Modeling Meropenem Treatment, Alone and in Combination with Daptomycin, for KPC-Producing Klebsiella pneumoniae Strains with Unusually Low Carbapenem MICs.

Klebsiella pneumoniae strains producing K. pneumoniae carbapenemase (KPC) cause serious infections in debilitated and immunocompromised patients and are associated with prolonged hospital stays and increased mortality rates. Daptomycin is a lipopeptide used against Staphylococcus aureus infection and considered inactive against Gram-negative bacteria. We investigated the effectiveness of a daptomycin-meropenem combination by synergy kill curve and a pharmacokinetic/pharmacodynamic model. The combination may represent a novel therapeutic strategy against infections caused by KPC-producing K. pneumoniae strains.

Inducible macrolide resistance in Corynebacterium jeikeium.

Corynebacterium jeikeium is an opportunistic pathogen primarily of immunocompromised (neutropenic) patients. Broad-spectrum resistance to antimicrobial agents is a common feature of C. jeikeium clinical isolates. We studied the profiles of susceptibility of 20 clinical strains of C. jeikeium to a range of antimicrobial agents. The strains were separated into two groups depending on the susceptibility to erythromycin (ERY), with one group (17 strains) representing resistant organisms (MIC > 128 microg/ml) and the second group (3 strains) representing susceptible organisms (MIC < or = 0.25 microg/ml). The ERY resistance crossed to other members of the macrolide-lincosamide-streptogramin B (MLSb) group. Furthermore, this resistance was inducible with MLSb agents but not non-MLSb agents. Expression of ERY resistance was linked to the presence of an allele of the class X erm genes, erm(X)cj, with >93% identity to other erm genes of this class. Our evidence indicates that erm(X)cj is integrated within the chromosome, which contrasts with previous reports for the plasmid-associated erm(X) genes found in C. diphtheriae and C. xerosis. In 40% of C. jeikeium strains, erm(X)cj is present within the transposon, Tn5432. However, in the remaining strains, the components of Tn5432 (i.e., the erm and transposase genes) have separated within the chromosome. The rearrangement of Tn5432 leads to the possibility that the other drug resistance genes have become included in a new composite transposon bound by the IS1249 elements.

Conversion of oxacillin-resistant staphylococci from heterotypic to homotypic resistance expression.

Staphylococci that acquire the mecA gene are usually resistant to beta-lactam antibiotics (methicillin or oxacillin resistance). mecA encodes a penicillin-binding protein (PBP 2a) that has a reduced affinity for beta-lactams. In some isolates with methicillin or oxacillin resistance, only a small proportion (< or =0.1%) of the population expresses resistance to > or =10 microg of oxacillin per ml (heterotypic resistance [HeR]), while in other isolates most of the population expresses resistance (homotypic resistance [HoR]). In the present study, growth of Staphylococcus aureus or Staphylococcus epidermidis strains with HeR in concentrations of oxacillin (0.3 to 0.7 microg/ml) that produced a fall or a lag in optical density converted the strains from the HeR to the HoR phenotype. The conversion from the HeR to the HoR phenotype appeared to be due to the selection of a highly resistant mutant population, as determined by fluctuation analysis and the failure of populations with HoR to revert to HeR after 60 generations of growth in antibiotic-free media. The frequencies of conversion were as high as 10(-3) to 10(-2). Conversion to HoR required an intact mecA gene and an increase in the level of mecA transcription since no highly resistant subpopulation could be selected after growth in oxacillin when mecA transcription was constitutively repressed or when mecA had been inactivated. In addition, in both S. epidermidis and S. aureus the level of resistance to vancomycin, which also acts directly on the staphylococcal cell wall, was greater among convertants with HoR than their isogenic parents. The conversion of a population from HeR to HoR involves the selection of a mutation(s) that occurs at a high frequency and most likely requires abundant PBP 2a.