Electrochemical interactions between some beta-lactam antibiotics and aminoglycoside antibiotics

Complexation reactions between the two aminoglycosides tobramycin and gentamycin and the two beta-lactam antibiotics carbenicillin and ticarcillin were studied conductimetrically, in aqueous solution. Carbenicillin and gentamycin form a 21 adduct in which about 75% of the antibiotics are bound. Likewise, carbenicillin and tobramycin form a 21 adduct binding about 67% of its components. Tobramycin and ticarcillin also interact, but weakly, binding about 12% of the adduct components. Only a trace of adduct formation was observed between cephalothin and gentamycin and between cephalothin and tobramycin. Cephalothin did not interact with carbenicillin. It appears that the adsorption behavior of the aminoglycosides differs considerably from that of the beta-lactams.     

Antimicrobial activity of new beta-lactams and aminoglycosides in vitro under conditions of anaerobiosis

Sensitivity of 135 strains of aerobic, facultative anaerobic and anaerobic asporogenous bacteria was tested in vitro with respect to 7 beta-lactam antibiotics and 4 aminoglycosides. It was shown that anaerobiosis influenced the MICs of the drugs for the majority of the strains. Under such conditions sensitivity of the aerobic and facultative anaerobic organisms to the beta-lactams increased 2-8 times. On the contrary, the MICs of the aminoglycosides for 74.6-85.1 per cent of the strains increased 2-16 times. The asporogenous anaerobic bacteria of clinical origin were highly sensitive to the beta-lactam antibiotics such as cefoxitin, cefotaxime, mezlocillin and carbenicillin whose MICs did not exceed 16-31.2 micrograms/ml.     

In vitro activity of cefamandole, cefoxitin, cefuroxime, and carbenicillin, alone and in combination with aminoglycosides against Serratia marcescens.

Synergistic antibiotic studies were undertaken to compare the effectiveness of two new beta-lactamase resistant cephalosporins, cefamandole, and carbenicillin, with four aminoglycosides against clinical strains of Serratia marcescens. The strains demonstrated various combinations of resistance and/or susceptibility to the antibiotics tested. Tobramycin was the most effective aminoglycoside when used in combination with beta-lactam antibiotics. Carbenicillin and cefamandole demonstrated similar activity with aminoglycosides in synergy experiments. Tobramycin-carbenicillin was found to be the superior pairs as indicated by the total number of strains inhibited. This combination was the only one effective against certain high drug resistant strains and the strain resistant to all four aminoglycosides. Carbenicillin or cefamandole with tobramycin exhibited comparable activity against multiple drug resistant organisms. However, mutants significantly more resistant to cefamandole developed during susceptibility testing. The findings of this study have clinical relevance for treating infections by this formidable pathogen.     

Production of hydrolases by lactic acid bacteria and bifidobacteria and their antibiotic resistance

It was demonstrated that bifidobacteria and lactic acid bacteria B. adolescentis and Lactobacillus sp. synthesized extracellular enzymes cleaving glycoside bonds in the molecules of dextran, pectic acid, and soluble starch. The maximal production of extracellular beta-galactosidase by B. adolescentis 91-BIM and 94-BIM at a rate of 0.08 and 0.03 U/mg h was observed during the exponential growth phase at 5 and 12 h of cultivation, respectively. The cultures of bifidobacteria retained 60-70% of beta-galactosidase and alpha-amylase activities after six months of storage. The bifidobacterium strains studied were resistant to amphotericin and aminoglycosides (gentamicin, kanamycin, and netromycin). The lactam antibiotics (ampicillin, benzylpenicillin, bicillin 3, bicillin 5, and carbenicillin), the preparations inhibiting protein synthesis at the level of ribosomes (lincomycin), RNA polymerase inhibitors (rifampin), cephalosporin, and Maxipime inhibited the growth of bifidobacteria. Rifampin, erythromycin, amphotericin, Maxipime, Fortum, doxycycline, levomycetin, streptomycin, and the aminoglycosides netromycin, gentamicin, and kanamycin did not have an effect on the growth of Lactobacillus sp., whereas semisynthetic derivatives of penicillin, carbenicillin and ampicillin, inhibited its growth as well as Oxamp and lincomycin. The lactam antibiotics benzylpenicillin, bicillin 3, and bicillin 5 inhibited the growth of lactic acid bacilli by 30-90%.     

Monitoring aminoglycoside use in patients with severely impaired renal function.

Twenty patients with severely impaired renal function, 17 of wnom had recently transplanted kidneys, were treated with aminoglycosides for severe infections acquired in hospital. Serum aminoglycoside concentrations were closely monitored and dosages adjusted individually to obtain peak and trough concentrations that ensured adequate treatment while avoiding toxicity. Causative organisms were susceptible to treatment in 21 out of 26 episodes of infection (81%), and 12 of the 17 patients (71%) in whom organisms were isolated were cured. Nephrotoxicity attributable to aminoglycosides alone was not observed during the 35 courses of treatment. Ototoxicity occurred in only one patient, who had excessively high serum concentrations of amikacin. Serum aminoglycoside concentrations were directly affected by carbenicillin and flucytosine. The concurrent administration of cephradine and cephalexin with gentamicin may have produced nephrotoxicity. We conclude that aminoglycosides, when carefully monitored, are effective and safe in patients with severely impaired renal function.     

Production of hydrolases by lactic acid bacteria and bifidobacteria and their antibiotic resistance

It was demonstrated that bifidobacteria and lactic acid bacteria B. adolescentis and Lactobacillus sp. synthesized extracellular enzymes cleaving glycoside bonds in the molecules of dextran, pectic acid, and soluble starch. The maximal production of extracellular β-galactosidase by B. adolescentis 91-BIM and 94-BIM at a rate of 0.08 and 0.03 U/mg per h was observed during the exponential growth phase at 5 and 12 h of cultivation, respectively. The cultures of bifidobacteria retained 60–70% of β-galactosidase and α-amylase activities after six months of storage. The bifidobacterium strains studied were resistant to amphotericin and aminoglycosides (gentamicin, kanamycin, and netromycin). The lactam antibiotics (ampicillin, benzylpenicillin, bicillin 3, bicillin 5, and carbenicillin), the preparations inhibiting protein synthesis at the level of ribosomes (lincomycin), RNA polymerase inhibitors (rifampin), cephalosporin, and Maxipime inhibited the growth of bifidobacteria. Rifampin, erythromycin, amphotericin, Maxipime, Fortum, doxycycline, levomycetin, streptomycin, and the aminoglycosides netromycin, gentamicin, and kanamycin did not have an effect on the growth of Lactobacillus sp., whereas semisynthetic derivatives of penicillin, carbenicillin and ampicillin, inhibited its growth as well as Oxamp and lincomycin. The lactam antibiotics benzylpenicillin, bicillin 3, and bicillin 5 inhibited the growth of lactic acid bacilli by 30–90%.     

The Sterility Testing of Aminoglycosides: A New Approach Using Enzymic Inactivation

The inactivation of various aminoglycosides prior to sterility testing has been studied. The preparation of the enzyme used in the inactivation, a 3-N-acetyl transferase of wide substrate specificity from Escherichia coli JR 225, is described. The enzyme is partially purified and some of its kinetic parameters described. The extent of the inactivation of the individual aminoglycosides can be related to the physiological efficiency of the enzyme. The lyophilization of the components of the inactivating system is successful when undertaken individually, but not together.     

Synergy of Vancomycin with Penicillins and Cephalosporins Against Pseudomonas,Klebsiella, and Serratia

A model of antibiotic synergy based on a molecular mechanism of action which blocked sequential steps in a single metabolic pathway was tested. Twenty-five strains each of Pseudomonas, Klebsiella, and Serratia were tested in vitro against three different two drug combinations of vancomycin, carbenicillin, or cephalothin. Synergy was observed when vancomycin was combined with either carbenicillin or cephalothin against isolates of Pseudomonas or Serratia, whereas the combination of carbenicillin and cephalothin did not result in significant synergy against these isolates. The presence of synergy was not related to the sensitivity or resistance of the isolates to the drugs in the combination. Synergy was also observed with all three antibiotic combinations against Klebsiella isolates which may be related to enzyme inactivation by one of the drugs in the combination. These observations support the hypothetical model of antibiotic synergy based on sequential blocking of one biochemical pathway.     

Rapid evaluation of the effectiveness of antibacterial drugs in experimental tularemia

Rapid estimation of the protective effect of antibacterial drugs on Fransiella tularensis for not more than 2 days was shown possible in experiments on albino mice infected with tularemia. High efficacy of aminoglycosides (kanamycin, gentamicin, streptomycin, amikacin, netilmicin, tobramycin, sagamycin, ribostamycin and sisomicin), tetracyclines (tetracycline, doxycycline, minocycline and methacycline), rifampicin, phosphomycin and oxolinic acid was determined with the recommended rapid method. Amoxycillin, ampicillin, piperacillin, carbenicillin, erythromycin, levomycetin, cefradine, cefmetazole, cefatrizine, cefoxitin, cefsulodin and bactrim (biseptol) proved to be inefficient against the tularemia causative agent.     

Sensitivity of bacteria of the genus Acinetobacter to antibiotics and ofloxacin

Between 1989-1989 276 strains of Acinetobacter genus were isolated which contained: Acinetobacter calcoaceticus subsp. anitratus (n = 167), Acinetobacter calcoaceticus subsp. Iwoffi (n- = 83), Acinetobacter haemolyticus (n = 26). Their sensitivity to aminoglycoside antibiotics, beta-lactams, tetracyclines, chloramphenicol, colistin, and ofloxacin was tested. More than 90% of strains were sensitive to colistin and ofloxacin. The sensitivity to remaining antibiotics differentiated depending on species. Acinetobacter anitratus were highly resistant to Ist and IInd generation of cephalosporins, and moreover to penicillins, tetracyclines, and chloramphenicol. Cephalosporins of IIIrd generation were active against 70% of strains with exception of cefoperazone what was also the case for representatives of aminoglycosides as netilmicin and amikacin. Strains of Acinetobacter Iwoffi were in majority sensitive to all antibiotics with exception of cephalothin, cephradine and cefoperazone. More than 90% of Acinetobacter haemolyticus strains were sensitive to gentamicin, carbenicillin, azlocillin, ceftriaxone, cefotaxime and tetracyclines.     

Effect of ticarcillin/potassium clavulanate on callus growth and shoot regeneration in Agrobacterium-mediated transformation of tomato (Lycopersicon esculentum Mill.)

Ticarcillin/potassium clavulanate is a very effective combination of antibiotics to eliminate Agrobacterium tumefaciens during tomato transformation. It shows no toxicity to tomato tissues at a concentration of 150 mg/l and significantly promotes callus formation and shoot regeneration. The transformation frequency was raised more than 40% in comparison to cefotaxime. Cefotaxime itself did not inhibit callus growth in culture medium, but it clearly decreased shoot differentiation. Together with kanamycin, cefotaxime shows a strong negative effect on callus growth, shoot regeneration and transformation efficiency. Unlike the widely used carbenicillin and cefotaxime, ticarcillin/potassium clavulanate is light stable and resistant to inactivation by β-lactamase. Furthermore, ticarcillin/potassium clavulanate is more economical than carbenicillin and cefotaxime. In conclusion, ticarcillin/potassium clavulanate is a very good alternative to eliminate Agrobacterium tumefaciens in plant transformation and has the potential to be widely used for plants which are sensitive to carbenicillin and cefotaxime. Received: 22 September 1997 / Revision received: 7 November 1997 / Accepted: 15 December 1997     

Antibiotic prophylaxis of postoperative suppurative complications in surgical urology

Preoperative sanation of the urinary tracts is an obligatory condition for lowering the risk of severe infectious complications. When there is no bacteriuria it is recommended in the cases subject to short-term surgical interventions without subsequent drainage of the urinary tracts to perform single or one-day prophylaxis with cephalosporins or semi-synthetic penicillins in the routine doses. The same principle is applicable to transurethral operations, endourological manipulations and lithotripsy. When there are urinary fistulas preventing complete sanation of the urinary tracts before operations it is advisable to use combinations of aminoglycosides with carbenicillin. The treatment terms in such cases amount to 7 to 10 days. Antibiotics of the reserve group, i.e. amikacin, sisomicin and ureidopenicillins should not be used prophylactically in such cases.     

Clinical effectiveness of carbenicillin in suppurative inflammatory processes of varying localization]

The study on sensitivity of clinical strains of the causative agents of purulent infections to carbenicillin showed that 34.6% of the staphylococcal strains, 48.1% of the E. coli strains and 40.3% of the Proteus strains were sensitive to the antibiotic. The strains of Ps. aeruginosa were characterized by moderate sensitivity to carbenicillin. The MTC for most of the isolates ranged within 25-128 microgram/ml. High therapeutic efficacy of carbenicillin in treatment of cases with purulent inflammatory processes of various localization was shown. Positive results were obtained in 82.5% of the adults and 76.2% of the premature infants treated with carbenicillin. A satisfactory therapeutic effect was observed in the cases with sepsis, diffuse purulent peritonitis and abscessing pneumonia treated with carbenicillin in combination with gentamicin.     

Influence of Serum and Calcium on the Bactericidal Activity of Gentamicin and Carbenicillin on Pseudomonas aeruginosa

Because calcium was found to be antagonistic in vitro to the activity of colistin and polymyxin B on Pseudomonas aeruginosa, the effects of calcium and serum on gentamicin and carbenicillin were also examined. Serum was antagonistic to gentamicin in antibiotic tube dilution tests on five strains of P. aeruginosa. Serum was not antagonistic to carbenicillin in tube dilution tests. Physiologic concentrations of calcium antagonized the activity of gentamicin but not carbenicillin. The antagonism observed with gentamicin was less than that previously seen with colistin. The antagonistic effect of calcium and serum was removed by a chelating agent. Gentamicin and carbenicillin may be more active in vivo against P. aeruginosa than colistin or polymyxin B.     

The toxicity of antibiotics to plant cell cultures

We have examined the toxicity of over twenty antibiotics to protoplast-derived cells of Nicotiana plumbaginifolia. The least toxic antibiotics are the betalactams: ampicillin, carbenicillin and the cephalosporins can be used to provide broad spectrum antimicrobial activity without significant toxicity to plant cells. Similar broad spectrum activity can also be obtained by combining rifampicin and trimethoprim. Other antibiotics which may be useful are erythromycin and colistin. The aminoglycosides are not recommended.     

Carbenicillin in the treatment of acute and chronic bacterial pneumonias]

A total of 50 patients suffering from acute and chronic bacterial pneumonia were treated with sodium carbenicillin. The bacteriological analysis of the sputum showed that Str. pneumoniae predominated in the monoculture or its association with other bacteria. Connection of the results of the bacteriological analysis with the clinical efficiency of the therapy was studied. When carbenicillin was administered intramuscularly in a dose of 1 gm, its therepeutic effect was maintained in the blood for 4 to 6 hours. A satisfactory clinical effect was registered in 41 out of 50 patients treated with carbenicillin in a daily dose 4--6 gm for 8--10 days. No toxic effect of carbenicillin on the parenchimatous organs and peripheral blood was noted.     

Val-237 for Ala substitution in the TEM-2 β-lactamase dramatically alters the catalytic efficiencies towards carbenicillin and ticarcillin

Abstract The mutant 554 of TEM-2 β-lactamase was selected for a decrease in the resistance to carbenicillin of an Escherichia coli K12 carrier. The amino acid sequence of the mutant β-lactamase was determined by manual Edman degradation analysis of proteolytic peptides. A single substitution Val for Ala was localized at position 237. The mutant exhibited only 2% of the catalytic efficiency of the wild-type enzyme towards carbenicillin and ticarcillin, whereas it retained 30–60% of the hydrolytic activity towards other penicillin and cephalosporin substrates. Carfecillin, the phenyl ester of the side-chain carboxyl group of carbenicillin, was hydrolysed as a good substrate. This suggests that the behaviour of the mutant enzyme towards carbenicillin may result from ionic rather than steric constraints. A molecular model of the Val-237 TEM-2 mutant suggests possible electrostatic interaction between Glu-171 and the carboxylic group of the side chain of carbenicillin.     

Susceptibility of Recent Isolates of Pseudomonas aeruginosa to Gentamicin, Polymyxin, and Five Penicillins, with Observations on the Pyocin and Immunotypes of the Strains

The susceptibilities of recently isolated strains of Pseudomonas aeruginosa to gentamicin, polymyxin B, carbenicillin, ampicillin, penicillin G, and two newer penicillins were tested with the inocula-replicating technique by using undiluted and 10(-3) dilutions of the cultures. With either inoculum, polymyxin B was the most active agent, and a comparison with previous data from this laboratory showed that the susceptibility of P. aeruginosa to this antibiotic had not changed over the past 20 years. Gentamicin was nearly as active as polymyxin, all but 2 of the 141 strains tested with the diluted inoculum being inhibited by 6.25 mug/ml or less. AB-2288, an agent resembling carbenicillin, was four times more active than carbenicillin or BLP-1654; the last two were equally active against the 10(-3) inoculum. A more marked inoculum effect was noted with the penicillin analogues tested, the increase in minimum inhibiting concentration with the undiluted culture being eight-fold for carbenicillin and at least 16-fold for AB-2288 and BLP-1654. Pyocin typing and serotyping failed to demonstrate any clearly predominating types.     

Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin

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.