Newer penicillins and beta-lactamase inhibitors.

Penicillins continue to be essential antibiotics for the treatment and prophylaxis of many infectious diseases. Recent advances have resulted in compounds with favorable new antimicrobial and pharmacologic properties. This article reviews the spectrum of activity, toxicity, pharmacokinetics, and clinical uses of the extended spectrum penicillins and the beta-lactamase inhibitor combination agents.

Newer penicillins and beta-lactamase inhibitors.

The penicillins continue to be important antibiotics for the treatment and prophylaxis of many infectious diseases. The emergence of resistant microorganism has led to the development of newer penicillin compounds that have extended spectrums of antimicrobial activity. Beta-lactamase production by many pathogenic bacteria is the most common and clinically relevant mechanism of antibiotic resistance. The addition of beta-lactamase inhibitors to penicillin antibiotics has proven to be successful in preventing the inactivation of the parent penicillin compound by the more commonly produced beta-lactamase enzymes.

Structure-activity relationships of the N-methylcarbamate series in Salmonella typhimurium.

Aromatic hydrocarbons of low molecular weight, hydroxy and N-methylcarbamate derivatives were tested for mutagenicity by the reversion of histidine-dependent Salmonella typhimurium TA98 and TA1535 in the presence of a rat-liver 9000 X g supernatant fraction. The presence of 2 or 3 aromatic rings resulted in a weak increase in revertants. Hydroxylation and carbamylation of aromatic rings increased the mutagenic activity of these aromatic compounds. In order to evaluate the structure-activity relationship, the specific molecular connectivity indices were calculated. A significant inverse relationship exists between mutagenicity and zero- and second-order specific molecular connectivity indices. Only compounds with second-order specific molecular connectivity indices lower than 0.300 increased mutagenic activity.

Inhibition of Adenosine Triphosphatase Activity from a Plasma Membrane Fraction of Acer pseudoplatanus Cells by Carbanilate Derivatives.

Thirty-one carbanilate derivatives were assayed for their capabilities to inhibit the ATPase activity of a plasma membrane fraction from Acer pseudoplatanus cells. At a concentration of 100 micromolar, nine compounds strongly inhibited the ATPase activity, with I(50) ranging from 14.5 micromolar to 35 micromolar. These molecules were also inhibitory to plasma membrane ATPases of other origins: plant (maize shoot), yeast (Schizosaccharomyces pombe), and animal (dog kidney). The most efficient molecule appeared to be 2,2,2-trichloroethyl 3,4-dichlorocarbanilate.

Synergistic bactericidal activity of rat serum with vancomycin against enterococci.

Animal models of infectious diseases may not predict clinical efficacy when species-related factors come into play. Recently, unexpected bactericidal activity of vancomycin alone against enterococci was observed in a rat model of endocarditis. A factor or factors in rat serum, but not rabbit or human serum, enhanced in vitro killing by vancomycin in four of five clinical isolates of enterococci. Bactericidal activity was maintained on dilution of rat serum to 5.0% and after exposure of serum to 56 degrees C for 30 min. Activity was lost by heating at 60 degrees C for 2 h, ultrafiltration, or absorption with bentonite or heat-killed bacteria. Rat serum appears to contain a factor or factors that contribute bactericidal activity to vancomycin, a drug normally bacteriostatic for these enterococci. The mechanism by which this factor enhances killing of enterococci by vancomycin is unknown.

Inhibition of Adenosine Triphosphatase Activity from a Plasma Membrane Fraction of Acer pseudoplatanus Cells by 2,2,2-Trichloroethyl 3,4-Dichlorocarbanilate.

2,2,2-Trichloroethyl 3,4-dichlorocarbanilate (SW26) is toxic for Acer pseudoplatanus cell cultures. It inhibited the cellular proton extrusion and depolarized the plasmalemma. In vitro, it inhibited the plasma membrane ATPase. SW 26 was also inhibitory to membrane ATPases of other origins-plant (maize shoot), fungus (Schizosaccharomyces pombe), and animal (dog kidney)-with about the same efficiency (7.5 micromolar < I(50) < 22 micromolar). It did not inhibit the oligomycin-sensitive ATPase from purified plant mitochondria, nor molybdate-sensitive soluble phosphatases. SW26 was more specific for plasma membrane ATPases than diethylstilbestrol or vanadate. A Lineweaver-Burk plot analysis showed that inhibition kinetics were purely noncompetitive (K(i) = 14.7 micromolar) below 20 micromolar. Above this concentration, the inhibition pattern was not consistent with Michaelis-Menten kinetics, and a Hill plot representation revealed a positive cooperativity.

High-level penicillin resistance among isolates of enterococci. Implications for treatment of enterococcal infections.

STUDY OBJECTIVE: To determine the extent and clinical significance of high-level penicillin-resistant Enterococcus faecium at our institution. DESIGN: Surveillance of clinical enterococcal isolates, in-vitro susceptibility and timed survival studies, and determination of antibiotic efficacy in an experimental model of enterococcal endocarditis. MEASUREMENTS AND MAIN RESULTS: For a 6-month period, 14% of enterococcal isolates (30 of 212) were identified as E. faecium. One third of the isolates were highly resistant to penicillin G (minimum inhibitory concentration [MIC], greater than or equal to 200 micrograms/mL) but did not produce beta-lactamase. The findings from in-vitro survival studies showed that this high-level resistance resulted in the loss of bactericidal activity normally observed when an aminoglycoside antibiotic agent is combined with penicillin. An experimental rat model of endocarditis provided in-vivo data that confirmed our in-vitro observations. After the rats received therapy for 72 hours, penicillin G either alone or in combination with gentamicin did not significantly decrease the numbers of enterococci in vegetations on heart valves compared with untreated controls (P = 0.62 and P = 0.58, respectively). CONCLUSIONS: Enterococcus faecium accounts for a notable proportion of clinical enterococcal isolates. Many strains from patients at our institution, as well as from patients at other institutions throughout the country, are highly resistant to penicillin. Because high-level penicillin resistance has important therapeutic implications, periodic surveillance and MIC testing of significant enterococcal isolates, especially E. faecium, are suggested.