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Effect of N-Acetylcysteine Administration on 30-Day Mortality in Critically Ill Patients with Septic Shock Caused by Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii: A Retrospective Case-Control Study.

ABSTRACT: Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab) represent important cause of severe infections in intensive care unit (ICU) patients. N-Acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties, showing also in-vitro antibacterial activity. Aim was to evaluate the effect on 30-day mortality of the addition of intravenous NAC to antibiotics in ICU patients with CR-Kp or CR-Ab septic shock. A retrospective, observational case:control study (1:2) in patients with septic shock caused by CR-Kp or CR-Ab hospitalized in two different ICUs was conducted. Cases included patients receiving NAC plus antimicrobials, controls included patients not receiving NAC. Cases and controls were matched for age, SAPS II, causative agent and source of infection. No differences in age, sex, SAPS II score or time to initiate definitive therapy were observed between cases and controls. Pneumonia and bacteremia were the leading infections. Overall, mortality was 48.9% (33.3% vs. 56.7% in cases and controls, p = 0.05). Independent risk factors for mortality were not receiving NAC (p = 0.002) and CR-Ab (p = 0.034) whereas therapy with two in-vitro active antibiotics (p = 0.014) and time to initial definite therapy (p = 0.026) were protective. NAC plus antibiotics might reduce the 30-day mortality rate in ICU patients with CR-Kp and CR-Ab septic shock.

SUBMITTER: Oliva A

PROVIDER: S-EPMC8001571 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acinetobacter baumannii is an important opportunistic pathogen of nosocomial infections. A. baumannii presently exhibits increasing antibiotic resistance, which poses great challenges to public health. The occurrence of tigecycline-resistant A. baumannii is related to tigecycline treatment and the within-host evolution of bacteria. We analyzed isogenic A. baumannii isolates from two critically ill patients who underwent tigecycline treatment. Whole-genome sequencing and comparative analyses were performed to determine the characteristics of genomic evolution. We conducted phenotypic studies, including in vitro antibiotic sensitivity tests, biofilm formation tests, growth curve determination, serum bactericidal determination, and Galleria mellonella lethality assays. In vivo emergent tigecycline resistance was observed after tigecycline treatment. After the withdrawal of tigecycline pressure, tigecycline-resistant isolates were not isolated from one patient. Four tigecycline-resistant isolates exhibited lower growth rates. The biofilm formation and virulence characteristics of tigecycline-resistant isolates were reasonably different between the two patients. A special phenotype appeared after tigecycline treatment in both patients, accompanied by reduced serum tolerance, enhanced biofilm formation ability, and reduced virulence of Galleria mellonella. Most of the genomic variation occurred after the tigecycline treatment, primarily involving transcription-, signal transduction-, translation-, ribosomal biogenesis-, and cell wall biogenesis-related genes. We determined that the genomic variations in baeR, wzc, aroQ, rluC, and adeS and acquisition of ISAba1 were associated with tigecycline resistance in vivo. Capsular polysaccharide-related genes, wzc, and itrA2, and aroQ, were the key genes related to the virulence evolution of A. baumannii within the host. IMPORTANCE Multidrug-resistant Acinetobacter baumannii poses a huge challenge to clinical treatment, and tigecycline is considered a last-line drug for the treatment of multidrug-resistant A. baumannii. However, the mechanism of tigecycline resistance in vivo has not been elucidated. This study analyzed the genomic and phenotypic evolution of tigecycline-resistant A. baumannii in two critically ill patients. In this study, after treatment with tigecycline, tigecycline-resistant A. baumannii emerged with higher fitness costs. After the withdrawal of tigecycline pressure, tigecycline-resistant isolates were not isolated from one patient. The in vivo and in vitro virulence of the isolates exhibited diametrically opposite results in the two patients. Genomic variations in baeR, wzc, aroQ, rluC, and adeS and acquisition of ISAba1 were associated with tigecycline resistance in vivo. The capsular polysaccharide-related genes, wzc, itrA2, and aroQ, were the key genes related to the virulence of A. baumannii in hosts. Our research provides a theoretical basis for elucidating the mechanism of tigecycline resistance and presents new clues for future surveillance and treatment of multidrug-resistant A. baumannii.

Project description:BackgroundWith an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging.MethodsPatients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry.ResultsTwenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates.ConclusionsColistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

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Effect of N-Acetylcysteine Administration on 30-Day Mortality in Critically Ill Patients with Septic Shock Caused by Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii: A Retrospective Case-Control Study.

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