their physical condition. Our results imply that attention should be paid to CRKP infection, and that strict infection control measures and new antibiotics are required to protect against CRKP infection.

Over the last 20 years there have been 32 reports of carbapenem-resistant organisms in the hospital water environment, with half of these occurring since 2010. The majority of these reports have described associated clinical outbreaks in the intensive care setting, affecting the critically ill and the immunocompromised. Drains, sinks, and faucets were most frequently colonized, and Pseudomonas aeruginosa the predominant organism. Imipenemase (IMP), Klebsiella pneumoniae carbapenemase (KPC), and Verona integron-encoded metallo-β-lactamase (VIM) were the most common carbapenemases found. Molecular typing was performed in almost all studies, with pulse field gel electrophoresis being most commonly used. Seventy-two percent of studies reported controlling outbreaks, of which just more than one-third eliminated the organism from the water environment. A combination of interventions seems to be most successful, including reinforcement of general infection control measures, alongside chemical disinfection. The most appropriate disinfection method remains unclear, however, and it is likely that replacement of colonized water reservoirs may be required for long-term clearance.