Carbapenemase-producing Pathogens Research Articles

Ceftazidime-avibactam induced renal disorders: past and present.

With the increasing prevalence of multidrug-resistant Gram-negative bacterial pathogens worldwide, antimicrobial resistance has become a significant public health concern. Ceftazidime-avibactam (CAZ-AVI) exhibited excellent in vitro activity against many carbapenemase-producing pathogens, and was widely used for the treatment of various complicated infections. CAZ-AVI is well tolerated across all dosing regimens, and its associated acute kidney injury (AKI) in phase II/III clinical trials is rare. However, recent real-world studies have demonstrated that CAZ-AVI associated AKI was more frequent in real-world than in phase II and III clinical trials, particularly in patients receiving concomitant nephrotoxic agents, with critically ill patients being at a higher risk. Herein, we reviewed the safety data related to renal impairment of CAZ-AVI, and discussed its pharmacokinetic/pharmacodynamic targets and dosage adjustment in patients with impaired renal function. This review aimed to emphasize the importance for healthcare professionals to be aware of this adverse event of CAZ-AVI and provide practical insights into the dosage optimization in critically ill patients with renal dysfunction.

Genomic Analysis of a Highly Virulent NDM-1-Producing Escherichia coli ST162 Infecting a Pygmy Sperm Whale (Kogia breviceps) in South America.

Carbapenemase-producing Enterobacterales are rapidly spreading and adapting to different environments beyond hospital settings. During COVID-19 lockdown, a carbapenem-resistant NDM-1-positive Escherichia coli isolate (BA01 strain) was recovered from a pygmy sperm whale (Kogia breviceps), which was found stranded on the southern coast of Brazil. BA01 strain belonged to the global sequence type (ST) 162 and carried the blaNDM–1, besides other medically important antimicrobial resistance genes. Additionally, genes associated with resistance to heavy metals, biocides, and glyphosate were also detected. Halophilic behavior (tolerance to > 10% NaCl) of BA01 strain was confirmed by tolerance tests of NaCl minimal inhibitory concentration, whereas halotolerance associated genes katE and nhaA, which encodes for catalase and Na+/H+ antiporter cytoplasmic membrane, respectively, were in silico confirmed. Phylogenomics clustered BA01 with poultry- and human-associated ST162 lineages circulating in European and Asian countries. Important virulence genes, including the astA (a gene encoding an enterotoxin associated with human and animal infections) were detected, whereas in vivo experiments using the Galleria mellonella infection model confirmed the virulent behavior of the BA01 strain. WHO critical priority carbapenemase-producing pathogens in coastal water are an emerging threat that deserves the urgent need to assess the role of the aquatic environment in its global epidemiology.

Rapid spread of critical priority carbapenemase-producing pathogens in companion animals: a One Health challenge for a post-pandemic world.

The COVID-19 pandemic has increased relationships and interactions between human and companion animals, supported by widespread social distancing and isolation measures. Additionally, the COVID-19 pandemic has led to an exponential growth in antibiotic and biocide use worldwide, possibly inducing further pressure, contributing to the selection of antibiotic-resistant bacteria, including WHO critical priority pathogens. While data from global surveillance studies reveal a linear trend of increasing carbapenem resistance among Gram-negative pathogens from companion animals, the acquisition of carbapenemase-producing Enterobacterales through direct contact with colonized hosts and contaminated veterinary hospital environments has been documented. This article highlights the rapid spread of WHO critical priority carbapenemase-producing pathogens in companion animals, which is a One Health challenge for a post-pandemic world.

Ventilatorassociated lower respiratory tract infections: etiology and diagnosis

Objective. To review a literature published over the past 5 years and our own data on the etiology of lower respiratory tract infections (LRTI), antimicrobial resistance and its relationships between sepsis and choice of appropriate antibiotic therapy. Materials and Methods. National Nosocomial Infections Surveillance (NNIS) criteria were used to diagnose LRTI. A review of the articles regarding LRTI from the Russian and international English language journals published over 6 years was performed. Identification of microorganisms was performed by culture over the period of 2003–2013; since 2014, MALDI-TOF MS method was used for this purpose. Results. Despite the ongoing policy to limit the use of antimicrobial therapy in the ICUs, there is an increase in carbapenemase-producing isolates in the ICUs from 2.2% (2018) to 11.7% (2020, 9 months). Along with the trend to increase in carbapenemase-producing pathogens causing LRTI, their variability is also increasing. In particular, it applies to strains producing carbapenemases OXA-48 or combination of OXA-48 with KPC; with the trend to combined production of carbapenemase beginning at 2019. Conclusions. Carbapenemase producers are becoming more widespread in the ICU settings, including the lower respiratory tract in mechanically ventilated patients. Practitioners didn’t get used to associate VAP with the Sepsis-3 criteria. The changes in etiology include the increased rate of carbapenem-resistant Enterobacterales and non-fermenting Gram-negative bacteria, primarily Acinetobacter spp., in Russia. It’s due to improved quality of respiratory support and increased consumption of carbapenems, tigecycline and polymyxins. Significant increase of OXA-48-producing pathogens is likely to be associated with a poor compliance with temporary guidelines on COVID-19 with regard to antibiotic therapy.

Bedside Detection of Carbapenemase-Producing Pathogens with Plasmonic Nanosensors

Providing the right antibiotic treatment as soon as possible is crucial to improve sepsis outcomes. In this context, infections by bacteria resistant to β-lactams can be deadly. Current approaches for identifying these pathogens are longsome and require complex infrastructure. Here we introduce a diagnostic kit for detecting carbapenemase-producing pathogens at the bedside. It generates colored tests that are easily distinguished by eye or by analyzing a smartphone photograph. The color is generated by gold nanoparticles, which have been designed to detect β-lactamase activity robustly and with ultra-high sensitivity. Neither microbial culture nor specialized equipment are required. The kit can detect infections by carbapenemase-producing bacteria directly from urine samples within 2.5 h, even when these contain an excess of interfering bacteria. It can also detect them in sputum samples within 3 h. The rapid assay time coupled with the ability to detect hazardous infections enables the personalization of antimicrobial treatments much faster than a full antibiotic susceptibility test, which often takes several days to be accomplished. This kit can also be implemented in resource-constrained scenarios where other options for antimicrobial susceptibility testing may not be available.

In vitro Synergistic Activity of Antimicrobial Combinations Against bla KPC and bla NDM-Producing Enterobacterales With bla IMP or mcr Genes.

Carbapenemase-producing Enterobacterales have become a severe public health concern because of their rapidly transmissible resistance elements and limited treatment options. The most effective antimicrobial combinations against carbapenemase-producing Enterobacterales are currently unclear. Here, we aimed to assess the therapeutic effects of seven antimicrobial combinations (colistin-meropenem, colistin-tigecycline, colistin-rifampicin, colistin-erythromycin, meropenem-tigecycline, meropenem-rifampicin, and meropenem-tigecycline-colistin) against twenty-four carbapenem-producing Enterobacterales (producing blaKPC, blaNDM, coexisting blaNDM and blaIMP, and coexisting mcr-1/8/9 and blaNDM genes) and one carbapenem-susceptible Enterobacterales using the checkerboard assay, time-kill curves, and scanning electron microscopy. None of the combinations were antagonistic. The combination of colistin-rifampicin showed the highest synergistic effect of 76% (19/25), followed by colistin-erythromycin at 60% (15/25), meropenem-rifampicin at 24% (6/25), colistin-meropenem at 20% (5/25), colistin-tigecycline at 20% (5/25), and meropenem-tigecycline at 4% (1/25). The triple antimicrobial combinations of meropenem-tigecycline-colistin had a synergistic effect of 100%. Most double antimicrobial combinations were ineffective on isolates with coexisting blaNDM and blaIMP genes. Meropenem with tigecycline showed no synergistic effect on isolates that produced different carbapenemase genes and were highly resistant to meropenem (92% meropenem MIC ≥ 16 mg/mL). Colistin-tigecycline showed no synergistic effect on Escherichia coli producing blaNDM–1 and Serratia marcescens. Time-kill curves showed that antimicrobial combinations achieved an eradication effect (≥ 3 log10 decreases in colony counts) within 24 h without regrowth, based on 1 × MIC of each drug. The synergistic mechanism of colistin-rifampicin may involve the colistin-mediated disruption of bacterial membranes, leading to severe alterations in their permeability, then causes more rifampicin to enter the cell and induces cell death. In conclusion, the antimicrobial combinations evaluated in this study may facilitate the successful treatment of patients infected with carbapenemase-producing pathogens.

Antibacterial potential of plant extracts on ESBL and carbapenemase producing pathogens

Antibacterial potential of plant extracts on ESBL and carbapenemase producing pathogens

Antibacterial potential of plant extracts on ESBL and carbapenemase producing pathogens

The extensive spread of antibiotic resistance among pathogens is critically challenging the healthcare system with treatment options. Often, the physicians are left with no choice but to use high doses of antibiotics to combat infectious diseases in spite of the associated toxicity. In an attempt to investigate plant sources as an alternative source of drugs, the current study evaluated the antibacterial activity of extracts obtained from six commonly available plants against 16 pathogens isolated from skin, respiratory and urinary tract. Among these, 14 multi drug resistant pathogens and 7 ESBL producers were identified. Also, 4 isolates showed both ESBL and carbapenemase production whereas 2 S. aureus isolates showed ESBL production and resistance to Streptogramins. The plants used in our study included garlic, cinnamon, Indian borage, clove, green tea and onion. The qualitative analysis of antibacterial activity was carried out by well diffusion method for water and methanol extracts of these plants. The results indicated garlic and Indian borage water extracts to be active against both gram negative and gram positive test pathogens. The observed zones of inhibition were in the range of 11-27 mm (Indian borage) and 9-21 mm (garlic) against the test pathogens. However, no synergy was observed when these extracts were combined.

Photodynamic inactivation of bacterial carbapenemases restores bacterial carbapenem susceptibility and enhances carbapenem antibiotic effectiveness.

The global emergence of carbapenemases in bacterial pathogens has rendered many life-threatening infections untreatable. Even though using carbapenemase inhibitors are a proven strategy in the battle against bacterial carbapenem resistance, developing inhibitors that could universally inactivate all bacterial carbapenemases is extremely challenging given the large diversity and the continuous evolution of bacterial carbapenemases. Antimicrobial photodynamic therapy (aPDT), an upcoming antimicrobial therapy, is demonstrated here for the first time to be a generalized approach to impair the bacterial carbapenemases without being limited by the molecular identities of the carbapenemases. In addition, aPDT is shown to prevent carbapenem antibiotic degradation, thereby enhancing the efficacy of carbapenem antibiotic against the carbapenemase-producing pathogens. Besides the enzyme activity impairment, aPDT was documented here to be genetically toxic for bacteria, and thus radically damage the carbapenemase genetic determinants in bacteria and prevent the transmission of carbapenemases among pathogens. By leveraging the universal carbapenemase-inactivating property of aPDT, it may be possible to make the incurable infections caused by the bacterial carbapenemases susceptible to carbapenem again.

1195. Where You Live Matters: United States Region as a Significant Predictor of Mortality for ESBL Infection Based on a Descriptive Study Using NIS Database

BackgroundExtended-spectrum β-lactamase (ESBL) enzymes are produced by multidrug-resistant (MDR) pathogens and confer resistance to β-lactam antibiotics. Infections due to MDR organisms, particularly those ESBL producing pathogens, are of major concern worldwide and are associated with prolonged hospital stay and increased case-fatality rate. Carbapenems are the treatment of choice for severe infections however overuse of this class of antibiotics is leading Carbapenemase-producing pathogens. Variations have been observed in the prevalence of ESBL strains from different US regions; however, it is unclear whether morbidity and mortality follow a similar pattern. This study was conducted to explore the incidence of ESBL infections in the inpatient setting and factors that affect morbidity/mortality.MethodsThe National Inpatient Sample (NIS) was used to identify all hospitalizations during 2002 to 2014; all primary and secondary diagnoses were searched to identify-resistant infection that utilized the ICD-9 code “V091.” All hospitalizations were stratified based on the indication of resistant infection, and comparisons were made with the chi-square test and linear regression for categorical and continuous variables, respectively. A multivariable binary logistic regression model was used to examine survival for those with ESBL infection. All analyses were conducted with SAS version 9.4; P < 0.005 was considered significant.ResultsThe analysis identified 320,888,511 hospitalizations with 17,732 identified with ESBL infection. Significant differences for those with and without an ESBL infection were found based on the US region with the pertinent results as follows; Northeast: 19.95% vs. 23.30%, Midwest: 14.71% vs. 16.81%, South: 25.14% vs. 40.53%, and West: 40.20% vs. 19.35%; P < 0.001. Results indicated the US region as a significant predictor of mortality for those with ESBL infection. Regions identified in Figure 1.ConclusionNotable findings from this study include a statistically significant variation in mortality risk between US regions. Comparatively lower risk of mortality as related to ESBL infection was noted in the Midwest region when compared with the West region. A greater understanding of the regional epidemiology of β-lactamases is needed to clarify why this disparity exists.Figure 1Disclosures All authors: No reported disclosures.

Occurrence and characterization of carbapenem-resistant Gram-negative bacilli: A collaborative study of antibiotic-resistant bacteria between Indonesia and Japan.

To explore the occurrence and characterization of carbapenemase-producing pathogens among carbapenem-resistant Gram-negative bacilli isolated from hospitalized patients with urinary tract infection in Indonesia. This was a study promoted by the Japanese-Indonesian collaborative research program in the Japan Initiative for Global Research Network on Infectious Diseases. Bacterial pathogens were prospectively isolated from urine specimens of hospitalized urinary tract infection patients at Dr. Soetomo Hospital (Surabaya, Indonesia). All Gram-negative bacteria resistant to third-generation cephalosporin or carbapenem were included in this study. Carbapenemase genes were investigated for phenotype and genotype. In total, 1082 Gram-negative bacilli were isolated, of which 116 strains were resistant to imipenem or meropenem (carbapenem-resistant Gram-negative bacilli), and 22 strains were carbapenemase-producing Gram-negative bacilli. Carbapenemase-producing Gram-negative bacilli consisted of Acinetobacter baumannii (n=4), Pseudomonas aeruginosa (n=4), Klebsiella pneumoniae (n=5), Providencia rettgeri (n=4) and five others. The carbapenemase-producing Gram-negative bacilli included NDM-1 (n=18, 81.8%, in Enterobacteriaceae and Acinetobacter spp.) and IMP-7 (n=4, 18.2%, all in P.aeruginosa). Among carbapenem-resistant Gram-negative bacilli, all four P.aeruginosa were sensitive to colistin, and all six Acinetobacter spp. were sensitive to minocycline, colistin and tigecycline. Of those patients harboring carbapenemase-producing Gram-negative bacilli, 12 (54.5%) were seriously ill at the time of admission, with longer hospital stays and three deaths (13.6% mortality rate). Urinary tract infection-causing carbapenem-resistant Gram-negative bacilli are widely disseminated in Indonesia. The NDM-1 phenotype seems to be dominant, and it can be treated with colistin and tigecycline in most cases. Most patients harboring carbapenemase-producing Gram-negative bacilli are seriously ill, have a bad prognosis, with a longer hospital stay and a significant mortality rate.

Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens.

High antibiotic and antifungal concentrations in wastewater from anti-infective drug production may exert selection pressure for multidrug-resistant (MDR) pathogens. We investigated the environmental presence of active pharmaceutical ingredients and their association with MDR Gram-negative bacteria in Hyderabad, South India, a major production area for the global bulk drug market. From Nov 19 to 28, 2016, water samples were collected from the direct environment of bulk drug manufacturing facilities, the vicinity of two sewage treatment plants, the Musi River, and habitats in Hyderabad and nearby villages. Samples were analyzed for 25 anti-infective pharmaceuticals with liquid chromatography-tandem mass spectrometry and for MDR Gram-negative bacteria using chromogenic culture media. In addition, specimens were screened with PCR for bla VIM, bla KPC, bla NDM, bla IMP-1, and bla OXA-48 resistance genes. All environmental specimens from 28 different sampling sites were contaminated with antimicrobials. High concentrations of moxifloxacin, voriconazole, and fluconazole (up to 694.1, 2500, and 236,950µg/L, respectively) as well as increased concentrations of eight other antibiotics were found in sewers in the Patancheru-Bollaram industrial area. Corresponding microbiological analyses revealed an extensive presence of extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae and non-fermenters (carrying mainly bla OXA-48, bla NDM, and bla KPC) in more than 95% of the samples. Insufficient wastewater management by bulk drug manufacturing facilities leads to unprecedented contamination of water resources with antimicrobial pharmaceuticals, which seems to be associated with the selection and dissemination of carbapenemase-producing pathogens. The development and global spread of antimicrobial resistance present a major challenge for pharmaceutical producers and regulatory agencies.

Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae.

Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine β-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 μg/ml). Overall, meropenem alone (MIC50 and MIC90, 16 and >64 μg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 μg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 μg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 μg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 μg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 μg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 μg/ml of the inhibitor (MIC50, ≤0.06 μg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 μg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-β-lactamases (MIC, 16 to >64 μg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 μg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 μg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.

Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study

Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18-90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5-21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7-10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6-94·7] of 154 patients) and best available therapy (135 [91%; 85·9-95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa. AstraZeneca.

Detection systems for carbapenemase gene identification should include the SME serine carbapenemase

Carbapenemase detection has become a major problem in hospitals that encounter outbreaks of infections caused by carbapenem-resistant Gram-negative bacteria. Rapid detection systems have been reported using multiplex PCR analyses and DNA microarray assays. Major carbapenemases that are detected by these systems include the KPC and OXA serine carbapenemases, and the IMP, VIM and NDM families of metallo-β-lactamases. However, increasing numbers of the SME serine carbapenemase are being reported from Serratia marcescens, especially from North and South America. These organisms differ from many of the other carbapenemase-producing pathogens in that they are generally susceptible to the expanded-spectrum cephalosporins ceftazidime and cefepime while retaining resistance to almost all other β-lactam antibiotics. Thus, multiplex PCR assays or DNA microarray testing of carbapenem-resistant S. marcescens isolates should include analyses for production of the SME carbapenemase. Confirmation of the presence of this enzyme may provide reassurance that oxyimino-cephalosporins can be considered for treatment of infections caused by these carbapenem-resistant pathogens.

Intercontinental spread from Israel to Colombia of a KPC-3-producing Klebsiella pneumoniae strain

In 2008, an increase in the prevalence of carbapenem-resistant Klebsiella pneumoniae was noted in a 286-bed tertiary case hospital in Colombia, where 84 patients (32 infected and 52 colonized) had positive cultures. The identified index patient came from Israel for a liver transplantation. High level carbapenem resistance was observed. Polymyxin B and tigecycline were the only two antibiotics that remained active. PCR-restriction fragment length polymorphism analysis and sequencing revealed blaKPC-3 in the major clone, which was indistinguishable from the K. pneumoniae carbapenemase-3-producing clone described previously in Israel. This exemplifies the threat posed by the global spread of K. pneumoniae carbapenemase-producing pathogens.