In vitro activity of lomefloxacin against multiply resistant Pseudomonas aeruginosa, Enterobacter cloacae, and Staphylococcus epidermidis.

Lomefloxacin is a promising new difluorinated quinolone with good antimicrobial activity and favorable pharmacokinetic properties. The in vitro activity of lomefloxacin was compared to other quinolones, expanded spectrum beta-lactams, and gentamicin. The lomefloxacin MIC90 against multiply resistant strains of P. aeruginosa was 4 mcg/ml, comparable to norfloxacin and ofloxacin. Lomefloxacin was also active against methicillin-resistant S. epidermidis and JK corynebacteria. The role of lomefloxacin in the treatment of infections caused by multiresistant organisms remains to be determined in clinical trials.

Resistance to imipenem in Pseudomonas aeruginosa: clinical experience and biochemical mechanisms.

Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections is common and may result in treatment failure. Resistance emerges most often during therapy for lower respiratory tract infections. There are several unique features of this resistance to imipenem. First, cross-resistance to other beta-lactam agents is not observed. Second, the mechanism of resistance in most of the isolates studied to date appears to be related to a selective permeability barrier across the bacterial outer membrane, usually associated with discrete alterations in the electrophoretic profiles of outer membrane proteins. These data suggest that imipenem may traverse the outer membrane of P. aeruginosa via a specific porin protein that is not critical for penetration of other beta-lactam antibiotics.

Serious infections due to penicillin-resistant strains of viridans streptococci with altered penicillin-binding proteins.

We investigated the mechanism of resistance to penicillin in two penicillin-resistant clinical isolates of viridans streptococci that caused life-threatening infections in two patients not receiving chronic penicillin therapy. The first was a strain of Streptococcus intermedius that was isolated from the cerebrospinal fluid of a patient with post-neurosurgical meningitis. The second was a strain of Streptococcus mitis recovered from the bloodstream of a leukemic patient with neutropenia. Both patients failed to respond to penicillin. The mechanism of resistance in these strains was associated with diminished affinity for penicillin of their penicillin-binding proteins, as compared with those of penicillin-susceptible control strains. We conclude that penicillin-resistant viridans streptococci may cause serious infections even in patients not receiving chronic penicillin therapy, that this resistance is clinically significant and may result in failure of penicillin therapy, and that the mechanism of resistance in these strains is associated with diminished affinity of the penicillin-binding proteins for penicillin.

Activity of newer beta-lactam agents against clinical isolates of Bacteroides fragilis and other Bacteroides species.

The in vitro activities of beta-lactam antibiotics against Bacteroides fragilis and B. fragilis group isolates are presented. Clinical isolates from 1986 were compared with strains from 1979 to 1982. Imipenem, ticarcillin-clavulanic acid, and ceftizoxime were the most active agents. Cefotetan was equivalent to cefoxitin against B. fragilis but less active against B. fragilis group isolates. Enhancement of cefotaxime by its desacetyl metabolite was minimal.

Emergence of resistance to ceftazidime during therapy for Enterobacter cloacae infections.

The mechanism of resistance to ceftazidime in two clinical isolates of Enterobacter cloacae that emerged during therapy with broad-spectrum beta-lactam antibiotics was studied. Both isolates acquired broad resistance to advanced-spectrum beta-lactam drugs other than imipenem. Biotyping confirmed strain identity in both cases, and no new plasmids were detected in the resistant isolates. Both resistant isolates produced beta-lactamase constitutively. Slow but definite hydrolysis of ceftazidime was demonstrated by using purified beta-lactamase in a spectrophotometric assay. Further evidence that beta-lactamase is responsible for resistance in these organisms was provided by the demonstration that cefoxitin, a potent inducer of beta-lactamase, antagonized the activity of ceftazidime against these isolates. This antagonism could be prevented by inhibition of derepression of beta-lactamase with clindamycin. Clindamycin also prevented regrowth of ceftazidime-treated cells in time-kill studies and markedly reduced production of beta-lactamase in induced cultures at concentrations as low as 2 micrograms/ml.

Activity of ciprofloxacin against multiply resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, and group JK corynebacteria.

The susceptibilities of multiply resistant clinical isolates of Pseudomonas aeurginosa to ciprofloxacin, norfloxacin, and several beta-lactam and aminoglycoside antibiotics were evaluated. Ciprofloxacin also was compared with methicillin and vancomycin against methicillin-resistant Staphylococcus epidermidis and group JK corynebacteria. Ciprofloxacin exhibited the lowest MICs and MBCs for 90% of the isolates among all of the antibiotics tested against P. aeruginosa. In addition, ciprofloxacin exhibited excellent bactericidal activity against the gram-positive organisms. Clinical trials are necessary to confirm the in vitro results and monitor for emergence of resistance.

Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections.

We studied the mechanism of resistance to imipenem in three clinical isolates of Pseudomonas aeruginosa. Two of these isolates arose from imipenem-susceptible strains isolated during therapy with imipenem and were associated with treatment failure. One of these two strains had previously been broadly resistant to beta-lactams; the second acquired resistance to imipenem alone. One isolate of the third strain was resistant to imipenem but susceptible to other antipseudomonal beta-lactams. No isolate contained beta-lactamase activity capable of hydrolyzing imipenem at a detectable rate. Studies of the penicillin-binding proteins of all isolates revealed no differences in the number of proteins, molecular weight of, affinity for penicillin, or affinity for imipenem in any isolate. In each case the resistant isolate lacked one or more outer membrane proteins that were present in a susceptible isolate of the same strain. The observed alterations in outer membrane proteins may be associated with diminished permeability of the bacterial outer membrane to imipenem and may be the major factor responsible for resistance in these isolates.

Effects of aminoglycoside antibiotics on polymorphonuclear leukocyte function in vivo.

In vitro incubation of aminoglycoside antibiotics with human polymorphonuclear leukocytes (PMNs) has been shown to induce abnormalities in cell function. This study was designed to determine whether there are similar abnormalities in leukocyte function after exposure to the action of these agents in vivo. Four aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) were tested. In vitro incubation did not induce a chemotactic defect when measured by an under-agarose method. However, inhibition of candidacidal activity was reproducible after in vitro incubation of all aminoglycosides tested. Nevertheless, when the aminoglycosides were administered intravenously to normal volunteers, PMN function, including adherence to nylon wool columns, chemotaxis, phagocytosis, and killing of Candida albicans, was unimpaired at 1, 3, and 24 h postinfusion. Therefore, we conclude that aminoglycoside antibiotic administration does not induce PMN dysfunction in vivo.