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PubMed1993

Papillon Lefevre syndrome: treatment of two cases with a clinical microbiological and histopathological investigation.

Papillon Lefevre syndrome is presented in the cases of two female patients of the ages of 7 and 9, who exhibited all typical symptoms of the disease. Microbiological and histopathological studies were done and treatment provided. Actinobacillus actinomycetemcomitans, which is suspected as a pathogenic factor in the disease was identified as well as some other gram negative microorganisms and an antibiogram was performed in which amoxycillin plus clavulanic acid was most effective. Histopathological investigation also confirmed the presence of gram negative bacteria. Granular cell infiltration was predominant in the surface epithelium. Prosthetic appliances were provided for the patients after mechanical and chemical plaque control. In addition to this, antibiotics (amoxycillin plus clavulanic acid) were prescribed every six months. No tooth loss was observed in both patients after more than two years follow-up period. At the moment only one patient is under review and because she is uncooperative, mild periodontal inflammation is still present around the teeth which erupted before the antibiotic regime, but not in the other teeth.

Aggregatibacter actinomycetemcomitans↗
PubMed1988

Evaluation of MicroScan MIC panels for detection of oxacillin-resistant staphylococci.

Clinical isolates of staphylococci (420 Staphylococcus aureus isolates and 248 coagulase-negative staphylococci) were tested by both MicroScan MIC panels (MicroScan, West Sacramento, Calif.) and an oxacillin agar screen (Mueller-Hinton agar [Difco Laboratories, Detroit, Mich.] containing 6 micrograms of oxacillin per ml and 4% NaCl) to evaluate the ability of MicroScan to detect oxacillin-resistant strains. MicroScan panels and oxacillin agar screen plates were incubated at 35 degrees C for 24 h and at 30 degrees C for an additional 24 h. Endpoints were recorded at 24 and 48 h. By MicroScan, 23 (5.5%) and 30 (7%) S. aureus isolates and 161 (65%) and 162 (65%) coagulase-negative staphylococci were oxacillin resistant at 24 and 48 h, respectively. At both 24 and 48 h, 23 (5.5%) S. aureus isolates and 162 (65%) coagulase-negative staphylococci were resistant by the oxacillin agar screen. Five strains for which the oxacillin MIC was 2 or 4 micrograms/ml and eight strains resistant to oxacillin only at 48 h were further evaluated by broth macrodilution testing for oxacillin with and without clavulanic acid, by oxacillin and amoxicillin-clavulanic acid disk diffusion, and by oxacillin agar screen comparing Mueller-Hinton agars purchased from Difco and BBL Microbiology Systems, Cockeysville, Md. By this additional testing, all 10 S. aureus isolates and 1 of 3 coagulase-negative staphylococci examined produced increased amounts of beta-lactamase. One coagulase-negative staphylococcus appeared to be truly intermediately oxacillin susceptible. There was no significant difference in the rate of detection of oxacillin resistance between MicroScan and the agar screen. MicroScan panels should be incubated for 24 h only, because prolonged incubation caused strains producing excessive amounts of beta-lactamase to appear to be falsely oxacillin resistant.

Coagulase↗
PubMed1991

A randomized trial of ticarcillin and clavulanate versus gentamicin and clindamycin in patients with complicated appendicitis.

Secondary bacterial peritonitis is usually a polymicrobial infection of facultative gram-negative aerobic and anaerobic organisms. Treatment consists of operation and broad-spectrum antibiotic administration. The antibiotic treatment of choice in these infections has been the combination of gentamicin and clindamycin. However, this combination can have toxic side effects and necessitates frequent monitoring of serum levels. Beta-lactam antibiotics provide broad-spectrum coverage and low toxicity, but can be inactivated by species of bacteria producing beta-lactamase enzymes. Clavulanic acid is a potent inhibitor of beta-lactamases and has been shown to extend the efficacy of ticarcillin to bacteria producing these enzymes. This combination was compared with gentamicin and clindamycin in 99 consecutive patients with complicated appendicitis. Eradication of identified pathogens was greater in the ticarcillin and clavulanate group (98 per cent) than in the gentamicin and clindamycin group (92 per cent), even for the subgroup of organisms producing beta-lactamases (97 versus 90 per cent eradication). Complications and clinical response were not significantly different between the two treatment groups. Ticarcillin and clavulanic acid is a safe and effective alternative to gentamicin and clindamycin in the treatment of secondary bacterial peritonitis and offers advantages in dosing simplicity and freedom from ototoxic and nephrotoxic effects.

Abdomen↗
PubMed2005

Different proteins bind to the butyrolactone receptor protein ARE sequence located upstream of the regulatory ccaR gene of Streptomyces clavuligerus.

Cell-free extracts from Streptomyces clavuligerus, purified by elution from heparin-agarose with an ARE-containing DNA fragment or by salt elution chromatography, bind to a 26 nt ARE sequence, for butyrolactone receptor proteins (ARE(ccaR)). This sequence is [corrected] located upstream of the ccaR gene, encoding [corrected] the activator protein CcaR required for clavulanic acid and cephamycin C biosynthesis. The binding is specific for the ARE sequence as shown by competition with a 34 nt unlabelled probe identical to the ARE sequence. A brp gene, encoding a butyrolactone receptor protein, was cloned from S. clavuligerus. Sixty-one nucleotides upstream of brp another ARE sequence (ARE(brp)) was found, suggesting that Brp autoregulates its expression. Pure recombinant rBrp protein binds specifically to the ARE sequences present upstream of ccaR and brp. A brp-deleted mutant, S. clavuligerus Deltabrp::neo1, produced 150-300% clavulanic acid and 120-220% cephamycin C as compared with the parental strain, suggesting that Brp exerts a repressor role in antibiotic biosynthesis. EMSA assays using affinity chromatography extracts from the deletion mutant S. clavuligerus Deltabrp::neo1 lacked a high-mobility band-shift due to Brp but still showed a [corrected] slow-mobility band-shift observed in the wild-type strain. These results indicate that two different proteins bind specifically to the ARE sequence and modulate clavulanic acid and cephamycin C [corrected] biosynthesis by its action on ccaR gene expression.

Amino Acid Sequence↗
PubMed1985

In-vitro susceptibility of Nocardia asteroides to 21 beta-lactam antibiotics, in combination with three beta-lactamase inhibitors, and its relationship to the beta-lactamase content.

Twelve strains of Nocardia asteroides were studied for their susceptibility to 21 beta-lactam antibiotics, alone or in combination with clavulanic acid, sulbactam, or BLP 2013, and for their content of beta-lactamase. Eleven strains were shown to have beta-lactamase activities, which gave three different patterns after analytical isoelectric focusing. The only strain with no detectable beta-lactamase was the most susceptible to the antibiotics tested. The other strains containing beta-lactamases showed almost the same susceptibility profile. Clavulanic acid was the only beta-lactamase inhibitor to show a significant synergistic effect when combined with penicillins.

Anti-Bacterial Agents↗
PubMed1996

Detection of extended-spectrum beta-lactamase (ESBL)-producing strains by the Etest ESBL screen.

Resistance to contemporary broad-spectrum beta-lactams, mediated by extended-spectrum beta-lactamase (ESBL) enzymes, is an increasing problem worldwide. The Etest (AB Biodisk, Solna, Sweden) ESBL screen uses stable gradient technology to evaluate the MIC of ceftazidime alone compared with the MIC of ceftazidime with clavulanic acid (2 micrograms/ml) to facilitate the recognition of strains expressing inhibitable enzymes. In the present study, ESBL-producing strains (17 Escherichia coli transconjugants) were studied to define "sensitive" interpretive criteria for the Etest ESBL screen. These criteria (reduction of the ceftazidime MIC by > 2 log2 dilution steps in the presence of clavulanic acid) defined a group of 92 probable ESBL-positive organisms among the 225 tested strains of Klebsiella species and E. coli having suspicious antibiogram phenotypes. With a subset of 82 clinical strains, the Etest ESBL screen was more sensitive (100%) than the disk approximation test (87%) and was more convenient. The MICs of ciprofloxacin, gentamicin, and tobramycin at which 50% of isolates are inhibited were 16- to 128-fold higher (coresistance) for the ESBL screen-positive group of strains than for the ESBL screen-negative group of strains. Some strains for which cephalosporin MICs were elevated and which were Etest ESBL screen negative were also cefoxitin resistant, i.e., consistent with a chromosomally mediated AmpC resistance phenotype. The Etest ESBL screen test with the ceftazidime substrate appears to be a useful method for detecting or validating the presence of enteric bacilli potentially producing this type of beta-lactamase.

Anti-Bacterial Agents↗
PubMed1992

Does high level production of SHV-type penicillinase confer resistance to ceftazidime in Enterobacteriaceae?

We report the isolation of a clinical isolate of Klebsiella pneumoniae that showed resistance to ceftazidime (MIC: 8 micrograms/ml), susceptibility to aztreonam (MIC: 2 micrograms/ml) and cefotaxime (MIC: 0.015 micrograms/ml). A synergistic effect between clavulanic acid and ceftazidime or aztreonam against this strain was also observed. The strain hyperproduced SHV-1 penicillinase (990 U/g) which is encoded by a self-transferrable plasmid of at least 150 kb. That the ceftazidime-resistance phenotype could be due to hyperproduction of SHV-1 penicillinase is supported by the study of a spontaneous ceftazidime-resistant mutant in vitro obtained from an Escherichia coli strain containing plasmid p453 encoding the SHV-1. Indeed, this mutant hyperproducing SHV-1 (2200 U/g) was resistant to ceftazidime (MIC: 16 micrograms/ml) and aztreonam (MIC: 8 micrograms/ml) but susceptible to cefotaxime (MIC: 0.03 ng/ml). Clavulanic acid showed a synergistic effect when associated with ceftazidime or aztreonam. In contrast, the hyperproduction of TEM-1 (790 U/g) did not confer a ceftazidime- and aztreonam-resistant phenotype while hyperproduction of both TEM-1 and SHV-1 increased the resistance to amoxycillin/clavulanic acid and to cephalothin.

Ceftazidime↗
PubMed2005

Differential effects of beta-lactams on human IFN-gamma activity.

OBJECTIVES: To investigate whether a range of beta-lactam antibiotics conjugate to and hence reduce the activity of IFN-gamma, as has been shown for penicillin G. A selection of penicillins, cephalosporins, a monobactam (aztreonam), a beta-lactamase inhibitor (clavulanic acid), a carbapenem (meropenem) and the non-beta-lactam penicillin derivative d-penicillamine were tested for their effect on IFN-gamma activity. METHODS: Following exposure to a range of concentrations of these compounds, for varying lengths of time, IFN-gamma activity was assayed by induction of CD54 on the surface of the lung epithelial cell line A549, utilizing an ELISA. RESULTS: Clavulanic acid, cefoxitin and cefaloridine were the most potent inhibitors of IFN-gamma activity, followed by cefotaxime, ceftriaxone and phenoxymethylpenicillin. Ampicillin was less inhibitory than penicillin G, whilst meropenem and aztreonam had the least effect and d-penicillamine had no effect. The modulatory effect of these compounds was not due to a direct effect on CD54 induction. Unlike freshly prepared drugs, aged preparations of penicillin G and clavulanic acid had no significant effect on IFN-gamma activity. CONCLUSIONS: beta-Lactams differ in their capacity to modulate human IFN-gamma activity. This finding may have implications for the immunomodulatory effects of beta-lactams and for the design both of beta-lactams that do not affect the immune system and those which may be used therapeutically to target cytokine action.

Anti-Bacterial Agents↗
PubMed1994

Evaluation of antimicrobial activities of clarithromycin and 14-hydroxyclarithromycin against three strains of Haemophilus influenzae by using an in vitro pharmacodynamic model.

An in vitro pharmacodynamic model was used to simulate the in vivo pharmacokinetics of clarithromycin and 14-hydroxyclarithromycin in order to generate time-kill curves for three clinical isolates of Haemophilus influenzae (isolates 2019, 91-183, and 1746). Representative concentrations in serum or lung tissue and the pharmacokinetic parameters of clarithromycin and the 14-hydroxy metabolite, separately and in combination, were simulated for the time-kill studies. Amoxicillin-clavulanic acid was used as a control drug. The simulation of typical concentrations of the macrolides in serum in time-kill studies resulted in magnitudes of bacterial killing that were less than (for strains 2019 and 91-183, MICs = 4 mg/liter for clarithromycin and 14-hydroxy-clarithromycin) or equal to (for strain 1746, MIC = 1 mg/liter for clarithromycin and 14-hydroxyclarithromycin) those observed in amoxicillin-clavulanic acid studies. When typical concentrations in lung tissue were simulated, total log decreases in bacterial counts were greater than those achieved with typical concentrations in serum and, in the case of strain 1746, exceeded the magnitude observed with the control drug. In each case, the time to 3-log-unit killing was longer for the macrolides than for amoxicillin-clavulanic acid. Time-kill curve analyses demonstrated the presence of synergy (defined as a 2-log-unit decrease in the CFU per milliliter between the combination and the most active constituent at any time point) for the combination of clarithromycin and 14-hydroxyclarithromycin at simulated concentrations in serum for one strain of H. influenzae (isolate 91-183). Synergism is likely bacterial strain specific, and the presence of synergy may be dependent on the antibiotic concentrations that are tested. Evaluation of the kill curve kinetics in terms of bactericidal rate for the various starting concentrations of clarithromycin did not result in a clear demonstration of either concentration-dependent or concentration-independent bactericidal activity.

Amoxicillin↗
PubMed1990

Short-course cefotaxime compared with five-day co-amoxyclav in acute otitis media in children.

This randomized, multicentre prospective study was undertaken to compare the efficacy and tolerance of a one day course of injectable cefotaxime with a five day oral course of co-amoxyclav (amoxycillin plus clavulanic acid) in the treatment of acute otitis media in children. The study was conducted in 116 patients between the ages of three months and 12 years. No significant difference in efficacy was observed between the two treatment groups, but tolerance to the treatments differed significantly. There were no unwanted side-effects in the cefotaxime group whereas 22% of children in the amoxycillin plus clavulanic acid group suffered side-effects (P 0.0007). Short-course antibiotic therapy with cefotaxime appears to be a valuable alternative to conventional treatment regimens for acute otitis media in children.

Acute Disease↗
PubMed1983

In-vivo protection of group A beta-haemolytic streptococci from penicillin by beta-lactamase-producing Bacteroides species.

The incidence of persistent group A beta-haemolytic streptococci in tonsils, despite penicillin therapy, has increased in recent years. beta-Lactamase-producing organisms have previously been recovered from 74% of patients with persisting group A streptococci. We investigated the possibility that beta-lactamase-producing strains of Bacteroides spp. can protect streptococci from penicillin. A mixed infection was induced in mice in the form of a subcutaneous abscess involving a penicillin-susceptible group A streptococcus, and a beta-lactamase-producing strain of either Bact. melaninogenicus or Bact. fragilis. The infected animals were treated for seven days with parenteral penicillin, penicillin and clavulanic acid or clindamycin. Penicillin treatment prevented the formation of abscesses in animals inoculated with group A streptococci alone, but not in those inoculated with group A streptococci and Bacteroides spp. We attributed this resistance to penicillin therapy, and the subsequent formation of abscesses in mice, to protection of the streptococci from penicillin by beta-lactamase-producing strains of Bacteroides spp. Effective therapy for mixed infections was achieved when clavulanic acid, a beta-lactamase inhibitor, was administered with penicillin. A similar effect was noted with clindamycin, which is active against both group A streptococci and Bacteroides spp.

Abscess↗
PubMed1987

Comparison of four beta-lactamase inhibitors in combination with ampicillin against Mycobacterium tuberculosis.

The in-vitro activity of a beta-lactamase inhibitor (clavulanic acid, sulbactam, BL-P2013 or BL-P2090) in combination with ampicillin against 13 isolates of Mycobacterium tuberculosis was determined by broth dilution. The agents were tested in 1:1 molar ratio of ampicillin to beta-lactamase inhibitor. The beta-lactamase inhibitors alone did not inhibit growth at the highest concentration tested. The MIC90 for ampicillin alone was greater than 32 mg/l. Clavulanic acid plus ampicillin was the most active combination with an MIC90 of 11 microM (4 mg/l of ampicillin). The MIC90 of ampicillin in combination with sulbactam, BL-P2013 or BL-P2090 was 23 microM (8 mg/l of ampicillin). A 1:1 ratio of ampicillin to inhibitor was more active than was a 2:1 ratio. The addition of a beta-lactamase inhibitor to ampicillin greatly improves its in-vitro activity against M. tuberculosis.

Ampicillin↗
PubMed1992

Activity of cefpirome combined with beta-lactamase inhibitors and affinity for the penicillin-binding proteins of methicillin-resistant Staphylococcus aureus.

The susceptibility of 47 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) to cefpirome, ceftazidime and methicillin was determined with Isosensitest media, with/without 5% NaCl and incubation at 30 degrees, 37 degrees and 44 degrees C for 24 and 48 h. At 24 h the MIC50 of cefpirome was 8 mg/l compared to 64 mg/l ceftazidime; at 48 h this increased to 32 mg/l cefpirome. The addition of 10 mg/l clavulanic acid or sulbactam lowered the MIC of cefpirome (at 48 h) by greater than four-fold in 23% and 11% of the strains, respectively. Cefpirome had primary affinity for penicillin-binding protein (PBP) 1 and 2 in five MRSA and one methicillin-susceptible Staphylococcus aureus. PBP 2a was present in all MRSA and was not saturated by 64 mg/l cefpirome. Clavulanic acid at a concentration of 10 mg/l bound to PBP 2 by greater than 50% in all strains, and when combined with cefpirome, the density of PBP 2a was also reduced but not completely abolished. The data from this study suggests that the mechanism of synergy of a beta-lactamase inhibitor plus a cephalosporin for MRSA may be due to an additive effect against PBPs and not just inhibition of a beta-lactamase. No cefpirome-resistant mutants could be selected from a methicillin-susceptible Staphylococcus aureus, but mutants were selected from an MRSA (expressing homogeneous methicillin resistance) for which MICs of cefpirome were 8 to 32 mg/l.

Bacterial Proteins↗
PubMed2001

Construction and analysis of ss-lactamase-inhibitory protein (BLIP) non-producer mutants of Streptomyces clavuligerus.

The gene encoding BLIP, a beta-lactamase-inhibitory protein, was disrupted in wild-type Streptomyces clavuligerus and in a clavulanic acid non-producing mutant. The resulting BLIP mutant and BLIP/clavulanic acid double mutant showed no residual proteinaceous beta-lactamase-inhibitory activity, indicating that only a single beta-lactamase-inhibitory protein exists in S. clavuligerus. The lack of any proteinaceous beta-lactamase-inhibitory activity in the bli and bli/claR mutants also indicates that BLP, the BLIP-like protein, encoded by S. clavuligerus does not possess beta-lactamase-inhibitory activity despite its similarity to BLIP. The bli mutant and the bli/claR double mutant did not show any aberrant growth morphology, sporulation defects, or alterations in cephamycin C production or penicillin G resistance when compared to wild-type S. clavuligerus or to the claR single mutant. Mutants bearing the bli gene disruption did show an elevated level of production of clavam-2-carboxylate and hydroxymethyl clavam as well as clavulanic acid. This phenomenon was observed in the middle stages of production of these clavams but was not detected during maximum production. The production of BLIP was also determined to be down-regulated in a ccaR mutant, lacking the pathway-specific transcriptional regulator required for production of cephamycin C and clavulanic acid. Sequencing of the regions flanking the bli gene showed the presence of a partial open reading frame that encodes a DNA-binding protein, and several open reading frames apparently involved in the production of an ABC transporter.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

[The antibiotic treatment of respiratory infections in a pediatric emergency room].

Eight years after the first study published in this Journal (1985, 7: 533), we compared antibiotic treatment of respiratory infections at the Pediatric Emergency Department of the Children's Hospital in Trieste. All patients with pneumonia and pertussis received antibiotics, compared to 87% of otitis, 55% of pharyngo-tonsillitis, 4% of upper respiratory infections (U.R.I.); neither asthma nor laryngitis were treated with antibiotics. In particular, only 13% of otitis were treated by symptomatics, the others with amoxicillin (51%), amoxicillin + clavulanic acid (18%), cefaclor (12%), trimethoprim-sulphamethoxazole (5%), josamycin (1%). 45% of pharyngo-tonsillitis was treated with symptomatics, 32% with macrolides and 10% with penicillin; rarer treatment comprehended amoxicillin, amoxicillin + clavulanic acid (10%) and cefaclor (3%). Pneumonia was treated with amoxicillin or cefaclor (30% both), with amoxicillin + clavulanic acid (10%) or with macrolides (30%), the last in provision of mycoplasmal etiology. Antibiotic treatment of U.R.I. is progressively decreased from 79% in 1974 to 13% in 1983 and to 4% in 1991. Antibiotic treatment in our Department was appropriate in the majority of patients, with almost all bacterial form treated with first choice, cheaper antibiotic. A negative, limited trend was detected for pharyngo-tonsillitis: first choice antibiotics passed from 82% in 1983 to 76% in 1991. Another positive factor is due to the homogeneous manners of the doctors working at the Emergency Department, belonging to two different teams (Emergency and Clinical Departments), probably with the use of common clinical protocols.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Susceptibility of 114 isolates of the Bacteroides fragilis group to imipenem and eight other antimicrobial agents.

The minimal inhibitory concentrations (MICs) of the newer beta-lactam antibiotic, imipenem, were compared with those of cefoxitin, cefotetan, penicillin, amoxycillin, ticarcillin and metronidazole against 114 clinical isolates of the Bacteroides fragilis group of anaerobic organisms. The ability of clavulanic acid, a beta-lactamase inhibitor, to potentiate the in vitro activity of amoxycillin and ticarcillin was also studied. Using an agar dilution technique we found imipenem to be the most active beta-lactam antibiotic tested having an MIC50 of 0.25 microgram/ml and inhibiting all isolates at a concentration of 4 micrograms/ml. Metronidazole had comparable activity with a MIC50 of 0.5 microgram/ml and all isolates inhibited by 1 microgram/ml. Cefoxitin and cefotetan showed similar activity both with a MIC50 of 8 micrograms/ml against the B. fragilis group, while penicillin, amoxycillin and ticarcillin all had a MIC50 of 16 micrograms/ml. Clavulanic acid significantly reduced the MIC50 of amoxycillin and ticarcillin to 0.5 micrograms/ml and 0.25 micrograms/ml, respectively.

Anti-Bacterial Agents↗
PubMed1996

Cell density influences antibiotic biosynthesis in Streptomyces clavuligerus.

Production of cephamycin C and clavulanic acid by Streptomyces clavuligerus took place during the exponential phase of growth in a defined medium. Both antibiotic biosynthetic pathways were activated shortly after spore germination, but the timing and kinetics of activation were affected by inoculum density. Rapid activation was favoured by high inoculum density or by growth in medium conditioned by previous incubation of S. clavuligerus spores or mycelium. A heat-resistant conditioning factor able to accelerate the acquisition of antibiotic-biosynthetic capacity when added to low-density cultures was released in suspensions of spores in water. Conditioning factor was also obtained in suspensions of spores from different Streptomyces species or of Bacillus cells, indicating that the signal was not produced specifically by S. clavuligerus. Fractionation of conditioning factor showed that its effect was not due to a single molecule. The fractions contained amino acids (as free amino acids and oligopeptides) in amounts that roughly correlated with their respective conditioning power. Furthermore, the conditioning effect was reproduced by supplementing defined medium with amino acids and peptides in concentration that mimicked those found in conditioning factor. When individually tested at concentrations in the micromolar range, only some amino acids were able to stimulate antibiotic biosynthetic capacity. This stimulation ws also promoted by low concentrations (less than 1 microgram ml-1) of peptide mixtures obtained with different proteolytic enzymes. The results suggest that both amino acids and peptides are responsible for the effects of conditioning factor released by spores. Possible implications of intercellular signalling on activation of secondary metabolism are discussed.

Amino Acids↗