Therapy for methicillin-resistant Staphylococcus aureus.
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Anti-Bacterial Agents↗
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The treatment triangle for staphylococcal infections.
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Anti-Bacterial Agents↗
In-vitro activity of LY 146032, a novel cyclic lipopeptide, alone and in combination with gentamicin or tobramycin against enterococci.
The in-vitro activity of LY 146032, a novel cyclic lipopeptide and the effect of the combination of LY 146032 and gentamicin or tobramycin against 25 strains of enterococci isolated from blood cultures were studied. All strains of enterococci were inhibited by less than or equal to 2 mg/l LY 146032. The minimal inhibitory concentrations and minimal bactericidal concentrations were within one dilution. In the time-kill study, there was slow bactericidal activity. Complete killing of 10(7) cfu/ml of enterococci at 48 h by LY 146032 alone occurred with two strains. There was synergism between LY 146032 and gentamicin or tobramycin; complete killing at 24 h and 48 h occurred with many strains. No antagonism was demonstrated.
Anti-Bacterial Agents↗
Comparative in-vitro activity of LY146032 a new peptolide, with vancomycin and eight other agents against gram-positive organisms.
The in-vitro activity of LY146032, a new biosynthetic peptolide antibiotic, was compared with vancomycin and eight other antibiotics against 190 Gram-positive bacteria. Organisms tested included streptomycin-susceptible and resistant enterococci, nafcillin-susceptible and resistant Staphylococcus aureus, and nafcillin-susceptible and resistant Staph. epidermidis. LY146032 had excellent in-vitro inhibitory and bactericidal activity against nafcillin-susceptible and resistant staphylococci (MIC90 less than or equal to 0.5 mg/l) and against enterococci (MIC90 less than or equal to 2.0 mg/l). LY146032 was more active than vancomycin against the majority of isolated tested. With the exception of trimethoprim-sulphamethoxazole, LY146032 was the most active agent in vitro against enterococci, and was the most active against nafcillin-resistant staphylococci. LY146032 and vancomycin showed a marked increase in MIC when the inoculum was increased from 10(5) to 10(7) cfu/ml. LY146032 and vancomycin were bactericidal at concentrations within two dilutions of the MIC for staphylococci. LY146032 was bactericidal at less than or equal to 8 mg/l for all enterococcal isolates tested.
Anti-Bacterial Agents↗
In-vitro susceptibility of gram-positive cocci to LY146032 teicoplanin, sodium fusidate, vancomycin, and rifampicin.
LY146032, a new antimicrobial agent with activity against Gram-positive cocci, was tested against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, methicillin-susceptible and methicillin-resistant Staph. epidermidis, Staph. saprophyticus, and Streptococcus faecalis. MIC90s in cation-supplemented Mueller Hinton broth by the microdilution broth method were less than 1.0 mg/l for all organisms tested. Increasing or decreasing the inoculum size did not appreciably effect the MIC50 or MIC90 for any organism group nor did decreasing the incubation temperature. The addition of sodium chloride to the test system did not appreciably effect the susceptibility of methicillin-resistant Staph. aureus to LY146032. All organisms were 4 to 32 times more susceptible to LY146032 than to vancomycin. The Staph. aureus had LY146032 susceptibility patterns which were similar to those of teicoplanin and sodium fusidate. LY146032 was 4-16 times more active than teicoplanin against Staph. saprophyticus and Staph. epidermidis while teicoplanin was 8-16 times more active than LY146032 against Str. faecalis.
Anti-Bacterial Agents↗
Comparative in-vitro activity of LY146032 and eight other antibiotics against gram-positive bacteria isolated from children.
LY146032, a cyclic peptide antibiotic active against many Gram-positive bacteria, was compared to methicillin, vancomycin, clindamycin, cefuroxime and gentamicin against methicillin-resistant and methicillin-susceptible strains of Staphylococcus aureus and Staph. epidermidis. LY146032 was uniformly active against clinical isolates of staphylococci, inhibiting 90% of strains of Staph. aureus and Staph. epidermidis at a concentration of 0.5 mg/l. Vancomycin was slightly less active than LY146032 against Staph. aureus and Staph. epidermidis, inhibiting 90% of strains at concentrations of 1.0 and 2.0 mg/l, respectively. All other antibiotics tested were less active than LY146032 or vancomycin against staphylococci. LY146032 was compared to penicillin, ampicillin, vancomycin and chloramphenicol against strains of Streptococcus pneumoniae, group B streptococcus, group D streptococcus (enterococcus) and Listeria monocytogenes and was found to inhibit 90% of the strains at concentrations of 0.25, 1.0, 32.0 and 16.0 mg/l respectively. The combination of LY146032 and chloramphenicol was antagonistic in vitro for one strain each of Staph. aureus and group D streptococcus and showed indifference against other strains of Staph. aureus(2), Staph. epidermidis(2), group D streptococcus(1) and L. monocytogenes(2). LY146032 in combination with gentamicin showed indifference against the same bacteria. On the basis of its in-vitro activity, LY146032 appears to be a promising agent for the treatment of serious community- and hospital-acquired staphylococcal infections.
Anti-Bacterial Agents↗
In-vitro activity of LY146032 against Staphylococcus aureus, Listeria monocytogenes, Corynebacterium JK, and Bacillus spp., in comparison with various antibiotics.
The in-vitro activity of LY146032 was studied against Staphylococcus aureus, Listeria monocytogenes, Corynebacterium JK, and Bacillus spp. in comparison with several agents with action against Gram-positive bacteria. LY146032 showed an MIC90 of 0.4 mg/l for S. aureus, regardless of the resistance to penicillin or oxacillin. LY146032 was equivalent in activity to ciprofloxacin and vancomycin against S. aureus and moderately active against other species tested (MIC90, 0.8-3.2 mg/l).
Anti-Bacterial Agents↗
The effect of cultural conditions on the activity of LY146032 against staphylococci and streptococci.
The antibacterial activity of LY146032 was greatly potentiated in the presence of calcium ions. In the presence of a physiological concentration of calcium (ca 100 mg/l: 2.5 mM) the new compound was more active than vancomycin or teicoplanin against a selection of clinical isolates of staphylococci and streptococci. The requirement for calcium could not be satisfied by magnesium. The activity of LY146032 varied when tested in different culture media, including batches of Mueller-Hinton agar from different manufacturers. The highest minimum inhibitory concentrations of LY146032 were observed in tests on Iso-Sensitest agar, which contains little calcium. Supplementation of Iso-Sensitest agar with increasing concentrations of calcium caused a proportionate fall in the MIC of LY146032. Saponin-lysed horse blood; incubation in a CO2-rich atmosphere; and an increase in the bacterial inoculum from 10(3) to 10(6) cfu/spot had little effect on the activity of LY146032 in the presence or absence of calcium.
Anti-Bacterial Agents↗
In-vitro activity of LY146032 against gram-positive isolates from cancer patients.
The in-vitro activity of LY146032 was compared with that of other antibiotics against Gram-positive organisms, mostly isolated from cancer patients. LY146032 inhibited all isolates, including methicillin-resistant Staphylococcus aureus and Streptococcus faecalis, at a concentration of less than or equal to 2.0 mg/l. The MBCs of this new drug were within eight times the MICs for all bacteria tested.
Anti-Bacterial Agents↗
In-vitro activity of LY146032 against Staphylococcus aureus and S. epidermidis.
The antibacterial activity of LY146032, a new cyclic polypeptide, was compared with that of vancomycin against 163 isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus and S. epidermidis. The MICs of LY146032 and vancomycin for 90% of the isolates were 1.0 mg/l and 2.0-4.0 mg/l, respectively. Interpretative guidelines for 15 micrograms and 30 micrograms LY146032 discs could not be established because all isolates tested were susceptible to LY146032, on the basis of achievable serum levels. With one exception, MBC to MIC ratios of LY146032 and vancomycin were less than or equal to 2. Inoculum size had minimal effect on ratios. In time-kill studies, both drugs were 99.9% bactericidal at 6 h for four isolates at concentrations four times the MBC or less. No change in LY146032 activity was observed between isogenic pairs that were resistant to other antibiotics. Thus, LY146032 was very active in vitro against all staphylococcal isolates.
Anti-Bacterial Agents↗
LY146032: activity and resistance development in vitro.
LY146032, a new lipopeptide antibiotic, was compared with vancomycin, teicoplanin, cefamandole and ciprofloxacin, against 107 clinical isolates comprising methicillin-susceptible and methicillin-resistant Staphylococcus spp., Streptococcus faecalis and Corynebacterium spp. All staphylococci were susceptible to all agents, except that some of the methicillin-resistant strains were resistant to cefamandole. Only LY146032 and ciprofloxacin were bactericidal to Str. faecalis. Development of resistance was studied by serial transfers of ten selected strains. A stable greater than or equal to eight-fold increase of the MIC over the breakpoint was found to develop to a variable extent against all agents tested. Simultaneous development of resistance to any of the other antibiotics was registered in 11/200 tests.
Anti-Bacterial Agents↗
Nomenclature of LY146032.
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Anti-Bacterial Agents↗
Comparison of the investigational drug, LY146032, with vancomycin in experimental pneumonia due to methicillin-resistant Staphylococcus aureus.
The efficacy of LY146032 was compared with that of vancomycin in experimental pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). Emphysematous hamsters were challenged intratracheally with MRSA and given LY146032 (20 mg/kg 24h), vancomycin (40 mg/kg/24h) or normal saline by subcutaneous injection. Following infection with 2 X 10(9) cfu, survival among antibiotic-treated animals was significantly greater than that of the control group (P less than 0.01 at 96 h); however, no significant difference in survival between the hamsters given LY146032 and vancomycin was seen. To evaluate the influence of the antibiotics on the rate of bacterial killing within the lungs (pulmonary clearance), animals were challenged with a high inoculum (1 X 10(9) cfu) or low inoculum (1 X 10(6) cfu). Animals treated with LY146032 demonstrated a significant advantage in pulmonary clearance versus controls at both inocula; however, animals treated with vancomycin showed a statistically significant increase in pulmonary clearance versus controls only at the lower inoculum. We conclude that in this experimental model, LY146032 was as effective as vancomycin in treating infection with MRSA.
Animals↗
Influence of LY146032 on human polymorphonuclear leucocytes in vitro.
LY 146032 is a new acidic lipopeptide antibiotic with high in-vitro activity against Gram-positive bacteria. We have studied the influence of LY 146032 on the functions of polymorphonuclear leucocytes with two strains of Staphylococcus aureus, one susceptible to oxacillin and one resistant. LY 146032 (10 mg/l) was found to have no influence on superoxide generation stimulated by phorbol myristate acetate, nor on phagocytosis of opsonized Staph. aureus, furthermore there was no effect on chemotaxis in agar stimulated by opsonized zymosan. LY 146032 (MIC and MIC/4) did not modify the intracellular killing of the two strains when they were preincubated, or when the antibiotic was added either at the time or after the completion of phagocytosis both in aerobic and in strict anaerobic conditions. However, in aerobic conditions, LY 146032 was able to prevent the overgrowth of phagocytosed Staph. aureus after 24 h of incubation. The intracellular concentration of LY 146032, measured by microbiological assay, was 60% of the extracellular concentration.
Aerobiosis↗
Intraphagocytic penetration of antibiotics.
The penetration of several antibiotics into human polymorphonuclear leucocytes was measured with a bioassay. The aminoglycosides (gentamicin, netilmicin), oxacillin and LY146032, a new lipopeptidic antibiotic, had a penetration which was generally less than 60%, whereas new fluoro-quinolones (enoxacin, ciprofloxacin, CI934, Ro236240) and rifamycins (rifampicin, LM427) were concentrated 2.4 to 14.2-fold. The concentration of vancomycin and teicoplanin associated with the neutrophils appeared to be saturable over the range of extracellular concentrations tested (5-20 mg/l). Coumermycin, an inhibitor of DNA-gyrase, was highly concentrated (11.3 to 16.6-fold) within the neutrophils. The penetration of clindamycin and erythromycin was low (0.60- to 1.48-fold).
4-Quinolones↗
Aminoglycoside nephrotoxicity: do time and frequency of administration matter?
Aminoglycosides remains the mainstay in the treatment of gram-negative infections despite their potential oto-and nephrotoxicity although alternatives with equal or better efficacy are available. Several approaches were investigated to decrease aminoglycosides nephrotoxicity. Among them, only the once-daily dosing of aminoglycosides has been brought to the clinic and physicians are now increasingly adopting this approach to reduce the toxicity of these agents. The incidence of aminoglycoside nephrotoxicity can be further reduced in view of the recent data on the circadian variations of their nephrotoxicity. In fact, it has been clearly demonstrated in both experimental animals and humans that the toxicity is maximal when the drug is injected during the rest period compared with the activity period. Thus, injecting aminoglycosides once-daily at the time of the lowest toxicity is actually the most interesting and clinically applicable approach to reduce aminoglycosides toxicity.
Aminoglycosides↗
Introduction. Staphylococcal infections--whatever next?
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Anti-Bacterial Agents↗
Sampling the antibiotic resistome.
Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of antibiotics, evolving corresponding sensing and evading strategies. They are a reservoir of resistance determinants that can be mobilized into the microbial community. Study of this reservoir could provide an early warning system for future clinically relevant antibiotic resistance mechanisms.
Amino Acid Substitution↗