Imipenem-induced resistance to antipseudomonal beta-lactams in Pseudomonas aeruginosa

132

It is generally assumed that the antibiotic prescription policy of a hospital has a significant impact on bacterial resistance rates; however, few studies are available to support this concept with valid statistical data. During a 3-year period from 1997 to 2000, we monitored the consumption of ␤-lactam and other antibiotics with known activity against Pseudomonas aeruginosa in a 600-bed community hospital. Monthly isolations of P. aeruginosa were assessed, and resistance rates were recorded. Partial correlation coefficients between consumption and resistance rates were determined, taking into account possible associations with other variables such as seasonal effects and transfers from other hospitals. A total of 30 ؎ 7 novel P. aeruginosa strains per month were isolated without epidemic clustering. Prescriptions of imipenem varied significantly during the study period, while prescriptions of other antipseudomonal agents were stable, with the exception of an increase in piperacillin-tazobactam prescriptions. Rates of resistance of P. aeruginosa to the antimicrobial agents used showed a time course similar to figures for imipenem consumption. Monthly rates of resistance to imipenem (partial correlation coefficient [cc], 0.63), piperacillin-tazobactam (cc, 0.57), and ceftazidime (cc, 0.56) were significantly associated with imipenem prescription rates in the same or the preceding month, while consumption of ceftazidime or piperacillin-tazobactam had no apparent association with resistance. Among the variables investigated, imipenem consumption was identified as the major factor associated with both carbapenem and ␤-lactam resistance in endemic P. aeruginosa. Periods of extensive imipenem use were associated with significant increases in resistance. Our data support the concept that a written antibiotic policy which balances the use of various antibiotic classes may help to avoid disturbances of a hospital's microbial sensitivity patterns.Pseudomonas aeruginosa is a major pathogen in nosocomial infections, ranking second only to Staphylococcus aureus in a recent multicenter study of infections in European intensive care units (22). The organism may be involved in respiratory, urinary, wound, and bloodstream infections, primarily in patients with severe underlying diseases or impaired immune defense (3). Since the lethality of P. aeruginosa infections is high once the organism has caused disseminated disease, early and adequate antibiotic therapy is essential. Resistance of P. aeruginosa to antimicrobials used for primary treatment has been shown to correlate with an adverse clinical outcome (1, 9).While the incidence and risk factors for the development of antibiotic resistance in P. aeruginosa have been studied repeatedly in cohort studies or comparative studies evaluating the effects of novel antibiotics (2, 4, 11, 13), little is known about the influence of a hospital's antibiotic policy on resistance epidemiology in the hospital as a whole. In a 600-bed community hospital, we had the opportunity to observe sig...

Section: Discussionmentioning

confidence: 99%

Consumption of Imipenem Correlates with β-Lactam Resistance in Pseudomonas aeruginosa

Lepper

Grusa²,

Reichl

et al. 2002

132

“…Usually this enzyme is expressed at very low levels, but ␤-lactam inducers can raise these levels (23,40). In the course of therapy, ␤-lactam antibiotics can select P. aeruginosa mutants that overproduce AmpC in the absence of inducers.…”

mentioning

confidence: 99%

Inactivation of the ampD Gene in Pseudomonas aeruginosa Leads to Moderate-Basal-Level and Hyperinducible AmpC β-Lactamase Expression

Langaee

Gagnon

Huletsky

2000

It has been shown in enterobacteria that mutations in ampD provoke hyperproduction of chromosomal ␤-lactamase, which confers to these organisms high levels of resistance to ␤-lactam antibiotics. In this study, we investigated whether this genetic locus was implicated in the altered AmpC ␤-lactamase expression of selected clinical isolates and laboratory mutants of Pseudomonas aeruginosa. The sequences of the ampD genes and promoter regions from these strains were determined and compared to that of wild-type ampD from P. aeruginosa PAO1. Although we identified numerous nucleotide substitutions, they resulted in few amino acid changes. The phenotypes produced by these mutations were ascertained by complementation analysis. The data revealed that the ampD genes of the P. aeruginosa mutants transcomplemented Escherichia coli ampD mutants to the same levels of ␤-lactam resistance and ␤-lactamase expression as wild-type ampD. Furthermore, complementation of the P. aeruginosa mutants with wild-type ampD did not restore the inducibility of ␤-lactamase to wild-type levels. This shows that the amino acid substitutions identified in AmpD do not cause the altered phenotype of AmpC ␤-lactamase expression in the P. aeruginosa mutants. The effects of AmpD inactivation in P. aeruginosa PAO1 were further investigated by gene replacement. This resulted in moderatebasal-level and hyperinducible expression of ␤-lactamase accompanied by high levels of ␤-lactam resistance. This differs from the stably derepressed phenotype reported in AmpD-defective enterobacteria and suggests that further change at another unknown genetic locus may be causing total derepressed AmpC production. This genetic locus could also be altered in the P. aeruginosa mutants studied in this work.

“…Induction of P-lactamase by ,B-lactamase-resistant agents has been shown to occur frequently in P. aeruginosa; this induction has been associated with the development of in vitro resistance to many 3-lactam agents (23). CA has been described as a 3-lactamase inducer in Enterobacter cloacae (14).…”

mentioning

confidence: 99%

“…bacterial growth was evaluated at 8 h), then the cells were harvested by centrifugation, and crude ,B-lactamase extracts were prepared as described previously (23). The P-lactamase activity was measured at 255 nm with 100 ,uM cephaloridine as the substrate at 37°C by using a Beckman DU 8 spectrophotometer (Beckman Instruments, Inc., Fullerton, Calif.).…”

mentioning

confidence: 99%

Effect of clavulanic acid on the activity of ticarcillin against Pseudomonas aeruginosa

Tausk¹,

Stratton²

1986

Self Cite

We studied the ability of clavulanic acid (CA) to induce beta-lactamase in Pseudomonas aeruginosa isolates and what effect this might have on the susceptibilities to beta-lactam agents. We first used a disk approximation method to test 4 laboratory and 16 clinical P. aeruginosa isolates against antipseudomonal beta-lactam agents for truncation by CA and found this to be very common. All antimicrobial compounds except imipenem demonstrated truncation in the vicinity of CA. We also evaluated the extent to which chromosomal beta-lactamase is induced by CA and found this to occur to some degree in most isolates and to be dependent on the concentration of CA. Finally, we performed time kill curves on these isolates to compare bacterial growth in ticarcillin alone with growth in ticarcillin-CA (the CA at 2 or 4 micrograms/ml). We found that CA at this concentration has neither an antagonistic nor a synergistic antibacterial effect in combination with ticarcillin.