Dataset Information

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients.

ABSTRACT: Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAO?mutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (?7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

SUBMITTER: Rees VE

PROVIDER: S-EPMC6201118 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients.

Rees Vanessa E VE Yadav Rajbharan R Rogers Kate E KE Bulitta Jürgen B JB Wirth Veronika V Oliver Antonio A Boyce John D JD Peleg Anton Y AY Nation Roger L RL Landersdorfer Cornelia B CB

Antimicrobial agents and chemotherapy 20181024 11

Hypermutable <i>Pseudomonas aeruginosa</i> organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable <i>P. aeruginosa</i> Static concentration time-kill experiments over 72 h assessed ...[more]

PMID: 30104278

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Project description:RationalePseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity.ObjectivesTo characterize the population genetic structure of transmissible P. aeruginosa Liverpool Epidemic Strain in chronic infections of nine patients with cystic fibrosis, and infer evolutionary processes associated with adaptation to the cystic fibrosis lung.MethodsWe performed whole-genome sequencing of P. aeruginosa isolates and pooled populations and used comparative analyses of genome sequences including phylogenetic reconstructions and resolution of population structure from genome-wide allele frequencies.Measurements and main resultsGenome sequences were obtained for 360 isolates from nine patients. Phylogenetic reconstruction of the ancestry of 40 individually sequenced isolates from one patient sputum sample revealed the coexistence of two genetically diverged, recombining lineages exchanging potentially adaptive mutations. Analysis of population samples for eight additional patients indicated coexisting lineages in six cases. Reconstruction of the ancestry of individually sequenced isolates from all patients indicated smaller genetic distances between than within patients in most cases.ConclusionsOur population-level analysis demonstrates that coexistence of distinct lineages of P. aeruginosa Liverpool Epidemic Strain within individuals is common. In several cases, coexisting lineages may have been present in the infecting inoculum or assembled through multiple transmissions. Divergent lineages can share mutations via homologous recombination, potentially aiding adaptation to the airway during chronic infection. The genetic diversity of this transmissible strain within infections, revealed by high-resolution genomics, has implications for patient segregation and therapeutic strategies.

Project description:Epidemic strains of Pseudomonas aeruginosa are highly virulent opportunistic pathogens with increased transmissibility and enhanced antimicrobial resistance. Understanding the cellular mechanisms behind this heightened virulence and resistance is critical. Peptidoglycan (PG) is an integral component of P. aeruginosa cells that is essential to its survival and a target for antimicrobials. Here, we examined the global PG composition of two P. aeruginosa epidemic strains, LESB58 and LESlike1, and compared them to the common laboratory strains PAO1 and PA14. We also examined changes in PG composition when the strains were cultured under nutrient conditions that resembled cystic fibrosis lung infections. We identified 448 unique muropeptides and provide the first evidence for stem peptides modified with O-methylation, meso-diaminopimelic acid (mDAP) deamination, and novel substitutions of mDAP residues within P. aeruginosa PG. Our results also present the first evidence for both d,l- and l,d-endopeptidase activity on the PG sacculus of a Gram-negative organism. The PG composition of the epidemic strains varied significantly when grown under conditions resembling cystic fibrosis (CF) lung infections, showing increases in O-methylated stem peptides and decreases in l,d-endopeptidase activity as well as an increased abundance of de-N-acetylated sugars and l,d-transpeptidase activity, which are related to bacterial virulence and antibiotic resistance, respectively. We also identified strain-specific changes where LESlike1 increased the addition of unique amino acids to the terminus of the stem peptide and LESB58 increased amidase activity. Overall, this study demonstrates that P. aeruginosa PG composition is primarily influenced by nutrient conditions that mimic the CF lung; however, inherent strain-to-strain differences also exist. IMPORTANCE Using peptidoglycomics to examine the global composition of the peptidoglycan (PG) allows insights into the enzymatic activity that functions on this important biopolymer. Changes within the PG structure have implications for numerous physiological processes, including virulence and antimicrobial resistance. The identification of highly unique PG modifications illustrates the complexity of this biopolymer in Pseudomonas aeruginosa. Analyzing the PG composition of clinical P. aeruginosa epidemic strains provides insights into the increased virulence and antimicrobial resistance of these difficult-to-eradicate infections.

Dataset Information

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients.

Publications

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients.

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