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PubMed1995

Easier monitoring of aminoglycoside therapy with once-daily dosing schedules.

Little has been reported on serum levels attained using once-daily aminoglycoside regimens and their relation to dosage administered and renal function. Consecutive patients with serious infections were randomized to receive gentamicin 4 mg/kg q 24h i.v. (n = 69), gentamicin 1.33 mg/kg q 8h i.v. (n = 46) or netilmicin 5.5 mg/kg q 24h i.v. (n = 59) (with dose reduction in case of renal dysfunction). In the three groups, median first serum trough levels were 0.4, 1.0 and 0.4 mg/l, respectively, and median first serum peak levels were 9.5, 4.7 and 12.2 mg/l (p < 0.01 once-daily vs. thrice-daily regimens). Dose adjustment because of first trough concentrations of > 2 mg/l and/or peak concentrations of < 6 mg/l was required in 6%, 78% and 12% of patients, respectively. Second trough and peak concentrations were significantly higher in the thrice-daily gentamicin group; serum levels remained constant in the other two groups. The six patients in the once-daily groups who developed elevated trough levels later in therapy were characterized in most cases by a decline in renal function.

Adolescent↗
PubMed1996

Postantibiotic effects of subinhibitory concentrations of some antibiotics and their influence on Pseudomonas aeruginosa enzymic activity.

The postantibiotic effects of subinhibitory concentrations (PA SMEs) and virulence factor alterations induced by ciprofloxacin, tobramycin and netilmicin in Pseudomonas aeruginosa were studied. After induction of the postantibiotic phase (PA) (2x or 4x MIC) the cultures were exposed to subinhibitory concentrations (0.1, 0.2 and 0.3x MIC) of the same antibiotic (PA SME). The regrowth of treated as well as control cultures was followed for 24 or 45 h. In the sterile culture filtrates obtained from these bacterial cultures, elastase and proteinase were determined. Ciprofloxacin and aminoglycosides exhibited PA SMEs of 35-35 h for certain combinations of supra-subinhibitory antibiotic concentrations. Longer PA SMEs were observed after treatment with higher sub-MICs. Tobramycin at 0.2 and 0.3x MIC (postantibiotic phase induced by 2x MIC) and at alt sub-MICs added to the bacteria previously exposed to 4x MIC do not allow any regrowth of bacterial culture. PA SMEs of tested antibiotics affected virulence factors of P. aeruginosa. Elastase compared to proteinase was suppressed more effectively. Ciprofloxacin at 0.3x MIC reduced elastase and proteinase activity most significantly (to 14.2 and 60% of the control values).

Anti-Bacterial Agents↗
PubMed2004

Determination of minimal regrowth concentration (MRC) in clinical isolates of various biofilm-forming bacteria.

Based on the ability to attach to polymeric surfaces, the formation of biofilms was determined in 5 wild-type strains (Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii, Escherichia coli, Staphylococcus warneri). Using modified Christensen method, minimum regrowth concentration (MRC) of piperacillin, piperacillin-tazobactam, cefoperazon, ceftazidim, cefepim, meronem, ciprofloxacin, netilmicin and amikacin for Gram-negative and of ampicillin-sulbactam, chloramphenicol, tetracycline, clindamycin, vancomycin and teicoplanin for Gram-positive bacteria was estimated in trypticase-soy broth medium after a 1-d growth on polystyrene microtiter plates. Adherent bacterial populations exhibited reduced antimicrobial susceptibility, which was not shown in submerged cultures. Our results indicate that MRC can predict therapeutic outcome of antibiotic treatment better than the minimum inhibitory concentration tests commonly used.

Acinetobacter baumannii↗
PubMed2002

Renal function and effect of aminoglycoside therapy during the first ten days of life.

The effect of aminoglycoside administration on kidney functional maturation was evaluated in groups of 30 preterm and 30 fullterm infants who were treated for 7 days because of suspected infection. One of three different aminoglycosides was administered to each subgroup of ten preterm and ten fullterm infants. Changes in tubular function in groups of ten preterm and ten fullterm infants who were not given antibiotics were also compared. The mean gestational age for preterm infants from 32.5 to 33.6 weeks and for fullterm infants between 39.2 and 39.5 weeks. The renal tubular function was assessed by examining the fractional excretion of sodium (FENa), potassium (FEK), phosphorus (FEP), magnesium (FEMg) and uric acid (FEUA) as well as by the urinary excretion of calcium as the calcium/creatinine (UCa/UCr) ratio. Gentamicin affected the normal plasma creatinine (PCr) decline in both treated groups (fullterm and preterm). Disturbances in FENa and UCa/UCr were more pronounced in treated preterm than in fullterm infants especially after netilmicin and gentamicin administration. FEMg was significantly affected in preterm infants treated with gentamicin. The findings of this study indicate that the effect of aminoglycosides on tubular function is dependent upon kidney maturity and the type of the aminoglycoside used for therapy.

Amikacin↗
PubMed1996

Effect of aminoglycoside therapy on renal function in full-term infants.

The effect of aminoglycosides on renal function was evaluated in 30 full-term infants who were treated within 24 h of birth with either amikacin (10 infants, group A), gentamicin (9 infants, group B), or netilmicin (10 infants, group C). Renal function was assessed before, during, and 48 h after discontinuation of therapy by measuring the plasma creatinine concentration (PCr), the fractional excretion of sodium (FENa), potassium, magnesium, phosphate (FEP), uric acid, and the urinary excretion of calcium (UCA/UCr ratio) immediately before (trough) and after (peak) the infusion of the aminoglycosides. The results were compared with 10 control newborns who did not receive antibiotics. Significant alterations in renal function were observed only during therapy with gentamicin (group B). These consisted of a sustained elevation of FENa and UCa/UCr ratio throughout therapy, a latent increase in FEP on the 7th day (P < 0.05), and lack of the normal postnatal decline of PCr in 3 of 9 infants (P < 0.01). These abnormalities persisted up to 2 days after discontinuation of therapy. Therapeutic doses of gentamicin may result in significant electrolyte disturbances in sick full-term infants.

Amikacin↗
PubMed1986

Qualitative overview of randomized trials of aminoglycosides.

A qualitative overview was conducted of randomized clinical trials comparing two or more of the following aminoglycoside antibiotics--amikacin. gentamicin, netilmicin, sisomicin, and tobramycin--with respect to efficacy, nephrotoxicity, or auditory toxicity. Design features considered included number of participants in each treatment arm, proportion of randomized participants available for analysis, blinding of evaluators, and report of statistically significant results. The proportion of participants eligible for analysis was less than or equal to 75 percent for 66 percent of the comparisons regarding nephrotoxicity, 43 percent regarding efficacy, and 19 percent regarding auditory toxicity. Twenty-nine percent of the trials reported that evaluators were blinded to treatment group assignments. The results of most trials showed no significant differences, although sample sizes were, in general, smaller than necessary to detect moderate differences. Quantitative overviews may be a useful means of detecting real differences in risk that are not apparent from the results of several individual small trials.

Amikacin↗
PubMed1986

Aminoglycosides plus beta-lactams against gram-negative organisms. Evaluation of in vitro synergy and chemical interactions.

Combination antibiotic therapy has been used mainly to broaden the antibacterial spectrum and prevent the development of resistance. Antibiotic combinations proven to be synergistic in vitro are associated with a significantly better in vivo response, particularly in the compromised host in whom traditional treatment combines an antipseudomonal penicillin plus an aminoglycoside. Several investigators have examined combining new agents, such as the third-generation cephalosporins (cefotaxime, ceftriaxone, ceftizoxime, ceftazidime, cefoperazone, and moxalactam), aztreonam, or the ureidopenicillins, with amikacin. When compared with combinations of an older cephalosporin, carbenicillin or ticarcillin, plus gentamicin or tobramycin, these newer combinations produce higher rates of clinically meaningful synergy and rapid enhancement of in vitro bactericidal activity against the difficult-to-treat Enterobacteriaceae (i.e., Serratia, Citrobacter, Enterobacter, Providencia, and indole-positive Proteus species). This effect, without any evidence of antagonism, has been reported even for strains moderately or completely resistant to the former antibiotics. Unsatisfactory and unpredictable synergistic interactions against both resistant and susceptible strains of Pseudomonas aeruginosa--the most difficult nosocomial pathogen to treat--have been noted with combinations of tobramycin or gentamicin plus cefotaxime, moxalactam, or cefoperazone. Conversely, the use of amikacin plus various beta-lactams against multi-resistant strains is more frequently synergistic. Agents have been observed to exhibit such synergy in the following order of activity, from most to least synergistic: ceftazidime, ceftriaxone, moxalactam, aztreonam, cefotaxime, azlocillin, cefoperazone, cefsulodin, and carbenicillin. The combination of amikacin plus imipenem or ciprofloxacin against strains of P. aeruginosa resistant to the former and moderately resistant to the latter was recently reported to have a low probability of synergy; the combination of two of the newer beta-lactams had mostly an unpredictable or even antagonistic result. In vitro studies have also demonstrated that high concentrations of the antipseudomonal penicillins can inactivate the aminoglycosides. Among the latter compounds, the inactivation order, from most to least inactivated, was as follows: tobramycin, gentamicin, netilmicin, and amikacin. To date, the reports of aminoglycoside inactivation by the newer cephalosporins have been rather contradictory; only moxalactam has been shown produce a significant decrease in activity.

Amikacin↗
PubMed1989

Intravenous ciprofloxacin as empirical treatment of febrile neutropenic patients.

A randomized study of treatment with ciprofloxacin combined with benzylpenicillin (CB) versus a standard regimen of netilmicin combined with piperacillin (NP) as first-line empiric therapy was conducted in febrile neutropenic patients. Ninety-six patients were evaluable for determination of efficacy: 50 patients received CB and 46 patients received NP. There was no significant difference between the two groups in terms of age or primary diagnosis. Overall clinical response rate at the end of therapy was 66 percent for CB and 65 percent for NP. Microbiologic assessment revealed more pathogens eradicated by CB (64 percent) and fewer persisting (4 percent) than in the NP group (52 percent eradicated, 13 percent persisting). Only 10 percent of patients in the CB group had treatment-related adverse reactions as opposed to 28 percent of the NP-treated patients; these were predominantly renal impairment and were likely to have been due to the aminoglycoside. Staphylococcus epidermidis was the most commonly isolated pathogen, accounting for 38 percent of all isolates and 30 percent of all patients in whom treatment failed. Although streptococci accounted for 18 percent of the isolated pathogens, no treatment failures or superinfections were due to these organisms. This indicates an advantage of combining ciprofloxacin with benzylpenicillin. We conclude that the CB regimen is as effective as the NP treatment and is associated with fewer side effects.

Adult↗
PubMed1987

Characteristics of gentamicin uptake in the isolated crista ampullaris of the inner ear of the guinea pig.

The characteristics of aminoglycoside uptake in the inner ear were investigated in the isolated crista ampullaris. The organ was incubated with radiolabeled gentamicin, and the stable, nonexchangeable radioactivity was considered the intracellular pool of the drug. Gentamicin was transported against a concentration gradient, and the resulting tissue to medium ratios ranged from 1.4 to 18.6. Transport was inhibited by reduction in temperature or by the addition of metabolic blockers, indicative of an energy-dependent component. The uptake system showed at least two sites, the first a high-affinity site with a dissociation constant KD = 39 nM and a capacity of n = 0.2 pmole/crista; the second had a KD = 16 microM and a capacity of n = 11 pmoles/crista. Aminoglycosides competed with uptake of gentamicin in the order netilmicin greater than or equal to neomycin greater than tobramycin, and polyamines competed in the order spermine greater than spermidine greater than putrescine; glucosamine and the basic amino acids lysine and asparagine were ineffective, excluding the participation of glucose and basic amino acid transport systems in gentamicin uptake. These results along with direct comparisons with some characteristics of putrescine uptake suggest that aminoglycoside and polyamine transport have common features in the crista ampullaris.

Animals↗
PubMed1994

Computation of drug concentrations in endocardial vegetations in patients during antibiotic therapy.

The treatment of endocarditis often requires prolonged antibiotic therapy. Individualized drug dosage regimens have made such therapy possible even in patients with impaired renal function. However, the problem of efficacy remains. Especially for aminoglycosides, it would be a useful guide to have at least an approximate idea of the concentration of an antibiotic within an endocardial vegetation. This study was designed to develop software to model the drug concentrations at different layers within spherical vegetations to provide a guide during clinical therapy of patients with endocarditis. A general model describing the diffusion of antibiotics in spheres has now been developed and interfaced with the USC*PACK PC Clinical Programs in order to compute and plot concentrations, within the vegetation, based on the regimen given to the patient and the diffusitivity of the antibiotic into the vegetation. Some preliminary results of this research, which are still in progress, are presented. Diffusion into simulated spherical vegetations has been computed for different treatment regimens for endocarditis: amikacin or netilmicin and vancomycin were given to three elderly patients (3 women, 74, 75 and 92 years old, with initial estimated creatinine clearances of 51, 36, and 31 ml/min/1.73 m2, respectively). Although Amikacin has a low diffusivity, the concentrations, even in the center of the vegetation, appear to be effective. The effects of various regimens, including a 'once-a-day' aminoglycoside regimen, are presented.

Aged↗
PubMed1985

Enhanced survival in antibiotic-treated murine fecal peritonitis by administration of copovithane, a selective immunostimulative polymer.

The purpose of this study was to determine the effect of an immunostimulative polymer, Copovithane (Cpv), plus antibiotics (netilmicin and clindamycin) in a murine model of fecal peritonitis. Cpv augments humoral immunity with little effect on T cells and is nontoxic. Cpv 100 mg/kg iv administered at the onset of sepsis increased median survival time (MST) by 40-55% over untreated controls. Four experiments were performed. Cpv in combination with antibiotics when given at the time of onset of sepsis was significantly more effective than antibiotics alone (MST 235 vs 105 hr, P less than 0.05 at 144, 168, 192, 216 hr). In the second and third experiments Cpv alone and with antibiotics was administered 15 hr after the onset of sepsis. Cpv significantly augmented survival over controls in the second experiment (MST 87 vs 60 hr, P less than 0.025 at 96 hr). Cpv plus antibiotics was significantly better than antibiotics alone in the third experiment (MST 111 vs 64 hr, P less than 0.05 at 72 hr, P less than 0.005 at 120 hr). In the final experiment, Cpv did not inhibit growth of 20 bacterial species in agar and liquid media. Cpv significantly enhances survival in murine fecal peritonitis even when administered after the onset of sepsis; furthermore Cpv plus antibiotics in established peritonitis produces longer survival than antibiotics alone. Synthetic immunomodulators such as Cpv could eventually play a significant role in the management of peritoneal infection in humans.

Animals↗
PubMed1989

Development of lipofuscin-like fluorescence in the retinal pigment epithelium in response to protease inhibitor treatment.

Experiments were conducted to determine whether photoreceptor outer segment components contain precursors for lipofuscin fluorophores that accumulate in the retinal pigment epithelium (RPE) during senescence. Intravitreal injection of the lysosomal protease inhibitor leupeptin caused a rapid accumulation of inclusions with lipofuscin-like autofluorescence in the RPE of albino rats. These inclusions appeared to be derived from photoreceptor outer segments, which are normally phagocytosed and degraded by the RPE. The tripeptide leu-gly-gly, which is similar to leupeptin except that it does not inhibit proteolysis, had no effect on RPE autofluorescent pigment content. Likewise, netilmicin, a purported inhibitor of lysosomal phospholipases, did not enhance autofluorescent pigment deposition in the RPE. These findings are consistent with other experiments suggesting that RPE age-pigment fluorophores are derived from molecular components of the photoreceptor outer segments. The effect of leupeptin suggests that outer segment proteins may be among the precursors for these fluorophores. The RPE appears to differ from other cell types that accumulate lipofuscin in that the majority of the precursors for this pigment in the RPE are taken up by phagocytosis rather than being generated within the cells themselves.

Aging↗
PubMed1980

Course of gentamicin nephrotoxicity.

Metabolic balance and morphologic studies were performed on rats receiving gentamicin 100 mg/kg/day for a period of 8--10 days and during the recovery period. Daily urine flow rate increased with the administration of gentamiccin and remained elevated up to 20 days following the discontinuation of gentamicin, although BUN and plasma creatinine were virtually normal 10 days after the discontinuation of gentamicin. During the development of renal failure means daily electrolyte excretion remained normal. During the recovery period, however, sodium and potassium excretion exceeded control values while chloride and net acid excretion remained normal. Proteinuria developed during the administration of gentamicin and returned to normal 6--10 days after the discontinuation of gentamicin. Ten days of netilmicin administration (150 mg/kg/day) resulted in only mild tubular degeneration and no azotemia.

Animals↗
PubMed1994

The non-aqueous titrimetric assay of selected antibiotics using tetra-N-butylammonium hydroxide as titrant.

This study was carried out to develop a potentiometric titration method in non-aqueous media for the determination of some commonly used antibiotics. For this purpose, five antibiotics, namely ampicillin, amoxycillin trihydrate, rifampin, netilmicin sulphate and ciproflaxacin hydrochloride, were potentiometrically titrated using pyridine as solvent and tetrabutylammonium hydroxide as titrant, at 25 degrees C and under a nitrogen atmosphere. The method was found to be highly accurate and precise having a relative standard deviation of less than 1.0%. Also it was shown that the method could be successfully applied to assay of commercial pharmaceuticals containing the above-mentioned antibiotics. The results of recovery studies for standard additions in pharmaceutical preparations were satisfactory. The proposed method is simple, rapid and sufficiently precise for quality control purposes.

Amoxicillin↗
PubMed1994

In vitro synergism of ceftriaxone combined with aminoglycosides against Pseudomonas aeruginosa.

The antipseudomonal activities of ceftriaxone (CEF) or ceftazidime (CAZ), each combined with tobramycin (TOB) or netilmicin (NET), against 90 clinically significant Pseudomonas aeruginosa isolates were examined both by checkerboard and time-kill assays. As expected, susceptibility testing of single antibiotics by agar dilution demonstrated good activity for CAZ (89% susceptible), TOB (94%), and NET (58%), but poor activity for CEF (15%). Checkerboard studies revealed striking synergy (FIC indices < or = 0.5) for CEF, however, in combination with either TOB (72%) or NET (81%), compared with CAZ-TOB (44%) or CAZ-NET (60%) (P < 0.01, respectively). No antagonism (FIC indices > or = 4) was found in any of these combinations. The MIC90s of CEF, CAZ, or aminoglycosides in the combinations were reduced at least fourfold: CEF, from > 128 to 32 mg/liter; CAZ, from 16 to 4 mg/liter; TOB, from 4 to 0.5 mg/liter; and NET, from 32 to 4 mg/liter. With CEF and NET, the percentage of strains sensitive to < or = 8 mg/liter of both drugs alone and in combination increased from 9% to 69%. Results of the time-kill assay for CEF-NET agreed reasonably well with the checkerboard method (Spearman rank correlation coefficient, 0.40, P < or = 0.01), and generated a bactericidal outcome in 60% (24 of the 40 isolates), when tested with combinations at 1/4 MBC of either antibiotic alone. Importantly, concentrations of CEF and aminoglycoside combinations that demonstrated synergy by either checkerboard or time-kill assays were achievable in serum clinically. These data suggest a unique interaction of CEF-aminoglycoside combinations against P. aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceftazidime↗
PubMed1996

[Pneumococcal meningitis in children: should probabilistic antibiotherapy of infectious meningitis be modified?].

BACKGROUND: Since a significant proportion of Streptococcus pneumoniae strains is now resistant to penicillin and sometimes to third-generation cephalosporin, it is necessary to reevaluate the initial therapy of bacterial meningitis proposed before identification of the organism and its susceptibility pattern. POPULATION: From 1 January 1992 to 31 March 1994, nine children with acute S pneumoniae meningitis were treated with ceftriaxone plus aminoglycoside as conventional initial therapy. Eight children were less than 1 year-old (five from 3 to 6 months). Five S pneumoniae strains were penicillin-resistant; four had a ceftriaxone minimal inhibitory concentration (MIC) of 0.047 to 0.094 mg/L and one of 1.5 mg/L. Ceftriaxone was given intravenously at doses of 50 mg/kg twice a day to patients less than 12 months old and 100 mg/kg once a day to patients older than 12 months. Intravenous amikacin (7.5 mg/kg twice daily) or netilmicin (3 mg/kg twice daily) were administered in combination. Dexomethasone was given to all children as adjunctive therapy. Follow-up lumbar puncture was performed after 24 to 36 hours of treatment. RESULTS: For each of the nine patients, cerebrospinal fluid was sterile with normal glucose level. After 2 or 4 days, initial therapy had been modified according to antibiogram and MIC. Monotherapy with ceftriaxone was continued in five children. Rifampicin was associated with initial bitherapy in one case. In two other patients, initial empiric therapy was stopped and changed to chloramphenicol. CONCLUSION: No case of bacteriological failure was noted in our patients but evolution of epidemiology and emergence of decreased penicillin sensibility in S pneumoniae strains (55% in our study) suggests that a third antibiotic (vancocin or rifampicin) should be associated with the standard first-line drug when S pneumoniae is suspected.

Adolescent↗
PubMed2005

Short antibiotic prophylaxis for bacterial infections in a neonatal intensive care unit: a randomized controlled trial.

We compared the effectiveness of a single dose and a three-day course of antibiotic prophylaxis in preventing bacterial infections in high-risk neonates. The study was a prospective, randomized controlled trial conducted in a 20-bed tertiary referral neonatal intensive care unit (NICU). A series of 130 neonates admitted consecutively to the NICU, fulfilling risk factors for infection, were assigned at random to receive intravenous antibiotic prophylaxis with ampicillin and netilmicin either in two daily doses for 72 h (three-day-administration group, 67 infants) or in a single bolus injection on admission (bolus group, 63 infants). Hospital-acquired infection, the main outcome measure, was defined as infection that developed at least 48 h after admission, and vertical infection (maternally transmitted) was considered to be present when clinical symptoms and abnormal laboratory findings became evident within 48 h of birth. Infections were considered as suspected when clinical and laboratory findings of infection were present, without positive cultures, and as confirmed when positive cultures were also present. No significant differences were found between the two groups of neonates studied in mean birth weight, gestational age or postnatal age on admission. The incidence of vertical infection was similar in the two groups (16/67, 23.9% vs. 14/63, 22.2%). Of the 130 newborns studied, 29 (22.3%) acquired at least one nosocomial infection during their NICU stay; total hospital-acquired infections, calculated as the incidence density of infection (the number of infective episodes divided by the number of days in the NICU), were less frequent among newborns who received the three-day course than the bolus (relative risk 0.69). This difference, although not statistically significant, depended on the different incidence density of confirmed nosocomial infections rather than on suspected infections (relative risk 0.59; 95% confidence interval 0.32-1.09; P=0.1). There were no significant differences between the two groups in overall mortality. A single bolus administration on admission is therefore likely to be as effective as a three-day course of antibiotic prophylaxis in preventing bacterial infection in high-risk infants admitted to an NICU.

Ampicillin↗
PubMed1996

Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia.

PURPOSE: A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients. PATIENTS AND METHODS: A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored. RESULTS: Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor. CONCLUSIONS: Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.

Adolescent↗