Antistaphylococcal Agents Research Articles

Synergistic effect of quinolones and oxacillin on methicillin-resistant Staphylococcus species.

Various combinations of antistaphylococcal antimicrobial agents have been tested against 17 selected Staphylococcus isolates, including methicillin-susceptible and methicillin-resistant strains of S. aureus and coagulase-negative Staphylococcus species. With the checkerboard technique the following combinations were tested: oxacillin-ofloxacin, oxacillin-temafloxacin, oxacillin-fleroxacin, vancomycin-fleroxacin, gentamicin-fleroxacin, and rifampin-fleroxacin. Against methicillin-resistant staphylococci the combination oxacillin-quinolone tested at 35 degrees C always showed a fractional inhibitory concentration (FIC) index of less than 0.75, which is interpreted as synergistic or additive. Equal or more synergistic effects were observed at 30 degrees C. In contrast, when methicillin-susceptible Staphylococcus species were tested, the FIC for the combination oxacillin-quinolone was always 1 or 2, which is considered to be indifferent. For the other mentioned combinations the FICs were also 1 or 2. Killing kinetics showed synergistic or additive bactericidal activity for the combination oxacillin-ofloxacin against methicillin-resistant Staphylococcus species, killing 1.5 to 2.8 log10 CFU more of these per ml than did the most active drug after 24 h of incubation. This difference was not observed for methicillin-susceptible strains. In vitro evidence for the potential clinical use of quinolones in treating infections due to methicillin-resistant staphylococci in combination with a beta-lactamase-resistant penicillin is provided.

New Uses for Old Drugs

Existing therapies are often tried when new diseases are discovered or new manifestations of known organisms are recognized. This article reviews the successful application of older commonly used antibiotics to several representative "new" or "newly recognized" illnesses. Examples include new uses for the antistaphylococcal agents, penicillin, the tetracyclines, erythromycin, vancomycin, trimethoprim-sulfamethoxazole, pyrazinamide, metronidazole, clindamycin, and others.

A national survey of antimicrobial resistance in Staphylococcus aureus in Australian teaching hospitals.

An extensive survey of the in-vitro susceptibility of clinical isolates of Staphylococcus aureus to 18 antimicrobial agents was conducted over three separate periods during 1986-1987 in 14 teaching hospitals in major Australian cities. The survey aimed to document the prevalence of resistance to a wide variety of drugs that are important as antistaphylococcal agents or as epidemiological markers. More than 7500 isolates were examined. Nationally, the prevalence of resistance was 85.3% to penicillin G, 14.4% to methicillin, 14.0% to amoxycillin/clavulanate, 9% to cephalothin, 5.4% to cephamandole, 9.9% to cefotaxime, 25.0% to erythromycin, 11.2% to clindamycin, 21.7% to tetracycline, 13.0% to gentamicin, 1.9% to amikacin, 5.8% to chloramphenicol, 18.3% to trimethoprim, 0.6% to rifampicin, 3.0% to fusidic acid and 1.2% to novobiocin. For none of the strains was resistance to vancomycin confirmed by minimal-inhibitory-concentration determination. A high proportion of the resistances was harboured in methicillin-resistant Staph. aureus, except for resistance to penicillin G, erythromycin and tetracycline. The prevalence of methicillin resistance varied widely among the states: 25.2% in Queensland, 23.5% in Victoria, 12.6% in New South Wales/the Australian Capital Territory, 11.3% in South Australia and 0.4% in Western Australia. Isolates from blood cultures were slightly-more susceptible to antimicrobial agents than were isolates from other body sites. Six common profiles of resistance to penicillin G, methicillin, erythromycin, clindamycin and tetracycline accounted for more than 95% of the isolates that were tested against all five agents. Vancomycin remains the most important antistaphylococcal drug in areas where resistance to methicillin is common.

Comparative in-vitro activity of vancomycin, teicoplanin, ramoplanin (formerly A16686), paldimycin, DuP 721 and DuP 105 against methicillin and gentamicin resistant Staphylococcus aureus

The in-vitro activities of five anti-staphylococcal agents, teicoplanin, ramoplanin, paldimycin, DuP 721 and DuP 105 have been compared to vancomycin. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) have been determined for a collection of methicillin and gentamicin resistant Staphylococcus aureus (MGRSA), comprising 75 strains obtained from 22 centres. In terms of geometric mean MICs (inoculum size 10(5) cfu) paldimycin was the most active agent (0.4 mg/l) followed by ramoplanin (0.75 mg/l), teicoplanin (1.0 mg/l), DuP 721 and vancomycin (2.0 mg/l) and DuP 105 (6.8 mg/l). Ramoplanin was bactericidal within six hours to all strains at a concentration of 1.0 mg/l. The MBC90s for vancomycin and teicoplanin were greater than 32 mg/l after 22 h exposure to antibiotic and 2.5 and 4.0 mg/l respectively after 26 h exposure. Paldimycin was bactericidal against only some strains, while DuP 721 and DuP 105 were not bactericidal. Ramoplanin is the most interesting of the new antibiotics, on account of its rapid and consistent bactericidal activity.

Septicaemia due to gram-positive cocci in cancer patients.

Episodes of septicaemia caused by Gram-positive bacteria in five separate investigations of empirical antibiotic treatment for fever in patients with neoplastic disease have been analysed according to the antimicrobial agents administered and the outcome. The results suggest that the addition of an 'anti-staphylococcal agent', such as co-trimoxazole, vancomycin or teicoplanin, to the standard two-drug regimen (a beta-lactam antibiotic and an aminoglycoside) may be advantageous in improving the prognosis, particularly in Staphylococcus aureus septicaemia.

Susceptibility of Hong Kong isolates of methicillin-resistant Staphylococcus aureus to antimicrobial agents.

Two hundred and sixty-six non-replicate Hong Kong isolates of methicillin-resistant Staphylococcus aureus were tested for their susceptibility to various anti-staphylococcal agents. Multiple resistance was common. More than 95% of patient isolates were resistant to both gentamicin and tetracycline, 68% to erythromycin, 37% to chloramphenicol, 10% to trimethoprim, 5% to rifampicin and 2% to fusidic acid. No isolate was resistant to all these agents, but nineteen different patterns of resistance were identified. Selected gentamicin-resistant isolates were tested against other aminoglycosides, and were sensitive to amikacin and netilmicin. The pattern of aminoglycoside resistance indicated that all isolates produced the aminoglycoside-modifying enzymes APH-(2") and AAC-(6')-I. All isolates were sensitive to vancomycin and teicoplanin. A single strain was resistant to three of the five quinolones tested, but resistance to all the quinolones could be induced easily in vitro by exposure to increasing subinhibitory concentrations of norfloxacin in broth.

In vitro antistaphylococcal activity of pefloxacin alone and in combination with other antistaphylococcal drugs.

MICs of pefloxacin and nine antistaphylococcal drugs were determined for 200 isolates of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saprophyticus. All the strains were susceptible to pefloxacin, vancomycin, and rifampin. Oxacillin-resistant strains were uniformly resistant to cephalothin and were more likely to be resistant to gentamicin, erythromycin, clindamycin, doxycycline, and trimethoprim-sulfamethoxazole than were oxacillin-susceptible strains. Time-kill studies with 23 strains of S. aureus, S. epidermidis, and S. haemolyticus indicated that the relative order of bactericidal activities was gentamicin greater than or equal to pefloxacin greater than oxacillin greater than vancomycin greater than rifampin. Pefloxacin combined with oxacillin or vancomycin killed staphylococci more rapidly than oxacillin or vancomycin alone but less rapidly than pefloxacin alone. Gentamicin combined with oxacillin, vancomycin, or pefloxacin resulted in the most rapid killing of gentamicin-susceptible strains. Rifampin combined with oxacillin, vancomycin, or pefloxacin reduced the bactericidal activities of those drugs, but rifampin resistance was not observed as it was with rifampin alone. Pefloxacin is a potentially useful antistaphylococcal agent.

Staphylococcus aureus bacteremia in patients with hematological malignancies and/or agranulocytosis.

A total of 6,253 cases of Staphylococcus aureus bacteremia, including 274 (4.4%) endocarditis cases, were registered in Denmark in the period 1975-1984. Patients with hematological malignancies and/or agranulocytosis accounted for 479 of the bacteremia cases. The incidence of endocarditis in this group of patients was only 0.4% as compared to 4.7% in other patients with staphylococcal bacteremia (p less than 0.01). The lower incidence of endocarditis complicating bacteremia in these patients may justify a shorter course of therapy than usually recommended for suspected endocarditis. Patients with hematological malignancies and other patients with agranulocytosis had a higher mortality (49 and 46%, respectively) than other patients with S. aureus bacteremia (33%). The highest mortality was found in patients with multiple myeloma (71%, p less than 0.01), the lowest in patients with acute lymphocytic leukemia (28%, p less than 0.01). The higher mortality in these patients may indicate that empiric antibiotic regimens in granulocytopenic patients should include a specific anti-staphylococcal agent.

In vitro and in vivo study of fosfomycin in methicillin-resistant Staphylococcus aureus septicaemia.

Five hundred strains of methicillin-resistant Staphylococcus aureus were tested against various anti-staphylococcal agents. Vancomycin, fusidic acid and fosfomycin were found to be the most effective. Only 1 strain out of 500 was resistant to fosfomycin. Three patients with methicillin-resistant Staphylococcus aureus septicaemia were successfully treated by fosfomycin. We conclude that fosfomycin could be the drug of choice for methicillin-resistant Staphylococcus aureus infection.

In vitro interactions between teicoplanin and other antibiotics against enterococci and staphylococci

In this study we have evaluated the in vitro activity of teicoplanin, a potent anti-staphylococcal and anti-enterococcal agent, in combination with rifampicin, netilmicin, amikacin, fosfomycin and imipenem. Drug interactions were assessed using a microtitre checkerboard dilution method and a time-kill test. With rifampicin, indifference or an additive effect was the prevalent outcome with both methods. With netilmicin and amikacin synergism was seen against half of the enterococcal strains, whereas indifference was more common with staphylococcal isolates. Synergism predominated when teicoplanin was combined with fosfomycin and imipenem. Under no circumstances and with no combination of drugs were we able to detect antagonistic effects.

Imipenem-cilastatin in the treatment of methicillin-sensitive and methicillin-resistant Staphylococcus aureus infections

Imipenem-cilastatin was evaluated for efficacy and toxicity as an antistaphylococcal agent in 23 patients; 11 of these patients were infected with methicillin-resistant Staphylococcus aureus (MRSA), and 12 were infected with methicillin-susceptible S. aureus (MSSA). There were 15 soft tissue, 5 endovascular, and 3 skeletal infections and a total of nine patients with bacteremia. As determined by in vitro susceptibility testing, the MICs for 90% of the MRSA and MSSA isolates tested were 6.25 and 0.39 micrograms/ml, respectively. Two MRSA isolates were resistant to a concentration of greater than 16 micrograms/ml. When 11 MRSA isolates and 7 MSSA isolates were incubated for 48 h the MICs for 90% of the isolates increased to greater than 50 micrograms/ml for the MRSA isolates and 6.25 micrograms/ml for the MSSA isolates. Three S. aureus isolates emerged resistant. Ten of 11 (91%) MRSA infections and 11 of 12 (92%) MSSA infections were clinically cured. Adverse reactions occurred in 25% of the imipenemcilastatin-treated patients. These reactions included gastrointestinal intolerance (7% of the patients), rash or pruritus (6%), eosinophilia (6%), thrombocytosis (4%), and a positive, direct Coomb test without hemolysis (3%). One of the two patients for whom therapy was discontinued because of gastrointestinal intolerance had antibiotic-associated colitis. Imipenem appears to be an effective antistaphylococcal agent against both MRSA and MSSA infections.

Use of Aztreonam in the Treatment of Serious Infections Due to Multiresistant Gram-Negative Organisms, Including Pseudomonas Aeruginosa

Abstract Aztreonam is a novel antimicrobial agent belonging to the monobactam class of antibiotics. It Inhibits both beta-lactamase-producing and non-beta-lactamase-producing aerobic gram-negative bacilli, but it has no activity against gram-positive species or against anaerobic species. The efficacy of aztreonam in the treatment of infection in 76 patients and Its safety in 87 patients was evaluated. The majority (91 percent) of patients had significant underlying disease, and 47 percent were critically iii. Aztreonam produced an overall clinical response of 86 percent, with 10 of 11 cases of bacteremia cured, including four due to Pseudomonas aeruginosa, seven of eight cases of pneumonia, and seven of nine episodes of osteomyelitis. Infections due to bacteria resistant to ampicillin, carbenlclllin, cefazolin, cefamandole, cefoxitin, and gentamicin were cured. Although 15 of 18 patients with exacerbations of pulmonary Infection due to P. aeruginosa showed clinical improvement, bacteriologic cure was not achieved, as has been noted with other drugs. Similarly, patients with major underlying structural abnormalities of the urinary tract showed early relapses of bacteriuria. Aztreonam combined with antistaphylococcal, antistreptococcal, or anti-anaerobic agents provided an alternative to aminoglycoside use in these non-neutropenic patients. Administration of 1 or 2 g every eight hours yield serum bactericidal levels well in excess of 1: 8 against all Enterobacterlaceae and some P. aeruginosa strains. There was a low incidence of adverse side effects, none serious. Overall, aztreonam Is a useful alternative to the drugs available for use in hospital-acquired gram-negative infections and provides a chance for more directed therapy.

Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa

Aztreonam is a novel antimicrobial agent belonging to the monobactam class of antibiotics. It Inhibits both beta-lactamase-producing and non-beta-lactamase-producing aerobic gram-negative bacilli, but it has no activity against gram-positive species or against anaerobic species. The efficacy of aztreonam in the treatment of infection in 76 patients and Its safety in 87 patients was evaluated. The majority (91 percent) of patients had significant underlying disease, and 47 percent were critically iii. Aztreonam produced an overall clinical response of 86 percent, with 10 of 11 cases of bacteremia cured, including four due to Pseudomonas aeruginosa, seven of eight cases of pneumonia, and seven of nine episodes of osteomyelitis. Infections due to bacteria resistant to ampicillin, carbenlclllin, cefazolin, cefamandole, cefoxitin, and gentamicin were cured. Although 15 of 18 patients with exacerbations of pulmonary Infection due to P. aeruginosa showed clinical improvement, bacteriologic cure was not achieved, as has been noted with other drugs. Similarly, patients with major underlying structural abnormalities of the urinary tract showed early relapses of bacteriuria. Aztreonam combined with antistaphylococcal, antistreptococcal, or anti-anaerobic agents provided an alternative to aminoglycoside use in these non-neutropenic patients. Administration of 1 or 2 g every eight hours yield serum bactericidal levels well in excess of 1: 8 against all Enterobacterlaceae and some P. aeruginosa strains. There was a low incidence of adverse side effects, none serious. Overall, aztreonam Is a useful alternative to the drugs available for use in hospital-acquired gram-negative infections and provides a chance for more directed therapy.

Comparative Study of Ceftazidime and Cefamandole in the Treatment of Patients with Infections of Skin and Soft Tissues

Ceftazidime (Fortaz, Glaxo, Inc.) and cefamandole were compared in a randomized, prospective study of patients with infections of skin and soft tissue and/or septicemia. Infections caused by gram-positive and gram-negative bacteria were evaluated. Ceftazidime 1 gram IV every 8 hours was used in 20 patients and cefamandole 1 gram IV every 6 hours was used in 15 patients. If bacteria were not sensitive to the agent provided and if laboratory data confirmed resistance to cefamandole and susceptibility to ceftazidime, treatment was changed to ceftazidime. Bacteriological eradication of the initial pathogens and clinical improvement or cure occurred in all patients treated in each treatment group. There were no statistically significant differences (p > 0.05) between the two groups. Four patients originally placed on cefamandole were changed to ceftazidime therapy due to in vitro bacterial resistance. Each of these patients responded favorably with bacteriological eradication and clinical cure. Site of infection, age, sex and concurrent disorder were not determinants of clinical response. One patient experienced phlebitis during ceftazidime therapy; however, the infection continued to respond to IM administration of ceftazidime. Ceftazidime is safe and clinically effective in the treatment of patients with skin and soft tissue infections. It has advantages over cefamandole in the treatment of infections caused by resistant Proteus sp., E. coli, and Pseudomonas sp. Addition of a pure anti-staphylococcal agent to ceftazidime was unnecessary.

Rifampicin as an antistaphylococcal agent

Rifampicin as an antistaphylococcal agent

Production, purification and chemical properties of an antistaphylococcal agent produced by Staphylococcus epidermidis.

An antibacterial agent produced by Staphylococcus epidermidis strain 5 was isolated from culture supernatants; its spectrum of activity is restricted to staphylococci and micrococci. The bacteriocin-like substance was purified to homogeneity by column chromatography on Servachrome XAD-2, CM-Sephadex C-25 and Sephadex G-50. Chemical analysis showed it to be a peptide with a molecular weight of about 6000 and an isoelectric point of about 10.5. Purified material was rapidly inactivated by trypsin, chymotrypsin and pronase and it was relatively heat-stable. After acidic hydrolysis 10 amino acid residues and two unidentified ninhydrin-positive substances were detected. Production of the bacteriocin-like substance was not inducible with mitomycin C.

Hematogenous Staphylococcal Pneumonia Secondary to Soft Tissue Infection

Staphylococcal pneumonia is rare, has a high mortality and morbidity rate, and occurs commonly during influenza epidemics (airborne) or during the course of right sided bacterial endocarditis in drug addicts (blood borne). In recent years, much emphasis has been given to the staphylococcal infections in intravenous drug abusers. This report describes ten patients with staphylococcal pneumonia resulting from soft tissue infection who were previously healthy and had no history of drug abuse. They were 12 to 45 years old. Eight were male patients. Soft tissue infection was community-acquired in nine and was most commonly located in the lower extremities. Three patients had diabetes. All presented with a clinical picture of acute pneumonia. Hemoptysis occurred in three. Chest roentgenogram showed multiple large or small round discrete densities in most of the patients. Lobar involvement was notably absent. Eight developed cavitary lesions in their lungs. The average length of hospital stay was 40 days. One patient died and six developed complications. Staphylococcal etiology should be suspected in patients with acute pneumonia who have soft tissue infection or have characteristic chest roentgenogram findings; antistaphylococcal agents should be included in the therapeutic regimens of such patients until the results of the cultures are known.

Erythromycin-resistant clinical isolates of Staphylococcus aureus in a district hospital and their susceptibility to other antistaphylococcal agents

Erythromycin-resistant clinical isolates of Staphylococcus aureus in a district hospital and their susceptibility to other antistaphylococcal agents

Treatment of experimental staphylococcal infections: effect of rifampin alone and in combination on development of rifampin resistance.

Rifampin is a potentially useful anti-staphylococcal agent, but resistance develops frequently when the drug is used alone. The efficacy of rifampin, trimethoprim, and a penicillin alone or in combination was examined in mice with acute or subacute infections. Mice were infected intraperitoneally with penicillin-susceptible Staphylococcus aureus. Survival after penicillin therapy was only 9.1% in contrast to survival after rifampin therapy which was 68% (P less than 0.001). No rifampin-resistant S. aureus were isolated from peritoneal fluid or heart blood samples from dead animals in these short-term experiments. Rifampin was ineffective (survival, 4.8%) for infections instituted with rifampin-resistant strains. Long-term experiments were conducted after intravenous injection of 4 x 10(8) S. aureus. Forty percent of the animals survived after methicillin therapy; 77% survived after rifampin therapy (P less than 0.001). However, 40% of those animals that died after rifampin therapy died with rifampin-resistant organisms. No animal dying in groups treated with a combination of rifampin and trimethoprim (85% survival) or rifampin and methicillin (79% survival) died with rifampin-resistant organisms. Thus, rifampin combined with a penicillin or trimethoprim was effective in preventing the development of rifampin-resistant strains.

Current appraisal of the macrolides compared with other antibiotics and the main indications for their use

SummaryA short review is presented of the main indications for the use of the macrolide antibiotics such as erythromycin. Having been considered in the early days essentially as anti-staphylococcal agents to be held in reserve, experience has shown them to be antibiotics of first choice in a number of common infections in general practice as well as in severe infections treated in hospital. They have proved successful alternatives in patients allergic to penicillin and in the treatment of other patients when more active antibiotics are contra-indicated, for example in pregnancy. Moreover, they have produced effective results in a number of stubborn chronic infections, such as urinary tract infections, and have been widely used in prophylaxis. They are generally well tolerated and are regarded by many as being the safest of the antibiotics in general use.