Emergence of resistance to beta-lactam and aminoglycoside antibiotics during moxalactam therapy of Pseudomonas aeruginosa infections

Abstract

In four patients with Pseudomonas aeruginosa infections, the infecting strain developed resistance to moxalactam during therapy with this drug. In addition, P. aeruginosa isolates from two of these four patients showed increased resistance to aminoglycosides. Isolates from a third patient acquired cross-resistance to other antipseudomonal ,3-lactams. with a final volume of 3 ml and a final inoculum of 105 colony-forming units (CFU) per ml. The minimal inhibitory concentration (MIC) was defined as the lowest antibiotic concentration preventing macroscopically detectable growth after 18 h of incubation at 35°C in air. Subcultures (0.01 ml) were made of all clear tubes to drug-free agar, and the minimal bactericidal concentration (MBC) was defined as the lowest concentration preventing growth upon subculture. This represented a 99.9o kill of the original inoculum (12). MICs or MBCs for posttherapy isolates were considered increased above results obtained with pretherapy isolates if they differed at least fourfold. Tests on pre-and posttherapy isolates were performed simultaneously. Results of susceptibility tests were interpreted according to criteria pubished by the National Committee for Clinical Laboratory Standards (10). For moxalactam, an organism was considered (i) resistant if the MIC was 264 ,ug/ml and (ii) susceptible if the MIC was c32 pLg/ml. ,B-Lactamase assays were performed by a spectrophotometric test as described previously (16). Enzymes were induced by growing the strains overnight on cefoxitin agar (16). Strains resistant to aminoglycosides were tested for inactivating enzymes by R. Hare (Schering Corp., Bloomfield, N.J.).Agarose gel electrophoress. To compare the plasmid profiles of the isolates, cultures were lysed by the method of Meyers et al.

In vitro comparison of Pseudomonas aeruginosa isolates with various susceptibilities to aminoglycosides and ten beta-lactam antibiotics

“…There were no statistically significant increases in the ,-lactam MICs with increasing aminoglycoside resistance. These observations are in contrast to those in a report by Preheim et al (12), in which it is suggested that induced resistance to 0-lactams may be associated with increasing resistance to aminoglycosides. The isolates in our study, however, may have been uninduced.…”

Comparison of moxalactam and gentamicin in the treatment of complicated urinary tract infections

“…Perhaps of even greater concern was the concurrent decrease in susceptibility to aminoglycosides in two of these isolates. In addition, emergence of resistance to numerous antipseudomonal beta-lactam antibiotics has been seen during moxalactam therapy of P. aeruginosa infection (10). These findings suggest that inoxalactam should not be used as a single agent in the therapy of severe P. aeruginosa infections.…”

“…Moxalactam has a broad antibacterial spectrum (9). It is highly resistant to beta-lactamases (10). Except for nonfermentative organisms, its activity against aerobic gram-negative bacilli is equal to or exceeds that of currently available aminoglycosides and other beta-lactams (1,6).…”

Outer membrane alterations in multiresistant mutants of Pseudomonas aeruginosa selected by ciprofloxacin

“…The WT strain P850 and its mutant LK-12 possessed 3-lactamase and 2'-O"-nucleotidyltransferase, whereas neither P-lactamases nor aminoglycoside-modifying enzymes were detected in any other WT or mutant strain studied. The observations described above, taken together with the multiple nature of antibiotic resistance, suggest the involvement of an impaired cellular permeability (12,19,23,24). This has been investigated by rpeasuring the uptake of ciprofloxacin (Fig.…”