Chemoprophylactic efficacy against experimental endocarditis caused by beta-lactamase-producing, aminoglycoside-resistant enterococci is associated with prolonged serum inhibitory activity.

We studied the prevention of experimental aortic endocarditis caused by a beta-lactamase-producing, aminoglycoside-resistant strain of Enterococcus faecalis (HH22) in 146 catheterized rabbits. Both vancomycin and ampicillin-sulbactam readily killed this resistant enterococcus strain in vitro. At a challenge inoculum of approximately 10(9) CFU, vancomycin (40 mg/kg intravenously [i.v.]), ampicillin (40 mg/kg i.v.), or a combination of ampicillin plus a beta-lactamase inhibitor, sulbactam (20 mg/kg, i.v.), did not prevent the development of endocarditis in any of the animals, although mean intravegetation bacterial densities were significantly lower in animals that received vancomycin than they were in animals that received other therapies (P less than 0.001). At a challenge inoculum of 10(6) CFU, vancomycin was 100% effective in preventing enterococcal endocarditis compared with ampicillin (29%; P less than 0.00001) and ampicillin-sulbactam (65%; P less than 0.01). Factors associated with the superior prophylactic efficacy of vancomycin in this model included prolonged serum inhibitory activity and time above MICs. Factors not associated with the antienterococcal prophylactic efficacy of vancomycin included the duration of the in vitro postantibiotic effect of the drug and the magnitude of the ability of this drug to enhance enterococcal in vitro opsonophagocytic killing by polymorphonuclear leukocytes. The superior prophylactic efficacy of vancomycin in this endocarditis model related to the superior pharmacokinetic profile of the drug when it was given intermittently at dose intervals of every 6 h.     

Efficacy of oxacillin and ampicillin-sulbactam combination in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus.

Optimal therapy of infections caused by borderline oxacillin-susceptible, beta-lactamase-hyperproducing Staphylococcus aureus has not been established. We used a rat model of aortic valve endocarditis to examine efficacies of antibiotic regimens against a borderline oxacillin-susceptible strain as compared with a fully susceptible S. aureus strain. Animals were treated with oxacillin alone or in combination with sulbactam or with ampicillin-sulbactam combinations at two dose levels. Infections caused by the borderline susceptible and fully susceptible strains responded equally well to oxacillin alone, with residual bacterial titers in vegetations falling to 4.8 +/- 1.6 and 4.4 +/- 1.7 (mean +/- standard deviation) log10 CFU/g, respectively. Addition of sulbactam to oxacillin (1:2) did not enhance the efficacy of oxacillin against either strain in the animal model. A high-dose regimen of ampicillin-sulbactam (2:1) yielding mean (+/- standard deviation) levels in serum of 16.8 +/- 7.4 and 9.5 +/- 1.1 micrograms/ml, respectively, proved equally effective against both strains (bacterial titers, 6.6 log10 CFU/g). However, at lower doses (8.3 +/- 2.6 and 5.9 +/- 2.4 micrograms/ml, the combination showed greater efficacy against the fully susceptible strain, with residual titers of 7.1 +/- 2.0 versus 9.0 +/- 1.6 log10 CFU/g (P less than 0.05). In vitro studies revealed that the beta-lactamase inhibitor sulbactam was also a potent inducer of staphylococcal beta-lactamase at clinically relevant concentrations. Based on this short-term in vivo therapy study, oxacillin would be predicted to be clinically effective in the therapy of infections caused by borderline oxacillin-susceptible strains of S. aureus, while the combination of ampicillin with sulbactam appears to be inferior to oxacillin alone against such infections.     

Ampicillin-sulbactam is effective in prevention and therapy of experimental endocarditis caused by beta-lactamase-producing coagulase-negative staphylococci.

Optimal strategies for the prophylaxis and therapy of endocarditis caused by oxacillin-resistant, coagulase-negative staphylococci in patients with native or prosthetic valvular heart disease are not well defined. We compared the in vivo efficacies of ampicillin-sulbactam-based regimens with those of vancomycin-based oxacillin-resistant, beta-lactamase-producing coagulase-negative staphylococcal isolate (Staphylococcus haemolyticus SE220). Ampicillin-sulbactam (100 and 20 mg/kg of body weight, respectively, given intramuscularly in a two-dose regimen) was equivalent to vancomycin (30 mg/kg given intravenously in a two-dose regimen) in its prophylactic efficacy against the coagulase-negative staphylococcal strain (93 and 80%, respectively). The combination of ampicillin-sulbactam plus either rifampin or vancomycin did not enhance the prophylactic efficacy compared with that of ampicillin-sulbactam or vancomycin alone. In the therapy of established aortic valve endocarditis in rabbits caused by this same coagulase-negative staphylococcal strain, animals received 7-day ampicillin-sulbactam-based or vancomycin-based regimens with or without rifampin. All treatment regimens were effective at lowering intravegetation coagulase-negative staphylococcal densities and rendering vegetations culture negative compared with the coagulase-negative staphylococcal densities and vegetations of untreated controls, with ampicillin-sulbactam in combination with rifampin or vancomycin being the most active regimen. However, only the regimen of ampicillin-sulbactam in combination with vancomycin effectively prevented relapse of endocarditis posttherapy after a 5-day antibiotic-free period. For animals receiving rifampin-containing regimens, relapses of endocarditis were associated with the in vivo development of rifampin resistance among coagulase-negative staphylococcal isolates in the vegetation. Ampicillin-sulbactam was highly effective in the prevention of experimental endocarditis caused by a beta-lactamase-producing, oxacillin-resistant coagulase-negative staphylococcal strain. Ampicillin-sulbactam was also efficacious for the therapy of coagulase-negative staphylococcal endocarditis, especially when it was combined with vancomycin to prevent posttherapeutic relapses.     

Comparison of daptomycin, vancomycin, and ampicillin-gentamicin for treatment of experimental endocarditis caused by penicillin-resistant enterococci.

Infections with enterococci that are resistant to multiple antibiotics are an emerging clinical problem. We evaluated the antibiotic treatment of experimental enterococcal endocarditis caused by two strains with different mechanisms of penicillin resistance. Enterococcus faecalis HH-22 is resistant to aminoglycosides and penicillin on the basis of plasmid-mediated modifying enzymes; Enterococcus raffinosus SF-195 is susceptible to aminoglycosides but is resistant to penicillin on the basis of low-affinity penicillin-binding proteins. Animals infected with strain HH-22 received 5 days of treatment with the following: no treatment; daptomycin (20 mg/kg of body weight twice daily [b.i.d.], intramuscularly [i.m.]), vancomycin (20 mg/kg b.i.d., intravenously), or ampicillin (100 mg/kg three times daily, i.m.) plus gentamicin (2.5 mg/kg b.i.d. i.m.). Although vancomycin was superior to ampicillin-gentamicin (P less than 0.01), daptomycin was significantly better than all other treatment regimens (P less than 0.01) in reducing intravegetation enterococcal densities, although no vegetations were rendered culture negative by this agent. Animals infected with strain SF-195 received 5 days of no therapy, ampicillin, ampicillin-gentamicin, vancomycin, or daptomycin (all at the dosage regimens described above). Daptomycin, vancomycin, and ampicillin-gentamicin each lowered intravegetation enterococcal densities significantly better than did ampicillin monotherapy or no treatment (P less than 0.01); moreover, these three treatment regimens rendered significantly more vegetations culture negative than did ampicillin monotherapy or no treatment (P less than 0.05). Serum daptomycin levels remained above the MICs and MBCs for both enterococcal strains throughout the 12-h dosing interval used in the study. Daptomycin and vancomycin were both active in vivo in these models of experimental enterococcal endocarditis caused by penicillin-resistant strains, irrespective of the mechanism of resistance. This activity correlated with the unique cell wall sites of action of these agents (binding to lipoteichoic acid and pentapeptide precursor, respectively) compared with the sites of action of beta-lactams (penicillin-binding proteins). Beta-Lactamase production by strain HH-22 precluded in vivo efficacy with ampicillin-gentamicin combinations. In contrast, this combination was active in vivo against strain SF-195, which exhibited intermediate-level penicillin resistance (MIC, 32 micrograms/ml), likely reflecting the ability of high-dose ampicillin to achieve enough binding to low-affinity penicillin-binding proteins to cause augmented aminoglycoside uptake.     

Treatment of Experimental Staphylococcal Endocarditis Due to a Strain with Reduced Susceptibility In Vitro to Vancomycin: Efficacy of Ampicillin-Sulbactam

We evaluated several 3-day antimicrobial regimens in the treatment of experimental endocarditis caused by an oxacillin-resistant Staphylococcus aureus strain exhibiting intermediate susceptibility in vitro to vancomycin (VISA). Neither vancomycin alone nor trovafloxacin exhibited in vivo efficacy; addition of amikacin to vancomycin yielded a modest in vivo effect. In contrast, the combination of ampicillin and sulbactam was highly effective in vivo, causing a mean decrease in VISA vegetation densities of >5 log(10) CFU/g versus those of untreated controls.     

Ampicillin resistance in Haemophilus influenzae: identification of resistance mechanisms

The incidence and mechanisms of ampicillin resistance (MIC greater than 1 mg/l) were investigated in 105 clinical isolates of Haemophilus influenzae collected in Edinburgh during 1983/4. Fifteen (14.3%) ampicillin-resistant strains were identified and these were non-serotypable and comprised six biotypes. Isoelectric focusing and beta-lactamase-inhibition studies demonstrated that production of the TEM-1 beta-lactamase was the principal mechanism of resistance in nine (60%) strains. Radiolabelling revealed that one beta-lactamase-positive strain also had an unusual penicillin-binding protein (PBP) profit. No beta-lactamase activity was detected in the other six (40%) ampicillin-resistant strains. Two beta-lactamase-negative ampicillin-resistant strains had atypical PBP profiles. SDS-PAGE analysis showed that four beta-lactamase-negative ampicillin-resistant strains, including one with altered PBPs, exhibited outer membrane protein profiles which differed from those of sensitive strains of the same biotype. The ampicillin-resistance mechanism of the remaining strain could not be determined. Thus, several resistance mechanisms, either acting individually or in combination, are implicated in ampicillin resistance in H. influenzae.     

Efficacy of ticarcillin-clavulanic acid for treatment of experimental Staphylococcus aureus endocarditis in rats.

The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log10 CFU/g), or delayed until 24 h after infection, when the vegetations usually contained greater than 9 log10 CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by beta-lactamase-producing strains of S. aureus, illustrating the beta-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal beta-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.     

Bacteriological studies with ampicillin/sulbactam on selected strains of gram-negative bacteria

Antibacterial activity of sulbactam or ampicillin alone and in combination on ampicillin-resistant, beta-lactamase-producing Gram-negative bacteria (Citrobacter freundii and Escherichia coli) was studied. Inhibition of beta-lactamase activity by sulbactam was investigated using intact and disrupted cells. Minimal inhibitory concentrations of ampicillin were high but decreased significantly in the presence of sulbactam. Similar enzyme inhibition was observed with intact and disrupted bacterial cells, thus indicating efficient penetration by sulbactam into the periplasmic space. Bacterial killing was achieved in approximately 4 hrs with ampicillin/sulbactam at concentrations that neither killed nor inhibited the same strains when the drugs were used alone. Sulbactam was more effective against plasmid-cured strain of E. coli than the same plasmid-containing organism.     

Treatment evaluation of experimental staphylococcal infections: comparison of beta-lactam, lipopeptide, and glycopeptide antimicrobial therapy

LY 146032, teicoplanin, vancomycin, oxacillin, cephalothin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam were studied against six isolates of staphylococci (including both Staphylococcus aureus and coagulase negative staphylococci) using in vivo and in vitro methods. In vitro susceptibility measurements demonstrated that all six isolates were sensitive to LY 146032 and vancomycin and that five of six isolates were sensitive to tiecoplanin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam. Comparison of antimicrobial therapy in an in vivo rabbit model demonstrated that cefoperazone plus sulbactam was active against the greatest number of isolates (five of six) based on a reduction of greater than or equal to 5.0 log10 colony forming units per milliliter (CFU/ml) from growth control at the end of the animal treatment study. Vancomycin and oxacillin were equal in achieving reductions of greater than or equal to 5.0 log10 CFU/ml in four of the six isolates. Comparing each isolate's in vivo outcome to in vitro data shows that in vitro susceptibility tests overpredict the sensitivity of these six isolates to LY 146032 and vancomycin, are variable for teicoplanin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam, and underpredict for oxacillin.     

Role of beta-lactamase and different testing conditions in oxacillin-borderline-susceptible staphylococci.

A group of staphylococcal isolates for which oxacillin MICs were intermediate (1 to 4 micrograms/ml) were studied to establish the role of beta-lactamase in this phenomenon. MICs and MBCs of oxacillin and penicillin with and without clavulanic acid or sulbactam (4 or 16 micrograms/ml, respectively) were determined for 11 Staphylococcus aureus and 2 coagulase-negative Staphylococcus isolates for which oxacillin MICs were 1 to 4 micrograms/ml. The susceptibility studies were done with incubation at 35 and 30 degrees C, and the MICs were read at 24 and 48 h. Of the 13 isolates, 4 became resistant when longer incubation or 30 degrees C incubation was used, and the MICs for 9 remained in the intermediate range. Only three of these strains were susceptible to penicillin, and beta-lactamase was not detected. For 6 of 10 beta-lactamase-positive strains, there was a greater-than-twofold-dilution reduction in oxacillin MICs with the addition of clavulanic acid or sulbactam. Of the four strains that became resistant with incubation at the lower temperature, a clavulanic acid effect was observed in three but only at 35 degrees C. The oxacillin MIC for one of the beta-lactamase-negative strains was also reduced with clavulanic acid; however, this strain was inhibited by 1 microgram of clavulanic acid per ml alone. Bactericidal activity was observed with two or four times the oxacillin MIC in eight strains tested at both temperatures, and the combination with clavulanic acid was bactericidal at higher than four times the MIC in five of the strains at 30 degrees C. Our results suggest that oxacillin intermediate MICs for staphylococcal isolates are due not only to beta-lactamase hyperproduction but also some other unidentified factor. The reduction in oxacillin MIC observed when clavulanic acid was added to one strain was probably due to the intrinsic inhibitory activity of clavulanic acid.     

Susceptibility of Haemophilus influenzae to chloramphenicol and eight beta-lactam antibiotics

We examined the minimal inhibitory concentrations and minimal bactericidal concentrations of chloramphenicol, ampicillin, ticarcillin, cefamandole, cefazolin, cefoxitin, cefotaxime, ceforanide, and moxalactam for 100 isolates of Haemophilus influenzae, 25 of which produced beta-lactamase. Susceptibility was not influenced by the capsular characteristic of the organism. The mean minimal inhibitory concentrations of cefamandole, ticarcillin, and ampicillin for beta-lactamase-producing strains were 3-, 120-, and 400-fold higher than their respective mean minimal inhibitory concentrations for beta-lactamase-negative strains. No such difference was noted for the other antibiotics. We performed time-kill curve studies, using chloramphenicol, ampicillin, cefamandole, cefotaxime, and moxalactam with two concentrations of the antimicrobial agents (4 or 20 times the minimal inhibitory concentrations) and two inoculum sizes (10(4) or 10(6) colony-forming units per ml). The inoculum size had no appreciable effect on the rate of killing of beta-lactamase-negative strains. The rates at which beta-lactamase-producing strains were killed by chloramphenicol, cefotaxime, and moxalactam was not influenced by the inoculum size. Whereas cefamandole in high concentrations was able to kill at 10(6) colony-forming units/ml of inoculum, it had only a temporary inhibiting effect at low drug concentrations. Methicillin and the beta-lactamase inhibitor CP-45,899 were able to neutralize the inactivation of cefamandole by a large inoculum of beta-lactamase-producing H. influenzae.     

Antibiotic resistance among recent clinical isolates of Haemophilus influenzae in Japanese children

From January 1997 to July 1999, a total of 867 isolates of Haemophilus influenzae were recovered in the microbiology laboratory of Chiba Children's Hospital. The overall prevalence of beta-lactamase production was 12.8%. Ampicillin-MICs for all of the 111 beta-lactamase-producing isolates was > or =4 microg/ml. A total of 26 beta-lactamase-negative isolates (3.4% of all beta-lactamase-negative isolates and 3.0% of all isolates) were found to be resistant to ampicillin. The prevalence of beta-lactamase negative ampicillin-resistant strains (BLNAR) increased remarkably to 8.9% during the last 7-month period. It is noteworthy that the MICs not only of penicillins but also of cephems for BLNAR were significantly higher than those for ampicillin-susceptible isolates. Eight beta-lactamase-producing isolates of H. influenzae (7.2% of all beta-lactamase-producing isolates) were resistant to amoxicillin-clavulanate (AMPC/CVA). Consequently, the overall resistance to ampicillin was 15.8%, and that to AMPC/CVA was 3.0%. The results of this study corroborate the findings of previous investigators in the US (Doern et al., 1997) regarding the emergence of BLNAR and beta-lactamase-producing AMPC/CVA-resistant strains (BLPACR) of H. influenzae. Continued monitoring of susceptibility trends will be required to guide appropriate chemotherapy.     

Activity of ampicillin-sulbactam and oxacillin in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus.

Using a rat model of aortic valve infective endocarditis, we previously found that oxacillin was equally effective against an oxacillin-susceptible strain of Staphylococcus aureus and a beta-lactamase-hyperproducing borderline oxacillin-susceptible strain of S. aureus; also, ampicillin-sulbactam was less effective than oxacillin against both isolates and at low doses was less effective against the borderline-susceptible strain than against the fully oxacillin-susceptible strain (C. Thauvin-Eliopoulos, L. B. Rice, G. M. Eliopoulos, and R. C. Moellering, Jr., Antimicrob. Agents Chemother. 34:728-732, 1990). In the present study, we extended this work, using alternative treatment schedules and additional bacterial strains. Extending treatment with low doses of ampicillin-sulbactam (500 and 250 mg/kg of body weight per day, respectively) to 6.5 days resulted in equalization of effectiveness against the previously studied strains BOSSA-1 and OSSA-1 (3.75 +/- 1.61 log10 and 4.71 +/- 1.79 log10 CFU of residual viable bacteria per g, respectively). Against the borderline oxacillin-susceptible strain BOSSA-1, increasing the sulbactam dosage from 500 to 2,000 mg/kg/day while maintaining a fixed dose of ampicillin (1,000 mg/kg/day) by continuous infusion resulted in lower bacterial counts (4.93 +/- 1.84 log10 versus 3.65 +/- 1.26 log10 CFU of residual viable bacteria per g, respectively), but this difference was of only borderline significance; differences in efficacy between the low-dose and high-dose sulbactam regimens were exaggerated when intermittent intravenous administration was used (6.19 +/- 1.90 log10 versus 3.37 +/- 1.41 log10 CFU/g, respectively; P < 0.001). However, for any individual sulbactam dosage, the model of administration (continuous versus intermittent infusion) did not affect the activity of the regimen. When additional strains were used in the model, oxacillin and ampicillin-sulbactam (1,000 plus 2,000 mg/kg/day) were equally effective against both oxacillin-susceptible and borderline oxacillin-resistant strains of S. aureus. These results support the predictions that oxacillin would be clinically effective in the treatment of infections caused by borderline oxacillin-susceptible strains of S. aureus and that, except at very low doses, ampicillin-sulbactam would also be as effective against borderline-susceptible strains as against fully oxacillin-susceptible strains of S. aureus.     

Bacteremia due to Staphylococcus aureus with reduced susceptibility to vancomycin

Four cases of bacteremia caused by Staphylococcus aureus with heteroresistance to vancomycin (hetero-VRSA) were described. In at least two of these four mortalities, the cause of death was temporally related to the hetero-VRSA bacteremia. The vancomycin and teicoplanin MICs of the resistant subpopulations of these four hetero-VRSA were 8 and 24 microg/ml, respectively. All isolates were producers of beta-lactamase, produced penicillin-binding protein PBP2a, and possessed the mecA gene accounting for methicillin resistance. Thickening of the peptidoglycan cell wall was observed by electron microscopy. When ampicillin was combined with vancomycin, in vitro synergism was detected using the checkerboard titration method (epsilonFIC = 0.13). The use of vancomycin plus ampicillin-sulbactam could be a viable option in treating severe hetero-VRSA infection in view of the higher affinity of ampicillin toward PBP2a.     

Comparative activity of beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with beta-lactams against beta-lactamase-producing anaerobes.

The in vitro activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with six beta-lactams against 88 beta-lactamase-producing anaerobes were determined. When combined with the beta-lactams, the three beta-lactamase inhibitors showed no synergy against the 10 Bacteroides fragilis homology group II strains. When the beta-lactams were combined with the inhibitors, their geometric mean MICs against the remaining 78 strains were reduced from 4.2 to 150.2 micrograms/ml to 0.2 to 12.9 micrograms/ml. The activity of the beta-lactams combined with the beta-lactamase inhibitors was significantly greater than that of the beta-lactams alone against all groups except B. fragilis homology group II, with 76 to 100% of the strains susceptible to ampicillin plus inhibitor and greater than or equal to 90% susceptible to the other combinations.     

Coagulase-negative staphylococci resistant to beta-lactam antibiotics in vivo produce penicillin-binding protein 2a.

Strains of coagulase-negative staphylococci were tested for in vivo resistance in a rabbit model of prophylaxis of endocarditis. Regimens of nafcillin, cefazolin, cefamandole, and vancomycin were compared for efficacy in the prevention of infection caused by two methicillin-resistant strains and a susceptible strain. For the two resistant strains, vancomycin was the most effective drug tested. All regimens were effective against the susceptible strain. The two strains for which prophylaxis with beta-lactam antibiotics failed produced a beta-lactam antibiotic-inducible penicillin-binding protein (PBP) that comigrated in sodium dodecyl sulfate-polyacrylamide gels with the low-affinity PBP 2a that is associated with methicillin resistance in strains of Staphylococcus aureus. Like PBP 2a, this PBP had low binding affinity for beta-lactam antibiotics. Peptide maps after either V8 protease or chymotrypsin digestion of radiolabeled PBP 2a or silver-stained preparations were virtually identical to one another and to maps of PBP 2a from a heterogeneous and a homogeneous strain of S. aureus. Methicillin resistance in coagulase-negative staphylococci and therapeutic failure with beta-lactam antibiotics in vivo is associated with production of PBP 2a, which appears to be highly conserved structurally among different species of staphylococci.     

Effects of inner-membrane-associated beta-lactamase on penicillin-binding protein assays. Study of stably derepressed Pseudomonas aeruginosa strains from experimental endocarditis

We studied penicillin-binding protein (PBP) profiles of two Pseudomonas aeruginosa strains stably derepressed for constitutive, type Id beta-lactamase overproduction. Substantial levels of beta-lactamase were found to be strongly associated with isolated inner membranes of these two strains, as well as from a plasmid-encoded, TEM-2 beta-lactamase-producing control strain of P. aeruginosa. The inner membrane-associated beta-lactamase resulted in significant decreases in the intensity on autoradiographs of PBPs labelled with 35S-penicillin, yielding spurious PBP profiles for these strains. Inner membrane beta-lactamases could be substantially removed by a sonication-ultracentrifugation step, producing the bona fide PBP profiles.     

Efficacy of amoxycillin/clavulanic acid in experimental Staphylococcus aureus endocarditis in the rat

The efficacy of amoxycillin/clavulanic acid was compared with that of flucloxacillin, vancomycin and amoxycillin in an experimental model of Staphylococcus aureus endocarditis. Doses of the antibiotics were selected to produce peak concentrations in rat serum similar to those achievable in man after administration of parenteral therapeutic doses. Amoxycillin clavulanic acid was more effective than amoxycillin alone against endocarditis caused by beta-lactamase producing strains of Staph. aureus, illustrating the beta-lactamase inhibitory activity of clavulanic acid in vivo. Amoxycillin/clavulanic acid was as effective as flucloxacillin in these infections whereas vancomycin was generally less active. These results illustrate the clinical potential of amoxycillin/clavulanic acid in the prophylaxis, or in the therapy of severe staphylococcal infections.     

Pharmacokinetics of ampicillin and sulbactam in patients undergoing heart surgery.

The pharmacokinetics of ampicillin and sulbactam, a new beta-lactamase inhibitor, were investigated in 16 patients undergoing prosthetic cardiac valve insertion. The combination of 2 g of ampicillin and 1 g of sulbactam was administered as perioperative prophylaxis intravenously over 3 to 6 days. Several serum pharmacokinetic parameters were similar for the two drugs after three intravenous doses were given to patients following surgery. The half-lives of elimination of ampicillin and sulbactam were 79 +/- 4.9 and 88 +/- 5.9 min, the volumes of distribution were 15.6 +/- 1.4 and 17.7 +/- 1.2 liters/70 kg, and the total plasma clearances were 144.4 +/- 14.5 and 147.2 +/- 14.5 ml/min, respectively. The peak concentrations of ampicillin and sulbactam in serum were calculated to be 134.3 +/- 1.3 and 58.3 +/- 1.2 micrograms/ml, respectively. Ampicillin and sulbactam rapidly penetrated from the blood into various tissues collected during heart surgery, such as sternum, pericardium, myocardium, and endocardium. The concentrations of ampicillin in tissue ranged from 17.8 +/- 9.9 to 50 +/- 29.5 micrograms/g, and those of sulbactam in tissue ranged from 8.8 +/- 6.2 to 19.6 +/- 10.1 micrograms/g. The concentrations of ampicillin and sulbactam in serum and tissue also apparently exceeded the MICs against most beta-lactamase-producing bacteria usually involved in postoperative wound infections and prosthetic valve endocarditis. The ratio of the two compounds was approximately 2:1 in serum and in the various tissues affected by the operation. The pharmacokinetics of ampicillin and sulbactam in serum and investigated tissues suggest that the combination of the two beta-lactams will be effective in the perioperative prophylaxis of patients undergoing heart surgery.     

Susceptibilities of beta-lactamase-positive and -negative strains of Campylobacter coli to beta-lactam agents.

The percentages of susceptibility of 28 strains of Campylobacter coli to beta-lactam agents were 96% for amoxicillin and ampicillin, 57% for ticarcillin, 4% for cefoxitin and cefuroxime, 61% for cefotaxime, and 11% for ceftazidime. None of the strains were susceptible to penicillin G, piperacillin, cefazolin, cephalothin, cefamandole, and cefoperazone. All strains were susceptible to imipenem and ciprofloxacin, and 21% were susceptible to erythromycin. A beta-lactamase was detected in 68% of the strains by cefinase disks and by the nitrocefin method. The beta-lactamase-positive strains were significantly less susceptible to amoxicillin, ampicillin, and ticarcillin than the beta-lactamase-negative strains (P < or = 0.003). Clavulanic acid (0.25 microgram/ml) but not sulbactam and tazobactam (2 micrograms/ml) lowered to susceptible levels the amoxicillin and ampicillin MICs of the only strain of C. coli resistant to amoxicillin, ampicillin, and ticarcillin.