In vitro studies with sisomicin, gentamicin and tobramycin

Sisomicin, gentamicin and tobramycin were tested in vitro against 25 isolates each of five genera of clinically significant gram-negative bacteria. Both minimal inhibitory concentrations and minimal bactericidal concentrations were determined using Mueller-Hinton broth and agar. In terms of inhibition, sisomicin was the most active drug against Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens and Proteus mirabilis, while tobramycin was the most active against Pseudomonas aeruginosa. In terms of bactericidal activity, sisomicin was the more active drug against E. aerogenes, K. pneumoniae and P. mirabilis, while gentamicin was the most active against S. marcescens and tobramycin the most active against P. aeruginosa.     

Resistance to gentamicin,tobramycin and amikacin among clinical isolates of bacteria

Susceptibility to the administration of gentamicin, tobramycin and amlkacin was determined for all isolates of aerobic and facultative gram-negative bacilli submitted for testing to the clinical bacteriology laboratory of the Massachusetts General Hospital between July 1, 1974, and June 30, 1976. In this 24-month period more than 46,000 isolates of bacteria were tested by the single-disc diffusion (Bauer-Kirby) method. Resistance to one or more of the aforementioned aminoglycosidic aminocyclitol antibiotics was found among 4, 114 stains. Correlation with quantitative susceptibility test methods revealed that disc-diffusion methods using 10 μg discs accurately predicted resistance to gentamicin and tobramycin, but overestimated the prevalence of resistance to amikacin by 20 to 50 per cent. Most of the gentamicin-reslstant Enterobacteriaceae in this study were also cross-resistant to tobramycin but were susceptible to amikacin. Many gentamicin-resistant strains of Ps. aeruginosa were susceptible to both tobramycin and amikacin. Resistance to amikacin tended to be of relatively low magnltude (most had minimal Inhibitory concentrations (MIC's) between 31 and 125 μg/ml), but organisms which were resistant to the administration of amikacin were usually resistant to the other two aminoglycosidic antibiotics as well.     

Comparative cost effectiveness of gentamicin and tobramycin

Gentamicin and tobramycin were compared for cost effectiveness in the treatment of adult patients with serious infections in a general medical service. We used data from a randomized double-blind trial in which the only observed difference between the clinical effects of these aminoglycosides was the incidence of nephrotoxicity (26% with gentamicin and 12% with tobramycin). According to 1984 cost data, the combined average drug and nephrotoxicity costs per patient were $127 for tobramycin and $72 for gentamicin. An extensive sensitivity analysis--varying frequency and cost of nephrotoxicity, dialysis requirements, aminoglycoside acquisition costs, and length of hospitalization--showed gentamicin to be more cost effective than tobramycin, unless hospitalization is prolonged by an average of at least 15 days for patients with severe nephrotoxicity or at least 3 days for all patients with moderate or severe nephrotoxicity.     

A randomized study of tobramycin plus ticarcillin, tobramycin plus cephalothin and ticarcillin, or tobramycin plus mezlocillin in the treatment of infection in neutropenic patients with malignancies

Two hundred twenty-five patients with 358 febrile episodes were treated with tobramycin and ticarcillin (TT), tobramycin and mezlocillin (TM), or tobramycin, ticarcillin and cephalothin (TTC). There were no statistically significant differences in the response rates for patients who were proven to have infection (67% with TT, 69% with TTC and 53% with TM). Patients were more often cured of their infection if their neutrophil count rose during therapy. In this study, the addition of cephalothin to TT did not increase the frequency of azotemia (10% and 12%, respectively). Although mezlocillin has a broader spectrum of activity in vitro than ticarcillin, it was not more efficacious when combined with tobramycin than ticarcillin plus tobramycin for the treatment of infections in neutropenic patients.     

In vitro susceptibility of gentamicin and/or tobramycin resistant gram-negative bacilli to seven aminoglycosides

Summary The in vitro activity of gentamicin, tobramycin, sisomicin, netilmicin, amikacin, kanamycin and streptomycin was tested simultaneously by the agar dilution method against 584 clinical isolates of gram-negative bacilli that were resistant to gentamicin and/or tobramycin. About half of the gentamicin-resistantPseudomonas were susceptible to tobramycin but cross-resistance was virtually complete between gentamicin and tobramycin forEnterobacteriaceae. Sisomicin was much more active than gentamicin againstKlebsiella, Escherichia andCitrobacter species. Only 18.9%, 27.4% and 27.9% ofKlebsiella, Enterobacter andSerratia respectively were resistant to netilmicin. Amikacin was the most effective aminoglycoside with an overall resistance of 15.6%. Kanamycin was effective against 40% ofProteus andProvidencia species. Surprisingly, more than half ofKlebsiella andEnterobacter species and 85.3% ofSerratia species were susceptible to streptomycin.

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Empfindlichkeit gentamycin- und/oder tobramycinresistenter, gramnegativer Bakterien gegen sieben Aminoglykoside in vitro

Zusammenfassung Die Wirksamkeit von Gentamycin, Tobramycin, Sisomycin, Netilmycin, Amikacin, Kanamycin und Streptomycin in vitro wurde mit der Agarverdünnungsmethode gleichzeitig an 584 klinischen Isolaten gramnegativer Bakterien geprüft, die gegenüber Gentamycin und/oder Tobramycin resistent waren. Etwa die Hälfte der gentamycinresistentenPseudomonas-Arten waren gegen Tobramycin empfindlich, doch bestand bei denEnterobacteriaceae praktisch vollständige Kreuzresistenz zwischen Gentamycin und Tobramycin. Sisomycin war gegenKlebsiella, Escherichia undCitrobacter weitaus wirksamer als Gentamycin. Nur jeweils 18,9%, 27,4% und 27,9% der GattungenKlebsiella, Enterobacter undSerratio waren gegen Netilmycin empfindlich. Amikacin war mit einer Gesamtresistenz von 15,6% das wirksamste Aminoglykosid. Kanamycin war gegen 40% der GattungenProteus undProvidencia wirksam. Erstaunlicherweise erwies sich mehr als die Hälfte der GattungenKlebsiella undEnterobacter sowie 85,3% der GattungSerratia gegenüber Streptomycin empfindlich.

     

Renal and auditory toxicity of high-dose, prolonged therapy with gentamicin and tobramycin in pseudomonas endocarditis

The nephrotoxicity and auditory toxicity of high-dose (mean, 28.6 g) and prolonged (mean, 61.6 days) courses of gentamicin and tobramycin were monitored in 15 patients receiving 17 courses of treatment for pseudomonas endocarditis. Doses were adjusted in a manner that maintained peak levels of aminoglycoside in serum at 12-15 micrograms/ml and trough levels at less than 2 micrograms/ml. Drug-related renal dysfunction and auditory toxicity occurred in 63% and 44%, respectively, of gentamicin-treated patients and in 43% and 25%, respectively, of tobramycin-treated patients. Mean maximal rises (+/- SEM) in serum creatinine levels were 0.8 (+/- 0.4) mg/dl in the group given gentamicin and 1.6 (+/- 0.7) mg/dl in the group given tobramycin. Mean maximal decreases in pure-tone hearing threshold levels were greater in gentamicin-treated patients (58.3 dB) than in those given tobramycin (22.5 dB). Both forms of toxicity appeared earlier and at a smaller dose with gentamicin than with tobramycin.     

Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.     

Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin, and cephalothin.

Levels of rifampin, gentamicin, sisomicin, and cephalothin in normal and osteomyelitic rabbit bones were measured, and the efficacy of these drugs in the treatment of osteomyelitis was evaluated. Single drug regimens, including rifampin for 14 days and gentamicin, sisomicin, and cephalothin each for 28 days, were relatively ineffective (5%-33% sterile bone cultures). Rifampin, administered for 28 days, sterilized the bones of 55% of treated animals. The combination of gentamicin and rifampin, given for either 14 or 28 days, sterilized the bones of 67% of treated animals. The combinations of rifampin plus sisomicin and of rifampin plus cephalothin, given for 28 days, were significantly more effective than these agents alone, sterilizing 90%-95% of bones. The combination of rifampin, sisomicin, and cephalothin, given for only 14 days, sterilized the bones of all treated rabbits. Staphylococci isolated from the bones of therapeutic failures that had received rifampin alone or in combination with other antibiotics were highly resistant to rifampin (minimal inhibitory concentration, greater than 250 mug/ml), whereas the organisms recovered from animals not receiving rifampin remained sensitive. Results of in vitro studies of synergy and/or bactericidal activity of antibiotic combinations correlated with in vivo results in some, but not all, instances.     

Effect of cation content of agar on the activity of gentamicin, tobramycin, and amikacin against Pseudomonas aeruginosa.

Fifty-five strains of Pseudomonas aeruginosa were tested against arithmetic increments in concentrations of gentamicin, tobramycin, and amikacin in 14 different lots of Mueller-Hinton agar. The divalent cation content of each lot was determined by atomic absorption spectrometry. The relation between mean minimal inhibitory concentration (MIC) for strains within each lot and cation content was studied by stepwise regression. Among the cations, the content of Zn++ most highly correlated with the MIC of each aminoglycoside; however, Zn++ accounted for only 23%, 60%, and 47% of the variability in the mean MIC of gentamicin, tobramycin, and amikacin, respectively, against all strains. In two-cation models Zn++ with Ca++ or Cu++ was most highly correlated with the mean MICs of the three aminoglycosides against all strains. No divalent cation, either singly or in combination with one or two other cations, gave a good prediction of the MICs of the aminoglycosides in agar. Furthermore, there was variability in the cations that most highly correlated with the MICs for some strains. These observations support the concept that ionic strength, cations, and a variety of other as yet poorly defined components of media influence the activity of aminoglycosides against P. aeruginosa.     

Susceptibility to beta-lactam antibiotics and gentamicin of gram-negative bacilli isolated from hospitalized patients: a Swedish multicenter study

A total of 952 blood and 1543 urine isolates of gram-negative bacilli from hospitalized patients in 1986-1987 were consecutively collected by 10 Swedish laboratories and tested for susceptibility to 8 beta-lactam antibiotics and to gentamicin. The isolates were mostly Escherichia coli (58% and 44%, respectively) and Klebsiella sp. (17% and 18%). Resistance to ampicillin in blood and urine isolates was found in 35% and 45%, respectively, to piperacillin in 5% and 6%, to cephalothin in 26% and 34%, to cefuroxime in 12% and 22%, to cefotaxime in 3% and 5%, to ceftazidime in 1% and 1%, to imipenem in 0.5% and 0.1%, to aztreonam in 3% and 2%, and to gentamicin in 0.8% and 0%. Resistance of clinically important gram-negative bacilli to new beta-lactam antibiotics and to gentamicin is infrequent in Sweden.     

In vitro activity of combinations of antibiotics against staphylococcus aureus resistant to gentamicin and methicillin

Summary Twenty clinical isolates ofStaphylococcus aureus, resistant to both gentamicin and methicillin, were testedin vitro for sensitivity to rifampicin, novobiocin, fusidic acid, vancomycin, teicoplanin and an extended range of aminoglycosides. Rifampicin was the most active compound tested, having an MIC of < 0.02 mg/l. All the strains were inhibited by 1 mg/l of novobiocin, vancomycin and teicoplanin, and only one strain was resistant to fusidic acid. 50% of the strains were inhibited by less than 1 mg/l of amikacin and netilmicin, but other aminoglycosides were of poor activity. Resistant mutants were selected when strains were grown in the presence of rifampicin, novobiocin or fusidic acid alone, but this did not occur when rifampicin was combined with either novobiocin or vancomycin. Pharmacokinetic and other considerations suggest that a combination of rifampicin and novobiocin deserves further assessment for the treatment of infections caused by this type of organism.

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In vitro-Aktivität von Antibiotika-Kombinationen gegen Gentamicin- und Methicillin-resistente Staphylococcus aureus-Stämme

Zusammenfassung 20 klinische Isolate vonStaphylococcus aureus, die sowohl gegen Gentmicin wie gegen Methicillin resistent waren, wurden auf ihre Empfindlichkeit gegen Rifampicin, Novobiocin, Fusidinsäure, Vancomycin, Teichoplanin und eine ganze Reihe von Aminoglykosiden geprüft. Rifampicin erwies sich als die aktivste der untersuchten Substanzen; die MHK lag unter 0,02 mg/l. Alle Stämme wurden von Novobiocin, Vancomycin und Teichoplanin bei einer Konzentration von 1 mg/l gehemmt. Gegen Fusidinsäure war nur ein einziger Stamm resistent. 50% der Stämme wurden durch Amikacin und Netilmicin in Konzentrationen von weniger als 1 mg/l gehemmt, andere Aminoglykoside waren dagegen nur schwach wirksam. Wenn die Stämme in Anwesenheit von Rifampicin, Novobiocin oder Fusidinsäure allein kultiviert wurden, wurden resistente Mutanten selektiert. Wenn Rifampicin mit Novobiocin oder Vancomycin kombiniert wurde, trat hingegen keine Selektion resistenter Mutanten auf. Unter anderem ist aus pharmakokinetischen Überlegungen eine weitere Untersuchung der Kombination von Rifampicin und Novobiocin für die Behandlung von Infektionen durch die untersuchte Erregerspezies gerechtfertigt.

     

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)