Effectiveness of gentamicin and carbenicillin in a rat model against infections with Pseudomonas aeruginosa resistant to gentamicin or gentamicin and carbenicillin.
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Investigations on the potential nephrotoxicity of cefazedone and gentamicin and of their combination, in comparison with the combination of cefazolin and cephalothin with gentamicin.
The nephrotoxicity of (6R,7R)-7-(2-[3,5-Dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), cephalothin, cefazolin and gentamicin was investigated by the determination of alanine-amino-peptidase (AAP) in urine of healthy volunteers. The results were compared with those obtained by application of the respective combination. The beta-lactam antibiotics showed no effect on the elimination of the characteristic tubule enzyme, while gentamicin, as is known, induced a marked increase of the enzyme elimination. The results with cefazedone + gentamicin show that the determining component on the extent of AAP elimination is the aminoglycoside exclusively, where high and low responders can be observed. When the experiments with gentamicin and with the combination gentamicin and cefazedone were carried out with the same volunteers, no additive effects could be observed.
Adolescent↗
Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria.
Several mutants of Escherichia coli affecting aerobic energy generation and energization of the bacterial membrane have been examined for their effect on streptomycin and gentamicin accumulation and susceptibility. A heme-deficient mutant (K207) and two mutants (CJ-8 [colicin K insensitive] and NR-70) associated with defective aerobic active transport were associated with decreased transport of streptomycin and gentamicin and increased resistance to those antibiotics. These mutants also exhibited increased resistance to several other aminoglycoside antibiotics, but not the aminocyclitol spectinomycin. The same observations were made with a ubiquinone-deficient mutant, but a strA derivative of this mutant was shown additionally to be saturable for streptomycin accumulation at a concentration four or more times lower than that required for saturation of the parent. A mutant uncoupled for adenosine 5'-triphosphate synthesis from electron transport and membrane Mg-adenosine 5'-triphosphatase deficient was hypersensitive to those aminoglycosides tested and spectinomycin, and showed enhanced transport of streptomycin and gentamicin. A variety of compounds structurally related to streptomycin were examined at high concentrations for inhibition of streptomycin uptake in a strA mutant of E. coli K-12 SA 1306, but no evidence for competition was detected, suggesting the absence of a common transport carrier. Four different divalent cations were shown to inhibit streptomycin and gentamicin accumulation in E. coli K-12 SA 1306. Divalent cations were shown to inhibit uptake of these two drugs in two bacterial species with distinct cell wall structures, Pseudomonas aeruginosa and Staphylococcus aureus, and to inhibit streptomycin uptake in spheroplasts of streptomycin-susceptible and -resistant E. coli. However, calcium had almost no inhibitory effect on streptomycin uptake by the ubiquinone-deficient mutant E. coli AN66. These and previous findings have been used to formulate a model for aminoglycoside entry into bacteria using a low-affinity membranous complex involved in membrane energization that includes respiratory quinones, which probably act to bind and transport aminoglycosides across the cell membrane. This phase of transport is associated with the lowest accumulation rate (termed energy-dependent phase I) that is rate limiting for susceptibility. It is further proposed that subsequent association of the membrane-bound aminoglycoside with higher-affinity binding sites on membrane-associated ribosomes carrying out a normal ribosomal cycle and protein synthesis results in a more rapid transport rate (termed energy-dependent phase II). The increased rate could result from a state of membrane energization analogous to that causing enhanced aminoglycoside transport rates seen in the uncoupled mutant, AN120. How this model explains the mechanism by which enzymatically modified aminoglycosides render cells resistant to unmodified aminoglycosides is also discussed.
Adenosine Triphosphatases↗
A comparison of clindamycin-gentamicin and penicillin-gentamicin in the treatment of post-cesarean section endomyometritis.
A random comparison of clindamycin-gentamicin (C-G) and penicillin-gentamicin was made in 200 women who developed endomyometritis following cesarean section. All pretreatment profiles indicated similar populations. The clinical response was more favorable in the women receiving clindamycin-gentamicin. The implications of these results upon clinical practice is discussed.
Adult↗
Changing phage typing patterns of epidemic gentamicin-resistant Staphylococcus aureus. Evidence for transmission of gentamicin resistance.
In a 10-week period, infection with gentamicin resistant Staphylococcus aureus appeared in 24 adults and infants in one hospital. Medical staff were affected first, and subsequently 16 infants in the neonatal intensive-care unit. The gentamicin-resistant staphyloccal isolates showed three distinct phage susceptibility patterns in two distinct phage groups during the early, middle, and late phases of the outbreak. Although not confirmed with in-vitro or in-vivo laboratory data, this outbreak suggests that gentamicin resistance may be transferred between different strains of Staph. aureus in vivo.
Adult↗
An improved radioimmunoassay for serum gentamicin levels using 125I-labelled gentamicin.
1. A radioimmunoassay is described for the measurement of gentamicin in serum or plasma. 2. The assay technique uses a tracer labelled with iodine-125 rather than tritium, and has advantages over previously reported radioimmunoassay methods (Longmore et al., 1976; Lewis, Nelson & Elder, 1972) with regard to rapidity, precision and simplicity of preparation of labelled gentamicin. 3. The iodination technique is simple and gives tracer in high yield, at high specific activity, and with complete immunological identity to unlabelled gentamicin. 4. There is a significant correlation between results obtained by this technique and by a microbial assay method but the radioimmunoassay is more rapid, specific and accurate.
Acylation↗
1-N HAPA gentamicin B, a new aminoglycoside active against gentamicin resistant isolates--activity compared to other aminoglycosides.
1-N HAPA gentamicin B is a new aminoglycoside active against most Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. Among 504 clinical isolates at a concentration of 12.5 microgram/ml all Staph. aureus, Escherichia coli, Klebsiella, Enterobacter, Proteus rettgeri, Providencia and 78% of Pseudomonas, 86% of Proteus morganii were inhibited. Like other aminoglycosides, the activity was greatest at an alkaline ph and reduced by high cations concentrations. 1-N HAPA gentamicin B was equal in activity to amikacin against both gentamicin-sensitive and resistant isolates. It inhibited bacteria containing many of the aminoglycoside inactivating enzymes. When combined with carbenicillin it inhibited in a synergistic manner many Gram-negative bacteria, particularly Pseudomonas and Serratia.
Aminoglycosides↗
Gentamicin assay by enzymatic adenylylation and the application of a double osmotic shock procedure to prepare gentamicin adenine mono-nucleotide transferase.
The release of gentamicin adenine mono-nucleotide transferase (GAdT) during single cold osmotic shock treatment of E. coli K12 W677/HJR66 is not always maximal. The yield of GAdT could not be improved by using E. coli harvested at different stages of growth, by prolonging the exposure to the different steps of the shock procedure, by changing the sucrose concentration, or the magnesium chloride volume. The quantity of GAdT in osmotic extracts could be increased when a double shock procedure was performed. Using an aliquot (30 microliter) of the extract, an accurate and quick assay for gentamicin, sisomicin and tobramycin in microvolumes of serum (30 microliter) can be accomplished. To avoid high background activity in the assay, the extracts should be prepared from E. coli grown in gentamicin-free medium.
Adenosine Triphosphate↗
Double-osmotic-shock procedure to prepare gentamicin adenine mononucleotide transferase for the enzymatic assay of gentamicin.
The release of gentamicin adenine mononucleotide transferase during single, cold, osmotic-shock treatment of Escherichia coli K-12 W677/HJR66 is not always maximal. The quantity of gentamicin adenine mononucleotide transferase in osmotic extracts could be significantly increased when a double-shock procedure was performed.
Adenosine Monophosphate↗
Prospective comparative evaluation of gentamicin or gentamicin plus cephalothin in the production of nephrotoxicity in man.
Recent studies in animal models have demonstrated that in contrast with humans, cephalothin (CTIN) does not increase gentamicin (GENT) nephrotoxicity, but rather protects against it, particularly when CTIN is given simultaneously with GENT. To investigate this phenomenon in humans a study was designed in which 67 patients suffering from mild infections were investigated. Thirty-three of them served as the control group receiving GENT alone at a dose of 1.5 mg/kg/8 hourly, while the remaining 34 received CTIN at a dose of 2 g or 3 g 8 hourly by i.v. bolus, either simultaneously with GENT or separated by a 4-h interval. Findings showed that: (a) cylindruria developed in 66.6% and 82.3% and 82.3% in the GENT and GENT + CTIN groups respectively, (b) urinary beta-glycuronidase activity increased in 57.5% and 75% (c) serum creatinine exceeded by 0.3 mg the initial values in 21.2% and 27.6% and (d) the blood urea was above 50 mg% in 18.1% and 17.6% of the patients. These results indicate that: (a) regardless of the route and order of administration simultaneous treatment did not protect against nephrotoxicity in humans; (b) the combination of GENTA plus CTIN has no synergistic effect on the production of elevated serum creatinine and rising blood urea; (c) urinary beta-glycuronidase is not a significant predictor of eventual nephrotoxicity; (d) the following risk factors influenced the appearance of nephrotoxicity in both groups: (1) elevated GENT trough levels greater than or equal to 2 mg/l; (2) a course of treatment longer than 10 days.
Adult↗
Renal tubular transport of gentamicin in the rat.
The renal handling of gentamicin in the rat was examined by clearance, microinjection, and renal cortical-slice techniques. The steady-state renal clearance of 14C-gentamicin, when corrected for the 7.5% binding to plasma protein, was not significantly different from that of 3H-inulin. At the end of the renal clearance experiments, the cortical concentration of gentamicin was 93 +/- 7 microgram/g of tissue (N = 7), a concentration threefold greater than that of the medulla and 20-fold greater than that of serum. Absorption of 3H-gentamicin along the proximal convoluted tubule and loop of Henle was demonstrated by the tubular microinjection technique. No reabsorption of 3H-gentamicin was detected beyond the early distal convoluted tubule. The tubular absorption of 3H-gentamicin was load dependent. Fractional absorption of 3H-gentamicin averaged 30.1 +/- 2.7% when the dose of 3H-gentamicin injected into early proximal tubular convolutions averaged 132 +/- 17 pg. It was decreased to 13.6 +/- 2.6% when the microinjected dose of gentamicin was increased to 1996 +/- 388 pg. No evidence of transtubular absorption of 3H-gentamicin was detected during the microinjection experiments. Microperfusion of pertubular capillaries failed to demonstrate urinary precession of 3H-gentamicin over 14C-inulin, a finding which argues against a rapid transtubular secretory flux of gentamicin. Significant uptake of gentamicin was demonstrated by renal cortical slices incubated in medium containing 14C-gentamicin. The accumulation of 14C-gentamicin by renal cortical slices was not inhibited by probenecid or N1-methylnicotinamide but was inhibited by netilmicin and tobramycin. These data support the conclusion that the renal accumulation of gentamicin reflects transport of gentamicin across both the apical and basolateral membranes of proximal tubular epithelium.
Animals↗
Effect of gentamicin on p - aminohippurate metabolism and transport in rat kidney slices.
The mechanism by which gentamicin augments the uptake of p-aminohippurate (PAH) by rat renal cortical slices was investigated. In all experiments, gentamicin was administered as gentamicin sulfate at 100 mg/kg b.wt. per day for 2 days; control rats were injected with saline. The effect of gentamicin on the metabolism of PAH to p-aminobenzoic acid (PABA), acetyl-PABA and acetyl-PAH was studied by high performance liquid chromatography. No metabolites of PAH were detected in renal slices of gentamicin-injected or control rats incubated in medium containing PAH. Efflux of 14C-PAH was measured after incubating renal cortical slices for 2 hours in medium containing 8 X 10(-5) M 14C-PAH. The efflux rate constant was 0.080 +/- 0.003/min in control slices and 0.059 +/- 0.003/min in gentamicin slices, P less than .001. No significant difference in the diffusible pool of PAH was found between the two groups which supports an argument against increased tissue-binding of PAH as the explanation for the augmented uptake of PAH by slices of gentamicin-injected rats. Active PAH transport was assessed in terms of Michaelis-Menten kinetics. Vmax was 0.93 +/- 0.08 micronmol/g/15 min in control slices and 1.37 +/- 0.10 micronmol/g/15 min in gentamicin slices (P less than .005). The apparent reaction rate constant (Km) was not different; Km was 0.25 +/- 0.03 and 0.29 +/- 0.04 mM in control and gentamicin slices, respectively (P less than .4). In contrast to PAH, gentamicin did not alter uptake of N'-methynicotinamide, an organic base; nor did it alter the efflux rate constant or diffusible pool of N'-methylnicotinamide. Increased PAH uptake was still evident when slices of gentamicin-injected rats were incubated in medium without acetate. These studies indicate that gentamicin stimulates active PAH transport and decreases PAH efflux in rat renal cortical slices. Both changes implicate an effect of gentamicin at the antiluminal membrane of proximal tubular cells. The finding of an increase in Vmax without a change in Km raises the possibility that gentamicin increases the amount or availability of carrier protein-mediating PAH transport.
Acetates↗
Comparison of silver sulfadiazine and gentamicin for topical prophylaxis against burn wound sepsis.
Daily prophylactic application of either 1.0% silver sulfadiazine cream or 0.1% gentamicin cream was compared for effectiveness in preventing bacterial colonization of burn wounds and sepsis. Pseudomonas aeruginosa colonized the wounds of 37% of the 38 patients treated with silver sulfadiazine and 30% of the 33 patients treated with gentamicin; gentamicin-resistant P. aeruginosa colonized the wounds of 21% of the patients treated with gentamicin. Staphylococcus aureus colonization occurred in 55% of the patients treated with silver sulfadiazine, whereas colonization with Candida species occurred in 58% of the patients treated with gentamicin. Although gentamicin-resistant organisms caused no deaths their repeated appearance resulted in discontinuation of prophylaxiz with gentamicin cream. The next year P. aeruginosa strains resistant to gentamicin were isolated from burn wounds of only two patients who had not previously received parenteral therapy with gentamicin or tobramycin. Gentamicin cream should be reserved for treating patients with wounds infected by gentamicin-sensitive P. aeruginosa and those allergic to sulfa drugs. For most patients with burn wounds silver sulfadiazine is safe and effective as an antibacterial agent for topical prophylaxis.
Administration, Topical↗
Patient factors contributing to the emergence of gentamicin-resistant Serratia marcescens.
One hundred forty nosocomial Serratia marcescens infections (including 76 cases of bacteremia) were identified by prospective surveillance from 1975 through 1977 and retrospective chart review from 1968 through 1974. Thirty-four cases (24 per cent) involved gentamicin-resistant strains. All gentamicin-resistant strains appeared after 1974. Ninety per cent of the patients had undergone surgery, and 88 per cent had received prior antimicrobial therapy. The emergence of gentamicin-resistant S. marcescens paralleled the increase in usage of gentamicin. Prior use of gentamicin for more than two days in an individual patient was a significant risk factor (P = 0.0002) for being infected with a Serratia that was gentamicin-resistant. Other factors which separated gentamicin-resistant Serratia infections from gentamicin-sensitive Serratia infections were (1) urinary site of infection (P = 0.0005), (2) urinary catheter (P = 0.002), (3) endotracheal tube or tracheotomy (P = 0.03) and (4) increasing duration of hospitalization (P less than 0.05). Thirty-three of 34 (97 per cent) patients with gentamicin-resistant strains had urinary catheters. Specific measures to control infection were effective in decreasing the incidence of infections caused by gentamicin-resistant Serratia.
Adolescent↗
Gentamicin- and silver-resistant pseudomonas in a burns unit.
In 1977-8 gentamicin-resistant strains of Pseudomonas aeruginosa became very common in a burns unit, over 90% being resistant at the peak of the outbreak. Some strains were also resistant to silver nitrate, though silver resistance was not found in any other strains of Ps aeruginosa isolated. Unlike the gentamicin resistance, the silver resistance was unstable, and strains became sensitive on repeated subculture. All the gentamicin-resistant strains of Ps aeruginosa were of the same serotype (O:11, H:2,5). Though gentamicin resistance could be transferred in vitro from resistant strains of Ps aeruginosa to one sensitive strain of Ps aeruginosa, there was no evidence of in-vivo transfer of gentamicin resistance between strains of pseudomonas in the patients' burns, nor was there evidence of transfer of gentamicin resistance between Ps aeruginosa and enterobacteria. Carbenicillin-resistant and gentamicin-resistant Ps aeruginosa were sometimes found in the same burns, but no gentamicin-carbenicillin (doubly) resistant strains were found among the 986 strains tested during the outbreak. The outbreak of gentamicin-resistant Ps aeruginosa from burns was not reduced by stopping treatment with gentamicin and its analogues but only by segregating all patients with Ps aeruginosa in one of the two wards of the unit and admitting new patients only to the other ward.
Burns↗
Urinary myelin figures in gentamicin nephrotoxicity.
The nephrotoxicity of gentamicin is associated with formation of myelin figures within the proximal convoluted tubules of experimental animals and man. By electron microscopy, the authors studied urinary sediments of patients who were treated with gentamicin to detect the occurrence of myelin figures. All three patients who had renal impairment and were treated with gentamicin had numerous urinary myelin figures. By contrast, myelin figures were not observed in urinary sediments of four patients who had no renal impairment despite gentamicin therapy, or nine patients who had no renal impairment and did not receive gentamicin therapy. Occasional myelin figures were detected in a urinary sediment of one of eight patients who had renal impairment and no gentamicin therapy. When the urinary sediments of patients who had gentamicin nephrotoxicity were compared with those of patients with Fabry disease, morphologic differences between the myelin figures of the two groups were detected. The study demonstrates the presence of myelin figures in urines of patients with acute renal failure receiving gentamicin, and suggests that the finding of these myelin figures within urine samples may contribute to the diagnosis of gentamicin-induced nephrotoxicity.
Cell Membrane↗
In vitro activity of netilmicin, gentamicin, and amikacin.
The in vitro activity of netilmicin (Sch 20569), a new semisynthetic derivative of gentamicin, was compared with that of gentamicin and amikacin. One hundred and ninety-two clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested using both agar and broth dilution techniques. Netilmicin was comparable to gentamicin, with the following exceptions: (i) for Serratia marcescens and P. aeruginosa, gentamicin was more active than netilmicin; (ii) all strains of Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and Citrobacter freundii, which were resistant to gentamicin, were susceptible to netilmicin; (iii) some strains of S. marcescens, indole-positive Proteus, and Providencia, which were resistant to gentamicin, were susceptible to netilmicin. Netilmicin was more active than amikacin for all Enterobacteriaceae and S. aureus and equal to amikacin in activity against gentamicin-susceptible strains of P. aeruginosa. All strains of P. aeruginosa, resistant to gentamicin, were also resistant to netilmicin but were susceptible to amikacin. Minimal inhibitory concentrations (MICs) obtained with broth and agar showed no significant differences except for P. mirabilis, where broth MICs were twofold greater than agar MICs, and for P. aeruginosa, where agar MICs were twofold higher than broth MICs. The minimal bactericidal concentration (MBC) was either identical to or within one twofold dilution of the MIC for the strains tested. A 100-fold increase in inoculum size produced less increase in MIC and MBC with netilmicin than with gentamicin or amikacin.
Amikacin↗
[Gentamicin-susceptibility of various pathogens isolated from clinical materials].
We studied on the antibacterial activity of gentamicin against various pathogens isolated from clinical materials mainly isolated during 1974 and 1975, comparing with other antibiotics. Beta hemolytic streptococci, pneumococci and enterococci are less susceptible to gentamicin than staphylococci. Staph, aureus and Staph. epidermidis resistant to various antibiotics are very susceptible to gentamicin, and no resistant strain to this drug was found. Haemophilus influenzae, H. parainfluenzae and H. parahaemolyticus are very susceptible to gentamicin, and there is no resistant strain to this drug. Escherichia coli, Klebsiella, Citrobacter, Serratia and five species of Proteus are more susceptible to gentamicin and tobramycin than dibekacin and amikacin. A few resistant or less susceptible strains to gentamicin are found in E. coli, Citrobacerr, Serratia, Pr. morganii and Pr. rettgeri. Pr. inconstans is less susceptible to gentamicin than other species of Proteus. Antibacterial activity of gentamicin against Pseudomonas aeruginosa is very strong, but dibekacin and tobramycin are stronger. Gentamicin-resistant strains of Pseudomonas aeruginosa are now rather few.
Citrobacter↗