Evidence for biliary excretion of vancomycin into stool during intravenous therapy: potential implications for rectal colonization with vancomycin-resistant enterococci.

Sixty-three stool samples and five bile samples were prospectively collected from 33 patients receiving intravenous vancomycin therapy and were quantitatively analyzed for vancomycin by a competitive immunoassay. Vancomycin was excreted via bile into the stools of almost all patients at concentrations of 3.3 to 94.8 microg/ml after >/=5 days of a therapy of 1 g every 12 h.

Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination.

Twenty-four hour ratios of area under the curve (AUC(24)) to MIC of 200-240 h providing quinolone concentrations above the mutant prevention concentration (MPC) protected from enrichment of resistant Staphylococcus aureus in our recent study that simulated the pharmacokinetics of moxifloxacin, gatifloxacin, levofloxacin and ciprofloxacin. These protective AUC(24)/MICs might also be achieved by using antibiotic combinations, assuming additive effects of two anti-staphylococcal agents. To test this hypothesis, changes in S. aureus susceptibility were examined in a dynamic model that simulates 5-day treatment with moxifloxacin and doxycycline, alone and in combination at sub-optimal AUC(24)/MICs of each agent. Significant increases in MIC were observed with monotherapy where moxifloxacin or doxycycline concentrations fell into the mutant selection window (MSW) for more than 80% of the dosing interval (AUC(24)/MIC 60 h). Less pronounced changes in MIC occurred when the summed concentrations of moxifloxacin (AUC(24)/MIC 30 and 60 h) and doxycycline (AUC(24)/MIC 30 and 60 h) were inside the MSWs for the individual drugs for 30-50% of the dosing interval. No loss in susceptibility was found at moxifloxacin or doxycycline AUC(24)/MIC 170 h combined with the smaller AUC(24)/MIC (60 h) of the second compound. These data suggest that the total AUC(24)/MIC of 230 h might protect against S. aureus resistance. As this value is very close to that predicted in monotherapy with moxifloxacin (220 h), an additive protective effect of quinolone+doxycycline on the selection of resistant S. aureus is proposed. The use of drug combinations may be useful for restricting the enrichment of resistant mutants with agents whose clinically achievable AUC(24)/MICs do not provide concentrations above the MPC.

Evaluation of Oxoid combination discs for detection of extended-spectrum beta-lactamases.

OBJECTIVES: We evaluated the reliability of cefpirome/clavulanate (CD04) compared with ceftazidime/clavulanate (CD02) and cefotaxime/clavulanate (CD03) Oxoid combination discs for the detection of extended-spectrum beta-lactamases (ESBL) in several Enterobacteriaceae isolates, including Enterobacter spp. METHODS: Overall, a total of 105 ESBL-positive [positive double-disc synergy test (DDST)] and 94 ESBL-negative (negative DDST) Gram-negative isolates were evaluated. Ninety-eight isolates were confirmed as ESBL-positive on the basis of the sequence alignments of the blaTEM and/or blaSHV gene amplification products, which matched with previously identified ESBLs. The phenotypic detection of ESBLs was performed by the three combination discs according to the NCCLS and BSAC methods. The CD04 disc was evaluated with the manufacturer's recommended zone size difference breakpoint of > or =4 mm. RESULTS: In Escherichia coli and Klebsiella spp., the sensitivities (%)/specificities (%) of CD02, CD03 and CD04 discs, and the combination of CD02 or CD04 discs, were, respectively, 88/92, 90/92, 95/84 and 100/82, while the corresponding figures were 94/100, 4/100, 94/100 and 100/100 in Enterobacter aerogenes. NCCLS and BSAC methods yielded concordant results in 99% of the isolates. CONCLUSIONS: CD04 and CD02 discs were the best combination for detection of ESBLs in our collection of Enterobacteriaceae isolates, including E. aerogenes.

Clearance of quinupristin-dalfopristin (Synercid) and their main metabolites during continuous veno-venous hemofiltration (CVVH) with or without dialysis.

BACKGROUND: Quinupristin-dalfopristin (Q/D) is often utilized in critically ill patients, some of whom require CVVH. This study was undertaken to determine the clearance of O/D and their main active metabolites (RPR 100391, RP 69012, RP 12536) via CVVH in the swine model. METHODS: Q/D 7.5 mg/kg was intravenously administered over 0.5 h to 12 swine after induction of acute renal failure by ligation of the renal arteries. At 0.5 h post injection, the CVVH procedure was initiated and continued for 8 hours at the following pump rates: (1)100 mL/min, (2)180 rnL/min, and (3)100 mL/min with dialysis (flow rate: 1 L/h). Blood and ultrafiltrate samples were collected at 1 h intervals and assessed by a validated HPLC method. RESULTS: Plasma analysis suggests rapid metabolism to the main active metabolites which are appreciably cleared as demonstrated by high clearance and sieving coefficient estimates. Mean clearance estimates for RP 69012, RP 100391, and RP 12536 are 729, 777, and 578 mL/h in the 100 mL/min CVVH group, 772, 785, 685 mL/min in the 180 mL/min CVVH group, and 753, 791, 616 mL/min in the 100 mL/min CVVH group with 1 L/h dialysis, respectively. CONCLUSION: These data reveal that Q/D is rapidly metabolized and the metabolites are cleared to a large extent via CVVH. Due to the considerable contribution of the metabolites to overall in vivo activities, additional studies are required to fully quantify their removal before final dosage modifications for patients undergoing CVVH can be recommended.

Amoxicillin/clavulanate in chronic rhinosinusitis: tissue and serum distribution.

UNLABELLED: Amoxicillin/clavulanate in chronic rhinosinusitis: tissue and serum distribution. OBJECTIVE: The aim of the present study is to determine the concentrations of coamoxiclav in the sinusal mucosa of patients undergoing surgery for chronic sinusitis in comparison to serum levels after single oral administration. METHODOLOGY: 24 patients affected by chronic sinusitis, undergoing sinus surgery, were divided into three groups receiving an oral dose of 1 g of coamoxiclav (875 mg amoxicillin, 125 g of clavulanic acid, 7:1 ratio) at 2 h (first group), 4 h (second group) and 6 h (third group) before surgery. The mean concentration of amoxicillin and clavulanic acid were determined biologically in serum and in tissues. RESULTS: The highest concentrations of coamoxiclav both in serum and tissues were observed in the group which received the antibiotic 2 hours before surgery. However the tissue levels of both amoxicillin and clavulanic acid in the time period within 2-6 h after administration were higher than the Minimum Inhibitory Concentration (MIC) for the most frequent causative pathogens of sinus bacterial infections. CONCLUSIONS: Since penicillins need to maintain concentrations above the MIC for at least 40 to 60% of the interval time between administrations to be potentially effective, the Authors concluded that since both amoxicillin and clavulanic acid spread well in the ENT tissues, 1 g twice a day of the combination seems to be clinically effective even in patients suffering from acute episodes of chronic rhinosinusitis.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Cytotoxicity and probable mechanism of action of sulphimidazole.

Sulphimidazole (1-methyl-2((4-aminophenyl)-sulphonyl)-amino-5-nitroimidazole) is a new compound in which a p-aminobenzenesulphonamide radical has been attached at position 2 of the 5-nitroimidazole ring. It possesses a useful spectrum of activity in vitro against various anaerobic microorganisms and its action against aerobic and facultative bacteria is synergically enhanced in association with trimethoprim. In the present study, we determined the cytotoxicity in vitro of sulphimidazole and trimethoprim, both alone and in combination, and analysed the viability of Vero cells and the protein content of their cell lysate in the presence of increasing concentrations of these drugs. Also, in order to verify the hypothesis that the action of sulphimidazole against aerobic and facultative bacteria is mediated by the sulphonamide component of the molecule, while that against anaerobic bacteria depends on the action of the nitro group of the 5-nitroimidazole ring, we studied the mechanism of action of the new compound both indirectly, by means of microbiological techniques, and directly, by determining its oxidoreduction potential with respect to that of metronidazole. The results show that sulphimidazole is only slightly toxic in vitro for Vero cells, either alone or in association with trimethoprim, and that the combination of the two functional groups in a single molecule not only maintains its structure-activity relationship intact but also broadens its antibacterial spectrum.

Synercid Aventis.

Rhône-Poulenc Rorer (RPR) developed Synercid (RP-59500), an injectable synergistic combination of quinupristin and dalfopristin as a treatment for a variety of infections caused by Gram-positive anaerobic bacteria. The treatment was approved in the UK in July 1999, for use in patients with nosocomial pneumonia, skin and soft tissue infections and clinically significant infections due to Enterococcus faecium when there is no other active antibacterial agent [337556,335257]. It was launched in the UK and the US in September 1999 [342899]. In December 1999, Synercid successfully completed the Mutual Recognition Procedure in the EU under Aventis Pharma for use in patients with these infections [351525]. In September 2000, Merrill Lynch predicted first-year sales in 1999 of Euro 15 million, rising to Euro 171 million in 2004 [384874]. In January 1999, BT Alex Brown predicted sales of US $88 million in 1999 rising to US $450 million in 2002 [318220]. In April 1999, ABN Amro predicted annual sales of DM 30 million in 1999, rising to DM 150 million in 2002 [328676].

In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacterium avium.

MICs of clarithromycin, amikacin, isoniazid, rifabutin, ciprofloxacin, sparfloxacin, ethambutol, and clofazimine were determined for six isolates of Mycobacterium avium complex (MAC) from AIDS patients both by the radiometric method and by an ex vivo model of infection in human macrophages. The median MICs in macrophages were similar or slightly lower than values found in broth, except for amikacin, which had slightly higher MICs inside the cells. Combinations of clarithromycin with other antimicrobial agents showed that clarithromycin-clofazimine and clarithromycin-rifabutin were synergistic on five of six strains while clarithromycin-amikacin and clarithromycin-isoniazid were antagonistic on one and two strains, respectively. The addition of amikacin made the combinations of clarithromycin-clofazimine and clarithromycin-ethambutol synergistic against all the MAC strains. In the macrophage model, the combination of clarithromycin-clofazimine (mean survival, 21%) and clarithromycin-rifabutin (mean survival, 29%) showed a strong reduction in viable counts compared with single drugs, while clarithromycin-amikacin was less active than single drugs alone. In general, the addition of amikacin did not improve the activity of the combinations, except for clarithromycin-isoniazid-amikacin (mean survival, 19%), which was significantly more active than either clarithromycin-isoniazid or clarithromycin-amikacin. The use of the macrophage model can suggest new combinations of antimicrobial agents with anti-MAC activity which, on the basis of their in vitro effectiveness, would probably be disregarded for assay in animal models.

In-vitro sensitivity of amoxicillin/clavulanic acid (Augmentin) to isolated beta-lactamases and in-vitro antibacterial activity.

The in vitro sensitivity of amoxicillin alone and combined with clavulanic acid (ratio 4:1) as been studied by a spectrophotometric method utilizing crude extract of the following enzymes: TEM1, TEM2, SHV1, SHV2, TLE1, HMS1, LXA, P99, ENT208. The in-vitro antibacterial activity of ampicillin, amoxicillin alone and associated with clavulanic acid was also determined by an agar dilution method. Clavulanate protects amoxicillin from the hydrolytic activity of plasmid mediated beta-lactamase, conferring a stability on the beta-lactam comparable with that of cefotaxime. The protection of amoxicillin by means of clavulanic acid reduces the minimal concentration of antibiotic necessary to inhibit most bacterial species and allows bacteria to remain sensitive to the drug which might otherwise be resistant.

Antibiotic persistence and tolerance in the lactating sheep following a course of intramammary therapy.

The commercial use of sheep for the production of milk and milk products is attractive to farmers actively diversifying their dairy interests due to the impact of the quota system. As intensification of milking increases, flock sizes will enlarge and the incidence of ovine mastitis will inevitably increase. The pharmaceutical industry and the veterinary practitioner will be required to provide advice and data upon the performance of currently available bovine intramammary preparations for the sheep. This study produces evidence to confirm that one available bovine intramammary preparation, when infused into milking sheep, produced a withholding time approximately three times as long as that defined for the cow. Following a course of three infusions over a period of 24 hours after consecutive milkings, milk was not acceptable for human consumption or for the production of cheese and yoghurts until 136 hours following the final infusion. This situation is likely to be representative of that which will occur with other intramammary products used in the ovine species following infusion with bovine intramammary preparations.

[Can septicemia and ascitic fluid infections in cirrhotic patients be treated by the oral route alone?]. / Les septicémies et les infections du liquide d'ascite du cirrhotique peuvent-elles être traitées exclusivement par voie orale?

The aim of this study was to determine the efficacy of oral antibiotics in the treatment of severe infections in cirrhosis. Twenty-two patients (17 males, 5 females) with spontaneous bacteremia (n = 7) or bacterial peritonitis (n = 15) were treated with oral pefloxacin 400 mg per 24 hr alone (n = 1) or in combination with another oral antibiotic, trimethoprimsulfamethoxazole (n = 13), amoxicillin (n = 6), cefadroxil (n = 2), or metronidazole (n = 1). In patients with spontaneous bacteremia, all organisms were found to be sensitive to oral antibiotics, and a favorable response was elicited in 6 out of 7 (86 p. cent) within 3 days (mean) of treatment. In patients with spontaneous peritonitis, ascitic fluid cultures were positive in 11 cases, and organisms were sensitive to pefloxacin in 9 out of 11 cases. A favorable response was elicited in 13 out of 15 within 2 to 8 days of treatment. Fourteen patients died (64 p. cent), 3 of infection (bacteremia n = 1, peritonitis n = 2), and 11 patients of causes unrelated to infection, mainly variceal hemorrhage, hepatorenal syndrome or hepatocellular carcinoma, although the clinical symptoms of infection were controlled. One-year survival was 57 p. cent in patients with bacteremia and 33 p. cent in those with bacterial peritonitis. Oral treatment was well tolerated in all patients. We suggest that most bacteremia and spontaneous bacterial peritonitis in cirrhotic patients can be treated with oral antibiotics. In some patients, this may be accomplished on an out patient basis.

Beta-lactamase stability and antibacterial activity of cefpirome alone and in combination with other antibiotics.

The antibacterial activity of cefpirome (HR810), a new cephalosporin, was compared with that of other "third-generation" cephalosporins, as well as cefuroxime, piperacillin and gentamicin. Cefpirome was the most active beta-lactam antibiotic against Gram-negative bacteria. The MIC90 for Enterobacteriaceae was always less than 0.5 ml/l except for Enterobacter species. The MIC90 against Pseudomonas species was 2 mg/l, which was equal to that of ceftazidime and gentamicin. Cefpirome was also more active than the other beta-lactam antibiotics against Staphylococcus aureus. A relatively high frequency of synergy was observed when cefpirome was combined with aminoglycosides against both Gram-positive and Gram-negative bacteria. No antagonism was detected. This antibiotic was very stable to both plasmid- and chromosomally-mediated beta-lactamases. It was more resistant to Enterobacter cloacae P99 enzyme than ceftazidime, cefotaxime and cefotetan. Its stability to the Klebsiella K1 beta-lactamase was more than that of cefotaxime and ceftriaxone but slightly less than that of ceftazidime and latamoxef. MBC90 values for cefpirome were generally less than twice the corresponding MIC values.

In vitro activity of amoxycillin plus clavulanic acid and ticarcillin plus clavulanic acid compared with that of other antibiotics against anaerobic bacteria.

The activity of amoxycillin/clavulanic acid (Augmentin) and ticarcillin/clavulanic acid (Timentin) was tested against 303 unselected clinical anaerobic isolates recently collected in seven Belgian university hospitals and compared with that of 11 other antimicrobial agents. Bacteroides spp. accounted for 52.1% of the isolates, Clostridium spp. for 23.4%, anaerobic cocci for 15.5%, nonsporeforming gram-positive bacilli for 4.6% and Fusobacterium spp. for 3.3%. Ticarcillin/clavulanic acid (fixed clavulanic acid concentration of 2 mg/l) was the most active drug with an overall susceptibility rate of 99.7%. Amoxycillin/clavulanic acid (fixed ratio of 2:1) and chloramphenicol inhibited 97.4% of the isolates, metronidazole 95.4%, piperacillin 92.4%, ticarcillin 91.4%, clindamycin 87.8%, cefotetan 81.2%, cefazolin 63.0%, cefuroxime 60.4%, erythromycin 57.8%, penicillin 57.1% and doxycycline 52.1%. beta-lactamases were detected exclusively in Bacteroides spp. isolates (79.1% positive).