Spread of hypervirulent multidrug-resistant ST147 Klebsiella pneumoniae in patients with severe COVID-19: an observational study from Italy, 2020–21
Marco FalconeGiusy TiseoGabriele ArcariAlessandro LeonildiCesira GiordanoSara TempiniGiulia BibbolinoRoberto MozzoSimona BarniniAlessandra CarattoliFrancesco Menichetti
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To report an outbreak of hypervirulent Klebsiella pneumoniae (hvKp) in COVID-19 patients.Prospective, observational study including consecutive COVID-19 patients with hvKp infections admitted to the University Hospital of Pisa (Italy). Clinical data and outcome of patients were collected. All patients were followed-up to 30 days from the diagnosis of infection. Mortality within 30 days of the diagnosis of hvKp infection was reported. The hypermucoviscous phenotype was determined by the 'string test'. Molecular typing was performed on three strains collected during different periods of the outbreak. The strains underwent whole genome sequencing using the Illumina MiSeq instrument. The complete circular assemblies were also obtained for the chromosome and a large plasmid using the Unicycler tool.From November 2020 to March 2021, hvKp has been isolated from 36 COVID-19 patients: 29/36 (80.6%) had infections (15 bloodstream infections, 8 ventilator-associated pneumonias and 6 complicated urinary tract infections), while 7/36 (19.4%) had colonization (3 urine, 2 rectal and 2 skin). The isolates belonged to ST147 and their plasmid carried three replicons of the IncFIB (Mar), IncR and IncHI1B types and several resistance genes, including the rmpADC genes encoding enhancers of capsular synthesis. The hvKp isolates displayed an ESBL phenotype, with resistance to piperacillin/tazobactam and ceftolozane/tazobactam and susceptibility only to meropenem and ceftazidime/avibactam. The majority of patients were treated with meropenem alone or in combination with fosfomycin. Thirty-day mortality was 48.3% (14/29).ST147 ESBL-producing hvKp is associated with high mortality in COVID-19 patients. Strict microbiological surveillance and infection control measures are needed in this population.We used meropenem to successfully treat a patient with bacteremia due to ceftazidime-avibactam-resistant, meropenem- susceptible Klebsiella pneumoniae that carried mutant blaKPC-3. Meropenem was bactericidal against ceftazidime-avibactam- resistant K pneumoniae isolates in vitro. Nevertheless, the role of carbapenems in treating such infections remains uncertain, because meropenem resistance is selected readily during passage experiments.
Ceftazidime/avibactam
Bacteremia
Carbapenem
Avibactam
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Background: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units. Methods: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact. Results: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8–16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = −0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9–20.2), 7.9 (6.1–9.5), 3.8 (2.6–6.0), and 2.4 (1.6–2.7), respectively (p-value < 0.001). Conclusions: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations.
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Serum sensitivity and surface hydrophobicity of two Klebsiella pneumoniae strains (internal strain No. 378 and 3259) exposed to imipenem (CAS 64221-86-9) and meropenem (CAS 96036-03-2) at subinhibitory concentrations (sub-MICs; 1/4, 1/8 and 1/16 of the MICs) were evaluated. Carbapenems at all sub-MICs tested (with the exception of 1/16 of the MICs in strain 378) decreased susceptibility of bacteria to serum bactericidal activity. All sub-MICs of the antibiotics tested also reduced the bacterial surface hydrophobicity. The surface hydrophobicity of strain 3259 was most effectively decreased after the exposure to imipenem and meropenem at 1/4 of the MICs (to 3% or 5.2% of the control values). The highest decrease of hydrophobicity in strain 378 was found after exposure to imipenem and meropenem at 1/16 of the MICs (19.2% or 32.3%).
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Objective To evaluate the disk tests incorporating boracic acid inhibitor for the detection of Klebsiella pneumoniae carbopenem(KPC)-producing Klebsiella pneumoniae isolates.Methods A total of 36 genetically unrelated KPC-producing Klebsiella pneumoniae isolates were determined.The minimum inhibitory concentrations(MIC) of imipenem,meropenem and ertapenem were determined by agar dilution method.Polymerase chain reaction(PCR) and DNA sequencing were used for the identification of beta-lactamase genotypes.The modified Hodge test(MHT),using both standard and high inoculum of test organisms,was performed to detect carbopenem phenotype.The disk tests consisting of 8 antibiotics with and without boracic acid inhibitor were designed to detect KPC phenotype,and the diameter≥5 mm augmentation of inhibition zone was considered a positive result.Results All 36 KPC-producing Klebsiella pneumoniae isolates were resistant to at least one of the 3 carbopenems.The sensitivity and specificity of MHT were 97.2% and 91.0% for the detection of carbopenems,and they were 100.0% and 87.0% when a high inoculum was employed.For disk tests using cefepime,imipenem or meropenem with and without boracic acid detecting KPC phenotype in Klebsiella pneumoniae,the sensitivity and specificity were 100.0%.Conclusions Disk tests incorporating boracic acid inhibitor in combination with cefepime,imipenem or meropenem may help the phenotypic detection of KPC in Klebsiella pneumoniae,and are very easy to perform and interpret.
Ertapenem
Cefepime
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Agar dilution
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Meropenem heteroresistance was investigated in six apparently meropenem-susceptible, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) clinical isolates, compared with that in carbapenemase-negative, meropenem-susceptible controls. In population analyses, the KPC-KP isolates grew at meropenem concentrations of 64 to 256 microg/ml. Heteroresistant colonies had significantly elevated expression of the bla(KPC) gene compared with the native populations but did not retain heteroresistance when subcultured in drug-free media. Time-kill assays indicated that meropenem alone was not bactericidal against KPC-KP but efficiently killed the control strains.
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OXA-48 carbapenemases are frequently expressed by Klebsiella pneumoniae clinical isolates; they decrease the effectiveness of carbapenem therapy, particularly with meropenem. Among these isolates, meropenem-susceptible carbapenemase-producers may show decreased meropenem effectiveness. However, the probability of the emergence of resistance in susceptible carbapenemase-producing isolates and its dependence on specific K . pneumoniae meropenem MICs is not completely known. It is also not completely clear what resistance patterns will be exhibited by these bacteria exposed to meropenem, if they would follow the patterns of non-beta-lactamase-producing bacteria and other than beta-lactams antibiotics. These issues might be clarified if patterns of meropenem resistance related to the mutant selection window (MSW) hypothesis. To test the applicability of the MSW hypothesis to meropenem, OXA-48-carbapenemase-producing K . pneumoniae clinical isolates with MICs in a 64-fold range (from susceptible to resistant) were exposed to meropenem in a hollow-fiber infection model; epithelial lining fluid meropenem pharmacokinetics were simulated following administration of 2 grams every 8 hours in a 3-hour infusion. Strong bell-shaped relationships between the meropenem daily dose infused to the model as related to the specific isolate MIC and both the antimicrobial effect and the emergence of resistance were observed. The applicability of the MSW hypothesis to meropenem and carbapenemase producing K . pneumoniae was confirmed. Low meropenem efficacy indicates very careful prescribing of meropenem to treat K . pneumoniae infections when the causative isolate is confirmed as an OXA-48-carbapenemase producer.
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