Heterodimeric Rifampicin-Tobramycin conjugates break intrinsic resistance of Pseudomonas aeruginosa to doxycycline and chloramphenicol in vitro and in a Galleria mellonella in vivo model.

Intrinsic resistance in Pseudomonas aeruginosa, defined by chromosomally encoded low outer membrane permeability and constitutively over-expressed efflux pumps, is a major reason why the pathogen is refractory to many antibiotics. Herein, we report that heterodimeric rifampicin-tobramycin conjugates break this intrinsic resistance and sensitize multidrug and extensively drug-resistant P. aeruginosa to doxycycline and chloramphenicol in vitro and in vivo. Tetracyclines and chloramphenicol are model compounds for bacteriostatic effects, but when combined with rifampicin-tobramycin adjuvants, their effects became bactericidal at sub MIC levels. Potentiation of tetracyclines correlates with the SAR of this class of drugs and is consistent with outer membrane permeabilization and efflux pump inhibition. Overall, this strategy finds new uses for old drugs and presents an avenue to expand the therapeutic utility of legacy antibiotics to recalcitrant pathogens such as P. aeruginosa.

Effect of dietary n-3 and n-6 fatty acids on tobramycin induced nephrotoxicity.

Post fish oil(n-3 fatty acids) treatment (5mg/kg/day for 12 days) was effective in bringing the reversal of tobramycin (160mg/kg/day,ip for 12 days) induced nephrotoxicity in albino rats as was evident by normal urea, creatinine, cholesterol and inorganic phosphate levels in the serum of the treatment group compared with group receiving tobramycin only. The return of normal levels of alkaline and acid phosphatase in kidney homogenates of post fish oil treatment group also indicated the beneficial effect of dietary n-3 fatty acids(fish oil) more than n-6 fatty acids(olive oil).The results suggest that oral supplements of dietary n-3 fatty acids (fish oil) for nearly two weeks after tobramycin exposure is more beneficial than n-6 fatty acids (olive oil) as it results in reversal of nephrotoxicity induced by tobramycin.

[Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin]. / Eksperimental'noe izuchenie antibakterial'noi aktivnosti, terapevticheskoi éffektivnosti i toksicheskikh svoistv kombinatsii tobramitsina s karbenitsillinom.

Tobramycin combination with carbenicillin was studied experimentally. Tobramycin is a new aminoglycoside antibiotic prepared at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. It was shown that the combination had mainly synergistic action (67 per cent) on clinical strains of Pseudomonas aeruginosa which was confirmed in treatment of experimental sepsis caused by the organism. In acute experiments with albino mice there was observed summation of the general toxic action of the antibiotics used in the combination. The level and nature of the nephrotoxic action of the tobramycin combination with carbenicillin were shown in experiments with rats to be the same as those of the nephrotoxic action of tobramycin used alone. The presence of carbenicillin in the combination did not increase the inhibitory effect of tobramycin on excitement transmission in the neuromuscular synapses.

[Toxicity and antimicrobial properties of the new aminoglycoside antibiotic 535]. / Izuchenie toksichnosti i antimikrobnykh svoistv novogo aminoglikozidnogo antibiotika 535.

LD50 of antibiotic 535 (3'-desoxykanamycin C) on its intravenous, subcutaneous and oral administration to albino mice was 225, 1150 and at least 5000 mg/kg respectively. After a single subcutaneous administration to rabbits in a dose of 10 mg/kg antibiotic 535 was rapidly absorbed and detected in the blood and organs of the animals for 24 hours. The antibiotic was mainly excreted with the urine. Comparative investigation of the pharmacokinetics of antibiotic 535, tobramycin and kanamycin in rabbits revealed no significant differences. Antibiotic 535 showed a broad antibacterial spectrum and inhibited both grampositive and gramnegative bacteria. It was highly active against infections caused by S. aureus, E. coli and Pr. vulgaris and somewhat less active against infections caused by Ps. aeruginosa. In treatment of experimental tuberculosis of albino mice antibiotic 535 and tobramycin were inferior by their efficacy to kanamycin.

Nephrotoxicity of lysine and of a single dose of aminoglycoside in rats given lysine.

Hyperalimentation solutions have been shown to increase aminoglycoside nephrotoxicity in rats and rabbits. Lysine is a major constituent of hyperalimentation solutions and is known to inhibit tubular reabsorption of protein. To test the effects of lysine on renal function and structure and on aminoglycoside nephrotoxicity, three groups of rats were prepared. Groups 1 and 2 were infused with lysine (55 mumol/kg/min, 1.9 gm/kg total) for 4 hours. In group 2, gentamicin (60 mg/kg) was also infused during the third hour. In group 3, dextrose was given instead of lysine, and gentamicin was given as in group 2. In group 1 (lysine-saline solution), there was a decrease in glomerular filtration rate (GFR) and an increase in 125I-albumin clearance factored by GFR. In group 2 (lysine-gentamicin), the same effects were seen, but the reduction in GFR was significantly greater. Group 3 (dextrose-gentamicin) showed no change in GFR over the 4-hour period, but did show an increase in 125I-albumin clearance factored by GFR. Fractional excretion of sodium rose in group 2 but not in groups 1 and 3. A gradual mild (20%) and nonsignificant fall in renal blood flow followed the combined administration of lysine and gentamicin. In separate 20-hour studies, lysine (1.9 gm/kg intraperitoneally) or gentamicin or tobramycin (60 mg/kg subcutaneously) produced mild renal failure, but the combination of lysine and an aminoglycoside produced substantially greater renal failure. Serum creatinine in experimental groups was significantly correlated with medullary cast formation and tubular necrosis (p less than 0.001). Giant lysosomes with crystalloid inclusions in proximal tubular cells, individual cell necrosis in the pars recta, and casts in the thin limb of the loop of Henle were seen in rats given lysine. We conclude that lysine alone and single large doses of aminoglycosides alone are nephrotoxic, and when the two are combined, toxicity is additive. The nephrotoxicity of lysine may be related to direct tubular toxicity and to tubular obstruction.

Cardiovascular manifestations of acute antibiotic toxicity during E coli endotoxin shock in anesthetized dogs.

Surgically instrumented, pentobarbital-anesthetized dogs were used to examine the acute cardiovascular activities of gentamicin, tobramycin, sodium penicillin-G, and sodium cephalothin during a control state and during experimental circulatory shock induced by E coli endotoxin. Intravenous administration of 2.5, 5, 10, and 20 mg/kg gentamicin or tobramycin resulted in a transient (5--20-minute) state of cardiovascular depression, as reflected by dose-related decreases of systemic blood pressure, cardiac output, left ventricular pressure, dP/dt max, left ventricular contractile force, and dF/dt max; heart rate was affected little. Endotoxin produced a persistent state of circulatory depression characterized by hypotension, decreased cardiac output, arterial acidemia, and reduced indices of cardiac function. During endotoxin shock, the cardiovascular effects of gentamicin and tobramycin were relatively more pronounced (sometimes more than doubled) than effects observed during the control state. Equally large doses of penicillin or cephalothin, however, had no discernible circulatory effects in either control dogs or dogs subjected to endotoxin shock. Present data indicate that the cardiovascular toxicities of the aminoglycoside antibiotics gentamicin and tobramycin were augmented during experimental circulatory shock, and suggest the need for specific hemodynamic surveillance when intravenous administration of cardioactive antibiotics is required in patients with pre-existing circulatory dysfunction.

Tobramycin: a review of its antibacterial and pharmacokinetic properties and therapeutic use.

SYNOPSIS: Tobramycin is a new aminoglycoside antibiotic with a broad antibacterial spectrum in vitro, and pharmacokinetic properties similar to those for gentamicin. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa and active against many gentamicin resistant strains, but is not active against enterobacteriaceae resistant to gentamicin. Theoretically, tobramycin has an advantage over gentamicin against infections caused by P. aeruginosa, but any advantage in clinical practice has yet to be adequately demonstrated. Clinical experience with tobramycin is considerably less than with gentamicin. Whilst tobramycin appears to offer no clear advantages over gentamicin against sensitive organisms it is indicated in infection caused by strains of P. aeruginosa which are resistant to gentamicin, but sensitive to tobramycin. Like gentamicin, tobramycin acts synergistically with corbenicillin and the cephalosporins. The efficacy of the tobramycin-carbenicillin combination has been shown in endocarditis caused by P. aeruginosa which was unresponsive to gentamicin plus carbenicillin. Ototoxicity and nephrotoxicity similar to that seen with other animoglycosides have been encountered in therapeutic trials with tobramycin and wider clinical experience is necessary to determine the relative incidence of these side-effects with gentamicin and tobramycin used under similar conditions. Antimicrobial activity: In comparative studies, in vitro, tobramycin is more active than gentamicin against clinical isolates of Pseudomonas aeruginosa. Similarly, the inhibitory index, which is the ratio between the serum concentration attained at usual therapuetic doses and the minimum inhibitory concentration, for Pseudomonas aeruginosa is higher for tobramycin than for gentamicin. Against Gram-negative bacteria other than Pseudomonas spp. the spectrum of activity of tobramycin is similar to that of gentamicin. For most species the activity of tobramycin is slightly less than that of gentamicin. Gentamicin is consistently more active than tobramycin against Serratia marcescens. Like other aminoglycoside antibiotics, tobramycin is active in vitro in low concentrations against Staphylococcus aureus. Tobramycin is essentially inactive against Streptococcus pyogenes, Streptococcus faecalis and Streptococcus pneumoniae (pneumococci). Maner aminoglycosides and of other antibiotics against various bacteria in vitro, but comparisons between studies cannot always be interpreted literally because the activity of many antibiotics in vitro, including tobramycin, is influenced by the nature of the culture media and the presence of certain salts. The sensitivity of P. aeruginosa to tobramycin is influenced by the magnesium, and calcium content of the culture media whilst that of all species is reduced by sodium ions. Wide variations in the concentration of these ions may result in divergent MIC values and an inappropriate choice of antibacterial agent to treat pseudomonas infection...