In-vitro activity of RP 59500, a semisynthetic streptogramin, against staphylococci and streptococci

The in-vitro activity of RP 59500, an injectable streptogramin derived from pristinamycin, was determined by agar dilution and compared with that of pristinamycin. Two hundred and sixty-one recent clinical isolates of Gram-positive cocci were tested against both antibiotics. The two compounds displayed similar activities. The MIC90S of RP 59500 ranged from 0·5 to 2 mg/L in 114 strains of Staphylococcus aureus showing various phenotypes of antibiotic resistance (penicillin-susceptible; penicillin-resistant and methicillin-susceptible; methicillin-resistant; erythromycin-resistant, either inducible or constitutive; quinolone-resistant). Similar results were obtained with coagulase-negative staphylococci. RP 59500 was consistently active against streptococci, with MIC90s of 0·25, 0·25 and 0·50 mg/L for Streptococcus pyogenes (n = 20), Streptococcus agalactiae (n = 20) and Streptococcus pneumoniae (n = 20), respectively. Enterococcus faecalis (n = 20) appeared to be notably less susceptible (MIC90, 8 mg/L). In view of this consistent activity against all staphylococci and streptococci tested, including multiply resistant isolates, RP 59500 merits further investigatio

How predictable is development of resistance after β-lactam therapy in Enterobacter cloacae infection?

Certain non-fastidious Gram-negative bacilli, notably Enterobacter cloacae, although classified as susceptible by usual in-vitro susceptibility testing, often become resistant in patients treated with newer β-lactam antibiotics. Here various in-vitro tests were carried out together with an animal model allowing the quantification of resistance that emerges after short term therapy. Mice were challenged (102 cfu plus talcum) intraperitoneally with one each of four strains of Ent. cloacae. Two hours later, a single β-lactam dose was administered subcutaneously. The following day, the peritoneal bacterial population was analysed by using antibiotic-containing gradient plates. Development of resistance after therapy varied according to the compound considered. Imipenem (50 mg/kg) produced no resistance, and piperacillin (200 mg/kg) only a few, while resistance occurred frequently after therapy with aztreonam (50 mg/kg), ceftazidime (50 mg/kg), cefotaxime (50 mg/kg) and cefpirome (50 mg/kg). MICs increased by at least 16-fold when resistance developed. No simple correlations were found between these in-vivo results and initial MICs, killing kinetics, frequency of resistant variants within the bacterial populations before therapy, initial MIC of these variants or antibiotic concentrations assayed in peritoneal fluid 60 min after dosing. The most reliable predictive in-vitro test appeared to be the determination of resistance emerging in broth containing at least 16 times the MIC of the antibiotic tested. Such a test is unlikely to be used on a routine basis. When a β-lactam compound seems appropriate for treating an Enterobacter infection, it may be advisable to avoid drugs that are prone prone to produce resistance in experimental or clinical infections, whatever the results of conventional in-vitro susceptibility test

Usual and unusual antibacterial effects of quinolones

Recently documented antibacterial effects of quinolones are reviewed. DNA gyrase is most likely to be the primary target site for these agents. Quinolones rapidly kill susceptible bacteria; the mechanisms of the bactericidal activity, still poorly understood, probably involve new protein synthesis. Quinolones alter membrane integrity before cell death, leading to leakage of cytoplasmic constituents. In Gram-negative bacteria, quinolones act as chelating agents for outer membrane divalent cations, disorganizing the bacterial lipopolysaccharide layer and facilitating the further entry of quinolone molecules in a ‘self-promoted' pathway. Quinolones inhibit plasmid replication and reduce the efficacy of plasmid conjugation. Subinhibitory concentrations of quinolones can interfere with bacterial virulence factors, such as bacterial adherence to the host cell, phagocytosis and production of enzymes implicated in virulence. Recent studies also indicate synergism of quinolones with oxacillin against methicillin-resistant staphylococci and describe improved activity of newer compounds against Gram-positive pathogen

In-vitro activity of newer quinolones against aerobic bacteria

Nalidixic and five newer 4-quinolones, ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin were tested against 576 recent clinical aerobic bacterial isolates. The 4-quinolones were regularly active (MIC90 < 4 mg/1) against the following bacteria: Staphylococcus aureus, S. epidermidis, S. saprophyticus, different Enterobacteriaceae, Haemophilus influenzae, Campylobacter jejuni, Pseudomonas aeruginosa, Agrobacter spp., Aeromonas spp., Plesiomonas spp., Neisseria meningitidis. Other bacteria were usually intermediately susceptible or resistant: different streptococci, Listeria monocytogenes, Nocardia asteroides, P. maltophilia, Achromobacter xylosoxydans and Alcaligenes denitrificans. Ciprofloxacin was the most potent compound, followed by ofloxacin and pefloxacin, norfloxacin and enoxacin being less active. All the 4-quinolones were much more active than nalidixic acid. The MBC/MIC ratios of the 4-quinolones were between 1 and 2 with a majority of strains, and between 2 and 3 with Streptococcus agalactiae, Str. faecalis and L. monocytogenes. A two- to eight-fold increase of MIC was observed by increasing the inoculum 10,000-fold with most of the strains tested. Susceptible bacterial population of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and P. aeruginosa contained more clones resistant to nalidixic acid (104 to 108 at four times the MIC) than to 4-quinolones (105 to 109 at four times the MIC). Supplementing the media with MgSO4 produced smaller inhibition zone diameters with a disc diffusion method than those obtained with non-supplemented agar, with all quinolone or strains. Less regular effect, or no effect was obtained after supplementation with ZnSO4 or Ca(NO3)

Emergence of resistance after therapy with antibiotics used alone or combined in a marine model

A murine model of peritonitis allowing detection and quantification of in-vivo acquired resistance during short term therapy has been used in order to evaluate the capacity of antimicrobial combinations to limit emergence of resistance, as compared to individual components of the regimens. Mice were challenged intraperitoneally with 108 cfu of bacteria. Two hours later, a single antibiotic dose was injected subcutaneously: amikacin (15 mg/kg), ceftriaxone (50 mg/kg), pefloxacin (25 mg/kg), amikacin + ceftriaxone, amikacin + pefloxacin or ceftriaxone + pefloxacin. Escherichia coli and Staphylococcus aureus never became resistant. Single drug therapy yielded resistant mutants in Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae and Pseudomonas aeruginosa as follows: 74% of ceftriaxone-treated animals, 57% of pefloxacin treated animals and 27% of amikacin treated animals. All the tested combinations reduced the frequency of in-vivo acquired resistance produced by single drugs, and no combination selected resistance when the separate agents of the combination did not. Combining antimicrobial agents limits the risk of emergence of resistance during antibiotic therap

Comparative in-vitro activity of new quinolones against clinical isolates and resistant mutants

The in-vitro activity of five new fluoroquinolones, WIN 57273, sparfloxacin, flerox-acin, temafloxacin and tiprofloxacin was determined against 543 recent clinical isolates and eight quinolone resistant strains derived by mutation and their five parent strains. WIN 57273 was the most active compound against Gram-positive bacteria, sparfloxacin had a broad spectrum which was similar to that of cipro-floxacin. Ciprofloxacin showed the greatest activity against Gram-negative bacteria. Temafloxacin showing some activity against Gram-positive organisms and Acinetobacter spp. Fleroxacin was the least active compound studied. Compared to wild type parent strains, the mutated strains produced the following results. In Enterobacter cloacae OmpF deficiency increased the MICs of all quinolones by 8-32-fold. In Pseudomonas aeruginosa OmpF deficiency had a limited effect, Omp D2 deficiency combined with an increased lipopolysaccharide content produced greater resistance, i.e. 4-16-fold; mutations in gyrase were associated with variously increased MICs, depending on the strain and compound teste