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PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

Fundamental and clinical studies have been performed on BRL 25000 (clavulanic acid 1 part-amoxicillin 2 parts) granules in the pediatric field. The antibacterial activities of BRL 25000 and amoxicillin (AMPC) were investigated against clinically isolated and laboratory stocked strains. BRL 25000 was superior to AMPC against strains of E. coli, Salmonella sp. and Klebsiella sp., and similar against Gram-positive cocci. Serum concentrations of AMPC and clavulanic acid (CVA) were measured 0.25, 0.5, 1, 2, 4 and 6 hours after administration of BRL 25000 granules at dose levels of 7.5, 10, 15 and 20 mg/kg. At 7.5 mg/kg peak level of AMPC of 2.69 micrograms/ml was achieved about 2 hours after dosing with a biological half-life of 1.64 hours; corresponding value for CVA was 0.53 micrograms/ml at 1 hour with a T 1/2 of 1.46 hours. At 10 mg/kg, AMPC also peaked after 2 hours (3.82 micrograms/ml) and the T 1/2 was 1.63 hours, whilst for CVA the value was 0.56 micrograms/ml with a T 1/2 of 1.24 hours. Value for AMPC at 15 mg/kg was 5.18 micrograms/ml at 1 hour post dose with a T 1/2 of 1.48 hours, and for CVA 4.01 micrograms/ml at 1 hour with a T 1/2 of 0.89 hour. At the highest dose of 20 mg/kg, AMPC level reached 4.21 micrograms/ml after 2 hours with a T 1/2 of 2.39 hours, and the CVA peak was 1.64 micrograms/ml at 1 hour with a T 1/2 of 1.01 hours. The 6 hours urinary recovery of AMPC and CVA following administration of the BRL 25000 granules ranged from 38-64% and 2-33%, respectively. In the clinical studies, the BRL 25000 granules are administered to 15 cases with pediatric infections and the clinical response was excellent or good in all cases treated (100%). Bacteriological investigation was performed on 13 strains from 12 cases and all strains were eradicated (100%). Regarding side effects, elevation of eosinophil was observed in 1 case and vomiting in 3 cases.

Administration, Oral↗
PubMed1985

Clavulanic acid-potentiated activity of amoxicillin against Bacteroides fragilis.

Seventy-seven clinical isolates of Bacteroides fragilis from animal sources were examined for beta-lactamase production and resistance to amoxicillin. Sixty-five (84%) of the isolates produced detectable amounts of beta-lactamase. Concentrations of amoxicillin greater than 8 micrograms/ml were required to inhibit all but 13 (17%) of the isolates evaluated. Clavulanic acid, a beta-lactamase inhibitor, minimally inhibited growth of B fragilis when used alone. However, a synergistic effect was found when amoxicillin and clavulanic acid were used together against B fragilis. Ninety-nine percent of the isolates were inhibited by concentrations of 1 microgram of amoxicillin/ml in combination with 0.5 microgram of clavulanic acid/ml.

Amoxicillin↗
PubMed1985

[Experimental and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the field of pediatrics].

BRL 25000 granules, a formulation consisting of amoxicillin (AMPC) and clavulanic acid (CVA), was evaluated in the field of pediatrics. In a pharmacokinetic study, serum concentrations were determined in a patient after oral administration of BRL 25000 granules in the non-fasting state at a dose of 11.76 mg/kg. The serum levels of amoxicillin (AMPC) and clavulanic acid (CVA) 1 hour after administration were 7.76 micrograms/ml and 6.64 micrograms/ml, with biological half-lives of 0.86 hour and 0.88 hour respectively. The serum concentration profile at a dose of 31.58 mg/kg showed almost the same tendency as at 11.76 mg/kg, although the peak level and biological half-life of the serum concentrations were not obtained. These serum levels and their peak levels were considered reasonable compared with those obtained in adults at similar dose levels. In clinical studies, 34 patients were evaluated including 8 patients with acute pharyngitis or acute tonsillitis, 1 patient with acute bronchitis, 1 patient with bronchopneumonia, 23 patients with scarlet fever and 1 patient with pertussis. BRL 25000 granules were administered orally 3-4 times per day for 4-8 days to 2 patients at doses of 20 approximately less than 30 mg/kg/day, to 18 patients at doses of 30 approximately less than 40 mg/kg/day, to 11 patients at doses of 40 less than approximately 50 mg/kg/day, and to 3 patients at doses of 50-60 mg/kg/day. The clinical response was assessed excellent in 13 cases and good in 21 cases giving an overall clinical efficacy rate of 100% (34/34). The causative organisms were isolated in 17 cases and included 12 strains of Streptococcus group A, 2 S. pneumoniae, 3 H. influenzae and 1 H. parainfluenzae.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

[Clinical evaluation of Augpenin (clavulanic acid-ticarcillin) in urinary tract infections: especially against beta-lactamase producing strains].

Augpenin contains ticarcillin (TIPC) and clavulanic acid (CVA), at a ratio of 15:1. The beta-lactamase inhibitor, CVA, has been added to protect the TIPC from inactivation by beta-lactamase. To investigate the drug efficacy and safety against urinary tract infections (UTI), Augpenin was administered to 33 patients with chronic complicated UTI and 7 patients with acute pyelonephritis. Thirty two cases were evaluable by the UTI criteria. Excellent results were obtained in 6 of the cases of acute pyelonephritis, and moderate results in 1 case, with an overall effectiveness rate of 100%. Excellent results were obtained in 14 of the cases of chronic complicated UTI, moderate results in 9 cases, and poor results in 2 cases, with an overall effectiveness rate of 92%. No adverse reactions were noted, but a transient elevation of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels was observed in 2 cases.

Adolescent↗
PubMed2000

[Evolution of antimicrobial susceptibility of Acinetobacter baumannii clinical isolates].

Acinetobacter baumannii is a microorganism frequently implicated in colonization and infection in hospitalized patients. An increase of resistance has been observed in recent years making these infections difficult to treat. The in vitro activity of 24 antibiotics, 15 betalactam agents and nine nonbetalactams, was studied in 156 A. baumannii clinical isolates. The strains were collected from different clinical samples obtained from inpatients (92%) and 8% were from outpatients. Evolution of susceptibility from January 1995 to December 1997 was studied. MIC of the following antibiotics was determined by the agar dilution method: ampicillin, ticarcillin, piperacillin, ampicillin-sulbactam, amoxicillin- clavulanic acid, ticarcillin-clavulanic acid, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, meropenem, clavulanic acid, sulbactam, tazobactam, amikacin, gentamicin, tobramycin, ofloxacin, doxycycline, fosfomycin, rifampin, azithromycin and colistin. Low antimicrobial susceptibility was observed in most A. baumannii strains. Colistin, imipenem, meropenem and ampicillin-sulbactam showed the greatest susceptibility (100, 88.4, 88.4 and 84.6%, respectively). A. baumannii strains from inpatients showed a lower antimicrobial susceptibility than strains from outpatients, who showed a high percentage of susceptibility to most antibiotics. Rifampin and azithromycin showed certain in vitro activity against the most susceptible A. baumannii strains. A progressive decrease in susceptibility to most antibiotics was observed during the period studied. Carbapenem-resistant A. baumannii emerged in 1996 and increased in 1997.

Acinetobacter↗
PubMed1987

Pharmacokinetics of clavulanic acid-potentiated ticarcillin in renal failure.

The serum kinetics of an intravenous bolus of a combination of ticarcillin (TIC) (3 g) and clavulanic acid (CLAV) (0.2 g) have been determined in a number of patients with different degrees of renal failure as characterized by creatinine clearance. The volume of distribution for both drugs was unaffected by renal failure. Indices of serum and renal drug clearance were related to the degree of renal failure. TIC was cleared more slowly than CLAV. Anephric patients may have a higher serum clearance of CLAV than patients categorized by creatinine clearance as having severe renal failure; this could be due to an increase in metabolic clearance. Haemodialysis effectively clears both drugs. "Rebound" serum concentrations were consistently observed for TIC, but were observed in only one patient for CLAV. Continuous ambulatory peritoneal dialysis results in significant recovery of both drugs. The dosing requirements for the combination of TIC and CLAV in patients with renal failure are considered.

Adolescent↗
PubMed1999

In vitro efficacy of beta-lactam/beta-lactamase inhibitor combinations against bacteria involved in mixed infections.

Mixed infections are usually caused by a relatively limited range of bacteria, with the anaerobes and opportunistic pathogens contributing to their severity. In order to make the best therapeutic choice for a patient with a life-threatening infection, which is probably of mixed etiology, clinicians must be aware of the organisms that are likely to be involved, and the fact that most of them will produce beta-lactamase. Of the options available for empiric therapy, the beta-lactam/beta-lactamase inhibitor combinations represent a good choice. Their antibacterial spectra include both aerobic and anaerobic pathogens. Five combinations are available in clinical practice: ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanic acid, amoxicillin-clavulanic acid, and cefoperazone-sulbactam. More strains of clinically important anaerobic bacteria are susceptible to ampicillin-sulbactam than to either piperacillin-tazobactam or ticarcillin-clavulanic acid, which are also available widely and suitable for more life-threatening infections. In addition, sulbactam itself has the highest intrinsic activity of the beta-lactamase inhibitors against the opportunistic pathogen, Acinetobacter baumannii. Thus, ampicillin-sulbactam could be considered a drug of choice for the empirical treatment of mixed infections where there is a reasonable possibility of the presence of A. baumannii.

Anti-Bacterial Agents↗
PubMed1987

beta-Lactamase of Pseudomonas pseudomallei and its contribution to antibiotic resistance.

beta-Lactamase production was examined in nine strains of Pseudomonas pseudomallei isolated from human, animal and environmental sources in Thailand and Hong Kong. All produced the same weakly inducible, membrane associated chromosomal cephalosporinase, which had a molecular weight of 29,500 and an isoelectric point of 7.4-7.7. The enzyme resembled the cefuroximases of Ps. cepacia and Proteus vulgaris, but differed from the Class I cephalosporinases typical of Ps. aeruginosa and most enterobacteria, in being strongly active against carbenicillin, cefotaxime and cefuroxime and in being inactivated readily by clavulanic acid. Synergy experiments with clavulanic acid investigated the enzyme's contribution to antibiotic resistance, and these results broadly correlated with those of in-vitro hydrolysis assays. Thus, ampicillin, carbenicillin, cefoperazone, cefotaxime, cefuroxime and cephalothin, which were hydrolysed in vitro, were potentiated four to 64-fold by 2 mg/l clavulanic acid; but cefoxitin, ceftazidime, cloxacillin and imipenem, which appeared stable in vitro, were potentiated four-fold or less.

Animals↗
PubMed1985

Penetration of sulbactam-ampicillin and clavulanic acid-amoxicillin into the pelvic peritoneum.

Sixteen patients were given single intravenous injections of ampicillin (0.5 g) with sulbactam (0.5 g), and 15 patients were given amoxicillin (1 g) with clavulanic acid (0.2 g) before elective laparoscopy. At 2 h after dosing, the concentrations of the four compounds in serum and in the peritoneal fluid from the Pouch of Douglas and the ratio of each combination reached levels shown to be effective for antimicrobial activity in vitro.

Adult↗
PubMed1997

OXA-18, a class D clavulanic acid-inhibited extended-spectrum beta-lactamase from Pseudomonas aeruginosa.

Clinical isolate Pseudomonas aeruginosa Mus showed resistance both to extended-spectrum cephalosporins and to aztreonam. We detected a typical double-disk synergy image when ceftazidime or aztreonam was placed next to a clavulanic acid disk on an agar plate. This resistance phenotype suggested the presence of an extended-spectrum beta-lactamase. Isoelectric focusing revealed that this strain produced three beta-lactamases, of pI 5.5, 7.4, and 8.2. A 2.6-kb Sau3A fragment encoding the extended-spectrum beta-lactamase of pI 5.5 was cloned from P. aeruginosa Mus genomic DNA. This enzyme, named OXA-18, had a relative molecular mass of 30.6 kDa. OXA-18 has a broad substrate profile, hydrolyzing amoxicillin, ticarcillin, cephalothin, ceftazidime, cefotaxime, and aztreonam, but not imipenem or cephamycins. Its activity was totally inhibited by clavulanic acid at 2 microg/ml. Hydrolysis constants of OXA-18 (Vmax, Km) confirmed the MIC results. Cloxacillin and oxacillin hydrolysis was noticeable with the partially purified OXA-18. The blaOXA-18 gene encodes a 275-amino-acid protein which has weak identity with all class D beta-lactamases except OXA-9 and OXA-12 (45 and 42% amino acid identity, respectively). OXA-18 is likely to be chromosomally encoded since no plasmid was found in the strain and because attempts to transfer the resistance marker failed. OXA-18 is peculiar since it is a class D beta-lactamase which confers high resistance to extended-spectrum cephalosporins and seems to have unique hydrolytic properties among non-class A enzymes.

Amino Acid Sequence↗
PubMed1989

Bactericidal effects of amoxycillin/clavulanic acid against Legionella pneumophila.

The antibacterial activities of amoxycillin, clavulanic acid and the combination of both agents against Legionella spp. were compared in serial-dilution tests, time-kill curve studies and in turbidimetric studies in a continuous recording biophotometer. Both beta-lactam compounds showed high levels of activity against L. pneumophila in serial dilution tests, clavulanic acid (MIC 0.1-0.25 mg/l) being two-fold more active than amoxycillin. The combination of amoxycillin and clavulanic acid was more effective than either of the constituents and was two to four times more active than erythromycin. Clavulanic acid was shown to reduce the extent of inactivation of amoxycillin by L. pneumophila and amoxycillin/clavulanic acid was rapidly bactericidal against the organism in tests in which amoxycillin was ineffective. Microscopical examination showed distinctive morphological effects produced by amoxycillin and by clavulanic acid and synergy between the compounds could be attributed to beta-lactamase inhibition, or by binding to different penicillin binding proteins, or both. These results warrant further studies in vitro and in vivo to elaborate the bactericidal effects demonstrated by amoxycillin and clavulanic acid against Legionella spp.

Amoxicillin↗
PubMed1998

[Importance of the association ticarcillin-clavulanic acid-amikacin in the treatment of severe urinary infections after major urodigestive surgery. Report of 59 cases].

Ticarcillin-clavulanic acid (Claventin) and amikacin were administered in an open study to prevent and treat nosocomial urinary tract infections, to 59 patients after major urological surgery. Postoperative course was event-free in 44 cases. 10 patients presented asymptomatic urinary tract infections due to gram negative bacilli, that did not require any change in antimicrobial therapy. 5 patients experienced symptomatic nosocomial infections, whose one was associated with a methicillin-Resistant Staphylococcus aureus septicemia that was treated by vancomycin. The urinary tract infections were polymicrobial in only 3 cases. The tolerance was quite satisfactory, and the protocol was effective in about 92% of cases. The combination of ticarcillin-clavulanic acid-amikacin is valuable and can be used as first step therapy to preserve the ecology of the patients.

Adult↗
PubMed2003

Characterization of clinical isolates of Enterobacteriaceae from Italy by the BD Phoenix extended-spectrum beta-lactamase detection method.

Production of extended-spectrum beta-lactamases (ESBLs) is an important mechanism of beta-lactam resistance in Enterobacteriaceae: Identification of ESBLs based on phenotypic tests is the strategy most commonly used in clinical microbiology laboratories. The Phoenix ESBL test (BD Diagnostic Systems, Sparks, Md.) is a recently developed automated system for detection of ESBL-producing gram-negative bacteria. An algorithm based on phenotypic responses to a panel of cephalosporins (ceftazidime plus clavulanic acid, ceftazidime, cefotaxime plus clavulanic acid, cefpodoxime, and ceftriaxone plus clavulanic acid) was used to test 510 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Providencia stuartii, Morganella morganii, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Citrobacter freundii, and Citrobacter koseri. Of these isolates, 319 were identified as ESBL producers, and the remaining 191 were identified as non-ESBL producers based on the results of current phenotypic tests. Combined use of isoelectric focusing, PCR, and/or DNA sequencing demonstrated that 288 isolates possessed bla(TEM-1)- and/or bla(SHV-1)-derived genes, and 28 had a bla(CTX-M) gene. Among the 191 non-ESBL-producing isolates, 77 isolates produced an AmpC-type enzyme, 110 isolates possessed TEM-1, TEM-2, or SHV-1 beta-lactamases, and the remaining four isolates (all K. oxytoca strains) hyperproduced K1 chromosomal beta-lactamase. The Phoenix ESBL test system gave positive results for all the 319 ESBL-producing isolates and also for two of the four K1-hyperproducing isolates of K. oxytoca. Compared with the phenotypic tests and molecular analyses, the Phoenix system displayed 100% sensitivity and 98.9% specificity. These findings suggest that the Phoenix ESBL test can be a rapid and reliable method for laboratory detection of ESBL resistance in gram-negative bacteria.

Algorithms↗
PubMed2004

Resistance rates to commonly used antimicrobials among pathogens of both bacteremic and non-bacteremic community-acquired urinary tract infection.

This study examined the distribution of organisms and their antimicrobial resistance in patients admitted due to acute bacteremic and non-bacteremic community-acquired urinary tract infection (UTI). During a period of 1 year and 1 month, a total of 201 patients and 253 bacterial isolates were studied. Fever higher than 38.5 degrees C was significantly more common in the bacteremic group than the non-bacteremic group (68% vs 48%; p<0.05). Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis were the most common organisms isolated. E. coli was the leading pathogen and it was significantly more predominant in bacteremic UTI than non-bacteremic UTI (73% vs 49%; p<0.01). Bacteria other than E. coli (i.e., K. pneumoniae, P. aeruginosa, Proteus spp., Morganella morganii, Enterobacter cloacae, Citrobacter spp., Acinetobacter baumannii, Serratia marcescens, and Providencia spp.) were more common in non-bacteremic UTI than bacteremic UTI (44% vs 22%; p<0.01). E. coli isolated from both bacteremic and non-bacteremic patients had a high rate of resistance to ampicillin (80%), cephalothin (59%), gentamicin (29%), piperacillin (61%), trimethoprim-sulfamethoxazole (56%), amoxicillin-clavulanic acid (34%), and ticarcillin-clavulanic acid (36%). Isolates of P. aeruginosa, K. pneumoniae, and Proteus spp. from the non-bacteremic group showed a higher proportion of resistance to extended-spectrum cephalosporins, aminoglycosides (netilmicin and amikacin) and ciprofloxacin. The emergence of a high rate of resistance to commonly used antimicrobials (ampicillin, cephalothin, gentamicin, trimethoprim-sulfamethoxazole, piperacillin, amoxicillin-clavulanic acid and ticarcillin-clavulanic acid) may have an impact on the antibiotic treatment of patients admitted due to acute community-acquired bacteremic or non-bacteremic UTI in Taiwan. Further studies are needed to clarify the impact of antimicrobial resistance on the outcome in these conditions.

Adult↗
PubMed1989

Bactericidal effects of amoxycillin/clavulanic acid against intracellular Legionella pneumophila in tissue culture studies.

The bactericidal effects of amoxycillin, clavulanic acid and amoxycillin plus clavulanic acid were determined against Legionella pneumophila growing intracellularly in MRC-5 human fetal lung fibroblast cells. The strain of L. pneumophila was shown to be growing within the cells by transmission electron microscopy and this was confirmed by the results of bactericidal tests in which gentamicin was shown to be ineffective in preventing growth of the organism in the tissue culture system. Amoxycillin failed to prevent infection of the cell monolayers and had no effect on the growth of intracellular L. pneumophila. Transmission electron microscopy showed the presence of large numbers of bacteria of normal morphology within the fibroblasts. In contrast, clavulanic acid and amoxycillin/clavulanic acid protected the cell sheets from the effects of infection with L. pneumophila and reduced the numbers of intracellular bacteria to the same extent as erythromycin. Also, bacteria of abnormal morphology were observed within fibroblast cells of the cultures treated with clavulanic acid and the combination. These data demonstrate the penetration of clavulanic acid, when used alone or in the presence of amoxycillin, into cells infected with L. pneumophila and the resulting bactericidal activity of the agents against intracellular bacteria.

Amoxicillin↗
PubMed1985

[Bacteriological and clinical evaluation of BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

Bacteriological and clinical evaluations of BRL 25000 (1 part clavulanic acid plus 2 parts amoxicillin) granules in the pediatric field have been performed. The MICs of BRL 25000 against 25 clinically isolated strains of S. aureus, 40 E. coli, and 14 K. pneumoniae were compared with those of AMPC. Against beta-lactamase non-producing strains of S. aureus and E. coli, the MICs of both drugs were nearly equal, however, against beta-lactamase producing strains of these species and K. pneumoniae, BRL 25000 was superior to AMPC. The blood levels of AMPC and CVA after single oral administration of approximately 15 mg/kg of BRL 25000 granules to fasted children were studied in 3 subjects. The mean levels of AMPC and CVA peaked about 1 hour after administration at values of 11.40 and 5.49 micrograms/ml, respectively, with half-lives of 0.91 and 1.02 hours, and AUCs of 23.52 and 12.66 hr X micrograms/ml, respectively. The 6-hour urinary recovery of AMPC ranged from 30.59% to 52.03% and for CVA from 16.31% to 45.18%. There was no significant difference between the blood level of AMPC following single oral administration of approximately 10 mg/kg AMPC granules and that of AMPC following single oral administration of approximately 15 mg/kg BRL 25000 granules to the same children. Clinical evaluation of BRL 25000 granules administered orally 3-4 times a day at total daily doses of between 42.9-52.9 mg/kg resulted in improvement, judged excellent or good, in all 7 cases of tonsillitis and 2 cases of pyelonephritis. In particular, the clinical effect was excellent in the case of tonsillitis where a beta-lactamase producing H. influenzae was isolated. In the total 11 cases treated, including 2 cases of mycoplasmal pneumonia excluded from the clinical evaluation, 1 case of rash and eosinophilia was observed. No other adverse reactions or abnormal laboratory findings were observed. The taste and flavor of the drug were well accepted by the children. It was concluded that BRL 25000 granules are promising new drug which should be markedly useful in the treatment of infections in pediatric outpatients.

Administration, Oral↗
PubMed1995

Pharmacokinetic-based ticarcillin/clavulanic acid dose recommendations for infants and children.

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

Child↗