Activity of Gentamicin, Tobramycin, Polymyxin B, and Colistimethate in Mouse Protection Tests with
            <i>Pseudomonas aeruginosa</i>

A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model. This study was undertaken as a result of our interest in determining whether there were any important differences between the aminoglycoside antibiotics gentamicin and tobramycin. A review of the literature indicated only minor differences in in vitro antibacterial activity (1,6,8,14,20,31). Gentamicin is slightly more active against Serratia species, and tobramycin is slightly more active against isolates of Pseudomonas aeruginosa. In vivo animal studies of antibacterial activity again show similar degrees of activity, except that tobramycin is more active against P. aeruginosa infections (5,30). The pharmacokinetics of the two drugs in humans are felt to be virtually identical (9,12,22,28). Comparative toxicity studies of the effects of these two drugs in humans have not been reported.In a rat model, tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2). Tobramycin was considered less nephrotoxic than gentamicin in rats on the basis of subtle but consistent histological changes and differences in drug-induced urinary lysosomal enzymes (12, 21). Since a clear difference in nephrotoxic potential would have clinical importance, studies were designed to more precisely detect any abnormalities in renal structure or function.Initially, a prospective randomized doubleblind study in humans was considered. A recent report describes such a study comparing gentamicin and amikacin (26). However, it appears virtually impossible to determine the incidence of aminoglycoside-induced nephrotoxicity in humans. There is no way for the investigator to separate disease-induced toxicity from drug-induced toxicity. Also, preillness measurements of renal structure and function are rarely available. Because of these concerns, we chose to use a rat model of aminoglycoside nephrotoxicity. Nephrotoxicity was quantitated by histological changes and alterations in renal fimction. The results demonstrate that, in this model, tobramycin is less nephrotoxic than gentamicin.MATERIALS AND METHODS Animals. Adult male Fischer 344 rats, weighing 175 to 275 g, were used. The rats were kept sing...

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confidence: 59%

“…Tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2).…”

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confidence: 94%

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Gilbert

Plamp

Starr

et al. 1978

“…Although we achieved good results using local intrathecal colistin for treatment of catheter-associated ventriculitis (13) and successful intravenous therapy has also been reported in a case of meningitis (20) and in a variety of nosocomial infections (27), clinical experience with colistin is still limited (6,11), and relatively little is known of its efficacy in treating severe infections, especially in comparison with other antibiotics. Furthermore, very few experimental studies using colistin in animal models in protection tests using Pseudomonas aeruginosa have been published (9,35).…”

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confidence: 99%

Efficacy of Colistin versus β-Lactams, Aminoglycosides, and Rifampin as Monotherapy in a Mouse Model of Pneumonia Caused by Multiresistant Acinetobacter baumannii

Montero¹,

Ariza²,

Corbella³

et al. 2002

140

The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 g/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 g/ml for the three strains. Reduction of log 10 CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (⌬lung counts: ؊5.38 and ؊4.64 log 10 CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (؊4.16 and ؊5.15 log 10 CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (؊2.39 log 10 CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.

“…The strains as shown in Table 3 varied in virulence as judged by LD50. Strain PA103 is exceptionally virulent and has been recommended as a reference strain for mouse protection tests (6). The presence of R-factor R130 and RUA7 did not significantly affect the virulence of strain 280 in mice.…”

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confidence: 99%

Relationship Between Gentamicin Susceptibility Criteria and Therapeutic Serum Levels for Pseudomonas aeruginosa in Mouse Infection Model

Nicas

Bryan

1978

In this study estimations of in vivo and in vitro gentamicin susceptibility for a series of strains of Pseudomonas aeruginosa were compared. The series included an extremely susceptible strain, typically susceptible strains by current susceptibility criteria, and strains with enzymatic and permeability-mediated resistance. In vivo testing was done by using a mice protection test involving six 1-h doses of gentamicin and an inoculum of 50 50% lethal doses of P. aeruginosa. Both normal mice and cyclophosphamide-treated mice were used. It was found that peak serum levels and serum levels of gentamicin obtained just prior to the sixth dose (fifth dose trough levels) required for protection were much higher than miniimal inhibitory concentrations (MICs) or minimal bactericidal concentrations (MBCs) obtained in high-cation medium. However, first dose trough levels were similar to MICs or-MBCs. Only an extremely susceptible strain, 280, could be treated at antibiotic dosages and serum levels which are considered likely to be safe in humans. A distinct inoculum effect was found in the mice tests, with a 10-fold increase in inoculum producing a 4-fold increase in the amount of gentamicin required, but no inoculum effect was found for MICs. These results suggest that current susceptibility criteria in use for gentamicin and P. aeruginosa overestimate gentamicin susceptibility, particularly when low-cation growth medium is used for susceptibility testing and when treating disseminated infection.Gentamicin, either alone or in combination with carbenicillin, is currently considered to be one of the most useful antibiotics for treatment of infection by Pseudomonas aeruginosa. Despite many years of clinical experience, there is still considerable doubt about the efficacy of gentamicin in the treatment of Pseudomonas sepsis. Poor survival rates reported in several studies ofPseudomonas bacteremia suggest that gentamicin is not highly effective in disseminated infections (8,14,16), yet most strains of P. aeruginosa are considered susceptible by current laboratory in vitro susceptibility testing results.In the present study we examined the relationship of gentamicin susceptibility to in vivo efficacy of gentamicin in mouse models of disseminated infection by using a series of isogenic P. aeruginosa strains with different R-factors and a nonisogenic series varying in gentamicin susceptibility and virulence. Currently if strains have miniimal inhibitory concentrations (MICs) of -6 they are regarded as susceptible (17). We have included infection of cyclophosphamidetreated mice as a model of infection of hosts with compromised host defenses. Because the apparent susceptibility of P. aeruginosa to aminoglycosides is very highly influenced by media conditions (9, 10, 20,