Pseudomonas pseudomallei resistance to beta-lactam antibiotics due to alterations in the chromosomally encoded beta-lactamase

Abstract

Pseudomonas pseudomallei, the causative agent of melioidosis, is generally susceptible to some of the newer extended-spectrum cephalosporins or to combinations of a ,-lactam and clavulanic acid, a ,-lactamase inhibitor. Resistance to these agents may, however, emerge during treatment. We report on alterations in the chromosomal D-lactamase associated with the development of resistance. Three resistance patterns resulted from three different mechanisms in the strains investigated. Derepression of the chromosomal enzyme resulted in a general increase in the MICs of all of the f8-lactams tested. The second mechanism observed was an insensitivity to inhibition of the D-lactamase by clavulanic acid. In this case, the level of susceptibility to ,I-lactams as independent entities remained unchanged. The final "resistance" pattern occurred in a patient treated with ceftazidime and resulted in a I8-lactamase that was capable of hydrolyzing this antibiotic at detectable levels, but with reduced efficacy against other I-lactams. The net result was a strain that was generally susceptible to all of the I8-lactams tested except ceftazidime. In all cases, the level of susceptibility to antibiotics other than P-lactams remained unchanged. Such variability found within one genus over a relatively short time course suggests that treatment of infections caused by this organism should be carefully monitored to detect susceptibility alterations to the chosen therapy.

Melioidosis: Epidemiology, Pathophysiology, and Management

“…Functionally, the most important of these is the BushJacoby-Medeiros class 2e beta-lactamase BPS-1, encoded by the gene blaA (or penA; Ambler class A), which hydrolyzes most cephalosporins but is readily inhibited by clavulanate (91,274). Acquired resistance to beta-lactam antibiotics while on treatment with a beta-lactam-beta-lactamase inhibitor combination or ceftazidime resulted from three distinct phenotypic changes: derepression of the chromosomal enzyme, an insensitivity to inhibition by beta-lactamase inhibitors, and a betalactamase specific for ceftazidime (169). These were associated with mutations in the blaA gene (439).…”

Burkholderia pseudomallei Class A β-Lactamase Mutations That Confer Selective Resistance against Ceftazidime or Clavulanic Acid Inhibition

“…The bacterial strains and plasmid used in this study are shown in Table 1. B. pseudomallei strains used in this study were collected from blood and urine samples from melioidosis patients both before and during antibiotic treatment at Sappasitprasong Hospital, Ubon Ratchatani, Thailand, between 1986 and 1989 and have been described previously (7,10). All bacterial strains were grown at 37°C on Luria-Bertani (LB) agar or in LB broth.…”

“…Livermore, et al described a clavulanic acid-inhibitable ␤-lactam resistance phenotype of B. pseudomallei (13), and recently, the cloning of B. pseudomallei class A and D ␤-lactamases has been reported (4,14). Godfrey et al described three different phenotypes of clinical isolates from three patients which had undergone antibiotic treatment, and demonstrated that the resistance was due to derepressed ␤-lactamase production and structural mutations in the enzyme (10). Here, we examine the B. pseudomallei penA gene encoding a class A ␤-lactamase in the clinical isolates of B. pseudomallei described by Godfrey et al and from B. mallei ATCC 23344.…”

Calprotectin as a Biomarker for Melioidosis Disease Progression and Management

“…Treatment requires long and costly administration of antibiotics, and few antimicrobials are effective due to the intrinsic resistance of B. pseudomallei (2,23). The potential spread of acquired resistance (24,25) and the lack of any new promising drugs in development are ominous circumstances in regard to the future of melioidosis disease management. As generally only clinical symptoms are used for disease management, there is an unmet need for biomarkers that can help to monitor disease progression and guide antibiotic treatment.…”