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Biomedical subjects

A Philippon

Publications and source records attributed to A Philippon.

At least 109 records · Page 6Linked to original sources
PubMed1987

Transferable enzymatic resistance to third-generation cephalosporins during nosocomial outbreak of multiresistant Klebsiella pneumoniae.

Klebsiella pneumoniae strains that were resistant to third-generation cephalosporins and amikacin were recovered from 62 of 395 patients (15.7%) during 1986. 25 isolates (40%) caused urinary tract infections. The outbreak involved three intensive care units (54 isolates), and spread from one unit to another and then to four wards (8 isolates). K pneumoniae of various serotypes and strains of different Enterobacteriaceae demonstrating the same antibiotic resistance pattern were isolated, which suggests dissemination of an R-factor. The isolates had low-level resistance to third-generation cephalosporins (mode minimum inhibitory concentration of cefotaxime, 2 mg/l) but remained sensitive to cephamycins. Cefotaxime was effective in cases of uncomplicated urinary tract infection, but failed in major infections at other sites. 1-5 mg/l of the beta-lactamase inhibitors clavulanic acid or sulbactam restored normal activity to cefotaxime against the multiresistant strains. Resistance to third-generation cephalosporins was mediated by a new broad-spectrum enzyme of isoelectric point 6.3. Resistance to beta-lactams and aminoglycosides was transferable to Escherichia coli. The emergence of transferable enzymatic resistance to newer beta-lactams in K pneumoniae strains indicates a major risk of spread of such resistance to otherwise sensitive strains.

Amikacin↗
PubMed1987

Molecular genetic analysis of cephalosporinase production and its role in beta-lactam resistance in clinical isolates of Enterobacter cloacae.

Two strains of Enterobacter cloacae were isolated from a patient before (strain MHN1) and during (strain MHN2) treatment with moxalactam and gentamicin. Strain MHN1 exhibited inducible ampC cephalosporinase production. In contrast, strain MHN2 expressed the enzyme constitutively at a 3,000-fold higher level. With the Escherichia coli ampC gene as a hybridization probe it was shown that the genomic arrangement of the ampC region was the same in both strains. To gain more insight into regulatory phenomena, the ampC genes were cloned, and their expression was studied in E. coli K-12. The ampC gene from MHN1 behaved normally and conferred inducible beta-lactam resistance. A regulatory region of at least 800 base pairs involved in controlling repression-induction was located immediately upstream of ampC. Surprisingly, when present in E. coli the ampC gene from MHN2 no longer overproduced the cephalosporinase, and inducible expression was observed. This indicates that in MHN2 stable cephalosporinase overproduction is controlled by another factor which is not linked to the ampC gene.

Anti-Bacterial Agents↗
PubMed1987

Specific antibody response to Pasteurella multocida.

Six patients with culturally proven Pasteurella multocida infection were evaluated serologically. The infections were 1 foot abscess, 1 septicemia, 3 bronchitis and 1 bronchopneumonia. Most of them were elderly women closely exposed to pets or domestic animals. The serotypes of the strains were determined in 5 cases (3 A3, 2 A7). Specific antibodies against capsular and somatic antigens of P. multocida were determined by indirect hemagglutination and agglutination respectively. The antibodies were strictly directed against the capsular and somatic specificities of the isolated strain. The range of the serum antibody titers were 20 to 2,560 to capsular antigens and 5 to 640 to somatic antigens within 2 weeks after the first clinical signs of infection. Several months after successful treatment, the capsular antibodies were lower while the somatic antibodies had almost disappeared. These findings suggest a good sensitivity for these serologic methods in active cases. Declining antibody titers follow healing. Cross-reactivity of the serologic tests with other bacteria was not observed. Serologic diagnosis of P. multocida infections is a possible alternative to direct diagnosis when cultures are negative or when unusual localizations must be confirmed.

Adult↗
PubMed1987

[Titration curves of beta-lactamases using pH gradient electrophoresis].

The molecular relationships of two types of plasmid-mediated beta-lactamases, TEM-1 (R 111), TEM-2 (RP 4) and OXA-1 (RGN 238), OXA-4 (pMG 90) were analysed by combined isoelectrofocusing-electrophoresis. Titration curves of TEM-1 (pI 5.4) and TEM-2 (pI 5.6) together were consistent with the known substitution of a glutamic acid in the former by a lysin in the latter. When OXA-1 (pI 7.4) and OXA-4 (pI 7.45) were titrated, one single mobility curve was obtained reflecting their structural homogeneity. The titration curve technique will be usefull for the study of structure of beta-lactamases.

Electrophoresis, Polyacrylamide Gel↗
PubMed1986

[Mechanism of enzymatic resistance to beta-lactam antibiotics].

The resistance of bacteria, particularly Gram-negative bacteria, to beta-lactam antibiotics is principally caused by enzymes. Beta-lactamases inactivate these antibiotics by opening, more or less rapidly, the beta-lactam ring. The chronology of therapeutic discoveries is governed by natural and acquired resistance. The first step was to establish the characteristics of beta-lactamases (location, biogenesis, enzymatic profile, affinity constant, inhibition profile, isoelectric point, molecular weight, genetic determination, etc.). Advances in the selection of natural or semi-synthetic compound are centred on the following points: increased stability to beta-lactamases, inhibitory effect, reduced inducibility, low affinity for the enzyme, greater speed of penetration through the bacterial wall, increased tropism for targets. Notable among the new beta-lactam antibiotics are acylureidopenicillins, beta-lactamase inhibitors and carbapenems. The antibacterial activity of third generation cephalosporins is 10 to 1000 times higher than that of previous cephalosporins; the result is a wider spectrum including, in particular, cephalosporinase-producing organisms. Concerning acquired resistance, the behaviour of new antibiotics must be examined by comparing the minimum inhibitory concentrations of isogeneic and clinical strains, and according to phenotype or mechanism: sensitive, penicillinase producer, cephalosporinase producer or producer of both penicillinases and cephalosporinases. During synthesis of a penicillinase, penicillins and some cephalosporins are more or less inactivated. With a constitutive cephalosporinase, all cephalosporins are inactivated as are, to a lesser degree, penicillins and monobactams, e.g. aztreonam. The emergence of new enzymes, including broad-spectrum beta-lactamases, and their extension to sensitive bacteria show that the enzymatic mechanism still has potentials for development.

Anti-Bacterial Agents↗
PubMed1986

Detection, distribution and inhibition of Branhamella catarrhalis beta-lactamases.

Beta-lactamase-producing isolates of Branhamella catarrhalis were first detected in France in 1977. The frequency of beta-lactamase producers has increased, especially since 1980. An agar iodometric test, a fast chromogenic test and an acidimetric test were used to assess the beta-lactamase-producing capabilities of 188 isolates of B. catarrhalis obtained mainly from sputum and the pharynx. Data from the first 2 procedures indicated positive beta-lactamase activity for all 49 strains of B. catarrhalis identified, but there were some discrepancies in the acidimetric test results. Evidence from a diffusion technique showed significant increases in the inhibition diameters surrounding filter discs impregnated with amoxycillin in the presence of clavulanic acid, or with ampicillin in the presence of sulbactam, compared with discs of the penicillins used alone. Two types of enzyme activity emerged from examination of isoelectric focusing patterns. Type I, having pI values of 5.35, 5.55 and 5.85, accounted for 87.2% of the enzyme-producing isolates. Type II, with pIs of 5.5, 5.9 and 6.25, occurred in 12.8% of isolates and appeared to be less widely distributed. The beta-lactamase inhibitors clavulanic acid and sulbactam in combination with benzylpenicillin produced potentiated effects, as demonstrated by significant reductions in MIC (33- and 44-fold decreases, respectively). Higher concentrations of each inhibitor similarly affected the MICs of amoxycillin. A weak synergy occurred with cefoxitin, a beta-lactamase-resistant beta-lactam antibiotic, and the 2 beta-lactamase inhibitors. Because B. catarrhalis has been shown to be a beta-lactamase-producing pathogenic organism, the addition of enzyme inhibitors, such as clavulanic acid and sulbactam, to standard therapy may be beneficial.

Anti-Bacterial Agents↗
PubMed1985

[Enterobacter cloacae and E. aerogenes septicemia: emergence of resistant variants (derepressed cephalosporinase) during treatment with third-generation cephalosporins].

From three patients hospitalised in intensive care units with Enterobacter septicaemia (two cases with E. cloacae, and one with E. aerogenes), cefotaxime therapy, alone or in combination with an aminoglycoside, selected variants (R) with increased resistance to beta-lactam antibiotics. The cross-resistance extended to all the beta-lactam antibiotics tested, penicillins and cephalosporins, including third-generation cephalosporins. The crude extracts of uninduced cultures of R variants showed high beta-lactamase activity and of the cephalosporinase type. These variants were selected in vitro with a frequency of 10(-6) to 10(-7) and may result from a mutation involving the regulation of Enterobacter cephalosporinases, usually inducible. Data from the literature indicated that this new type of resistance is actually emerging and observed not only in Enterobacter sp. The problem of emergence of R variants exhibiting cross-resistance to beta-lactam antibiotics should be considered when third-generation cephalosporins are used.

Adult↗
PubMed1985

[Carbenicillin resistance of gram-negative bacteria: incidence, biochemical and genetic determinism].

Of nine hundred ampicillin resistant (Amp-R) enterobacteria strains, isolated in hospital between July and December 1981, 73,7% are also carbenicillin-resistant (Carb-R). This particular double resistance varies depending upon the species considered: indole positive Proteus (23%), Enterobacter cloacae (64%), Citrobacter freundii (67%), Acinetobacter calcoaceticus (73%), Proteus mirabilis (75%), Serratia marcescens (90%), Escherichia coli (91%), Providencia stuartii (96%) and Klebsiella pneumoniae (100%). The biochemical and genetic basis of resistance to beta-lactamines was studied in 27 strains belonging to these 9 species. A constitutive beta-lactamase was found in all the strains. These enzymes were identified by determination of the isoelectric point on crude sonic extracts, the enzymic activity profile, the inhibition by clavulanic acid and cloxacillin of enzyme activity. Two types of enzymes were predominant: TEM-1 (20 strains) and TEM-2 (7 strains); two strains of Klebsiella pneumoniae produced both SHV-1 and TEM-1. The transfer by conjugation to E. coli K12 of ampicillin and carbenicillin resistance was obtained with 14 strains: (E. coli: 9, C. freundii: 1, K. pneumoniae: 1, E. cloacae: 2, P. stuartii: 1). In all strains but one E. coli we noted the co-transfer of other antibiotic resistance markers.

Ampicillin↗
PubMed1985

beta-Lactamases of Pseudomonas aeruginosa and susceptibility against beta-lactam antibiotics.

A total of 4093 non-replicate Pseudomonas aeruginosa isolates supplied by 10 French hospitals from September 1981 to August 1983 was examined for susceptibility to ticarcillin (TIC) and to 11 other beta-lactam antibiotics. Overall incidence of TIC-resistance was low (20.9%) but variable between hospital, unit and culture site and primarily mediated by a constitutive beta-lactamase as observed by iodometric detection (66.3%). As suggested by analytical isoelectrofocusing on gel, PSE-1 (CARB-2) and OXA types were predominant but new types appeared. The comparative in vitro activities of 12 antipseudomonal beta-lactams appreciated by microtiter MICs with an inoculum of 10(5) CFU were established according to phenotype: TIC-susceptible, TIC-R with a constitutive beta-lactamase (PSE-1, OXA-1, OXA-2, OXA-3, PSE-2 and a new type, TEM-1 and TEM-2 and derepressed cephalosporinase) or without detectable activity. Different patterns of resistance were demonstrated, but imipenem, ceftazidime and aztreonam were the most active antibacterial agents.

Anti-Bacterial Agents↗
PubMed1985

Susceptibility of Pseudomonas aeruginosa to beta-lactam antibiotics.

Since the discovery of carbenicillin in 1970, several groups of beta-lactam agents with remarkable activity against P. aeruginosa are actually available among penicillins such as ticarcillin, azlocillin, piperacillin, apalcillin and among cephalosporins: cefoperazone, cefsulodin as well as new structures including monobactams (aztreonam) and carbapenems with imipenem. An attempt to establish hierarchy in terms of weight for weight activity, particularly against susceptible isolates is made. The most active antimicrobial agents are: imipenem, apalcillin, ceftazidime, cefsulodin, piperacillin and azlocillin. The bactericidal activity is reported for virtually all of them but more accurate techniques such as time-killing curves are needed to make comparisons, because some discrepancies were reported. Nevertheless, among several factors affecting their inhibitory and bactericidal activities, some of them appeared predominant: inoculum effect and beta-lactamases. The different behavior of beta-lactam antibiotics may be in relation with other mechanisms such as impermeability. A few surveys on the resistance mechanism indicated that impermeability can be prevalent, instead beta-lactamases. But in any case, the enzyme distribution showed carbenicillinases (PSE-1, PSE-4) and OXA were observed with a high prevalence among ticarcillin-resistant isolates and more recently cephalosporinases. These drugs acted synergistically with all of the aminoglycosides in vitro against P. aeruginosa isolates and also in animal models of infection. If the synergism appeared to play a major role in the therapy of P. aeruginosa infections, these new beta-lactam antibiotics offer the possibility of other approaches to combination therapy.

Ampicillin↗
PubMed1984

[Comparative effect of beta-lactam activity on Pseudomonas aeruginosa as a function of resistance phenotypes].

In a multicentre study of the distribution in France of constitutive beta-lactamases produced by Ps. aeruginosa, the activities of 12 antibiotics were investigated comparatively according to resistance phenotypes. Antibiotics with the best activity, on a weight-for-weight basis, against "wild" non carboxypenicillin-resistant strains were ureidopenicillins among penicillins, ceftazidime and cefsulodin among cephalosporins and a new beta-lactam compound: N-formimidoyl-thienamycin. Thirty per cent of carboxypenicillin-resistant strains do not possess constitutive beta-lactamases. With most antibiotics, except N-f-thienamycin, minimum inhibitory concentrations (MICs) against these strains were increased 2 or 3-fold. However, the MICs of ureidopenicillins remained well below critical concentrations. The activities of the penicillins tested and of cefoperazone and cefsulodin against strains with constitutive beta-lactamases were considerably reduced. Those of other cephalosporins, such as cefotaxime, ceftriaxone, moxalactam, ceftazidime and azthreonam were little modified. However, in view of the plasma concentrations obtained, with the exception of ceftazidime and azthreonam the MICs of these cephalosporins were too high for satisfactory therapeutic results to be expected. Ps. aeruginosa strains producing beta-lactamases of the chromosomal cephalosporinase type are still rare (0.9%), but their number seems to be increasing. These strains, probably selected by treatments, are resistant to all beta-lactam antibiotics, and their degree of resistance to cephalosporins, ceftazidime included, is particularly high.

Anti-Bacterial Agents↗
PubMed1984

[Distribution of constituent beta-lactamases in Pseudomonas aeruginosa].

Acquired resistance of Pseudomonas aeruginosa to beta-lactam antibiotics, e.g. ticarcillin, has the following characters: The incidence of ticarcillin-resistant strains is about 21% but it varies with hospitals from 10.9 to 35.1%. Resistance is predominantly due to beta-lactamases, which are produced by two-thirds of the strains (64.4% in 1982, 67.9% in 1983). The presence of beta-lactamase positive strains is dependent upon the type of patient, the hospital unit (e.g. urology or burns) and the nature of the specimen collected. Most beta-lactamase positive strains spontaneously produce one single penicillinase of the CARB (53.8%), OXA (30.5%) or TEM (8.7%) type. New types of beta-lactamases may develop and hydrolyse beta-lactam antibiotics such as ticarcillin, azlocillin, cefoperazone or cefsulodin. With beta-lactam antibiotics (cefotaxime, moxalactam, ceftazidime) that resist hydrolysis, bacterial resistance is due to production of a constitutive beta-lactamase of the cephalosporinase type. This enzyme has recently appeared and its incidence is low (6.8%). Associated beta-lactamases (e.g. penicillinase plus cephalosporinase) are exceptional.

Anti-Bacterial Agents↗
PubMed1984

[Treatment of human brucellosis with rifampicin].

Rifampin, which exhibits good intracellular diffusion and in vitro bactericidal activity on brucella, is effective in experimental brucellosis in mice, without selection of resistant strains. It was therefore legitimate to use rifampin in man since conventional treatment of acute brucellosis is followed by recurrence in 15% (tetracycline alone) or 3.7% (streptomycin-tetracycline combination) of cases. Rifampin was given to 13 patients with brucellosis (acute brucellosis in 8, osteoarticular brucellosis in 3 and chronic brucellosis in 2). Rifampin was given as sole therapy in a daily dosage of 600 to 1 200 mg. A tetracycline was subsequently needed in three cases, in combination with rifampin in two, and as replacement therapy in one. Treatment lasted 20 to 60 days in acute brucellosis and 2 to 15 months in other forms. Only one failure was recorded among the 11 cases of acute or localized brucellosis. Conversely, effectiveness of rifampin proved incomplete (1 case) or null (1 case) in chronic forms. The satisfactory effectiveness of rifampin is confirmed by a review of the literature which found 17 reports addressing the subject. These include 324 cases of brucellosis treated by rifampin, as sole therapy in 255 patients, with only 24 failures ascribable to faulty dosage. Indeed, rifampin must be given for at least 30 days, in a minimal daily dosage of 600 mg or 10 mg per kg, in a single dose. Cotrimoxazole is an antagonist and should not be associated with rifampin. Conversely, tetracyclines are synergistic and their association, which is useless in acute brucellosis, is helpful in localized and chronic forms.

Acute Disease↗
PubMed1984

[Enterobacter cloacae. In vivo emergence of a variant resistant to new beta-lactams during treatment with lamoxactam-gentamicin].

In a patient recently operated for an abdominal gun wound, and given gentamicin-cephalosporin (cefoxitin for one day, then moxalactam) for 11 days, treatment failed as a result of emergence of a E. cloacae variant resistant to beta-lactams only, i.e. carbenicillin, mezlocillin, cefamandole (CFM), cefoperazone (CPZ), cefotaxim (CTX) and moxalactam ( MOX ). The initial susceptible strains isolated from blood cultures (SH1, SH2) and the resistant ones isolated 11 days later from pancreatic pus (RP) and blood cultures ( RH1 , RH2 ) shared the same chemotype. MICs of CFM, CPZ, CTX, and MOX were much higher (1 000 to 4 000 fold) for RH1 than for SH1. The biochemical mechanism of resistance showed the six following features: loss of antimicrobial activity of CFM, CTX and MOX added to RH1 cultures; much higher (1 500 fold) beta-lactamase activity for RH1 than for SH1 (iodometric and microacidimetric methods); beta-lactamases focusing at the same pl (greater than 8) produced by RH1 , RP and also, but only after induction, SH1 and SH2; cephalosporinase-type beta-lactamase according to the enzymatic activity profile; restoration of RH1 's susceptibility to CFM, CTX and MOX merely by adding cloxacillin; apparently unchanged crypticity for RH1 . The enzymatic mechanism (cephalosporinase hyperproducing variant) seems very likely.

Adult↗