Sara-Jane Salstrom

Timentin versus piperacillin or moxalactam in the therapy of acute bacterial infections.

In a randomized comparative study, 116 patients with acute bacterial infections were treated with timentin (ticarcillin plus clavulanic acid) or a comparative agent (piperacillin for respiratory or urinary tract infections, and moxalactam for soft tissue infections). There were 91 clinically evaluated infections (timentin, 46; piperacillin, 29; moxalactam, 16). Twelve patients were bacteremic. A satisfactory clinical response occurred in all 46 patients treated with timentin and in 42 of the 45 treated with a comparative agent. Two clinical failures were due to superinfection (a Staphylococcus aureus pneumonia in the piperacillin group and an enterococcal skin infection in the moxalactam group), and one clinical failure was due to a primary S. aureus skin infection (moxalactam group). One wound isolate of Pseudomonas aeruginosa developed resistance to timentin during therapy (despite clinical improvement). Adverse reactions were uncommon but did include one patient treated with timentin who developed unexplained hallucinations.

Bacampicillin, Ampicillin, Cephalothin, and Cephapirin Levels in Human Blood and Interstitial Fluid

The diffusibility of bacampicillin, ampicillin, cephalothin, and cephapirin into human interstitial fluid was investigated by using crossover studies. We compared bacampicillin with ampicillin and found that bacampicillin was better absorbed after oral administration. Blood, interstitial fluid, and urine levels were consistently higher in volunteers who received bacampicillin. We compared cephalothin with cephapirin and found that blood and interstitial fluid levels were comparable throughout the study.

Timentin versus moxalactam in the treatment of skin and soft tissue infections.

T imentin is a combination of two beta-lactam antibiotics, ticarcillin and clavulanic acid. Clavulanic acid, a “suicide” inhibitor of beta-lactamases, enhances the spectrum of activity of ticarcillin to include beta-lactamase-producing Staphylococcus, gram-negative enteric bacteria including Klebsiella, Enterobacter, and Serratia, some strains of Pseudomonas aeruginosa, and Bacteroides species including 8. fragilis [1,2]. With this broadened spectrum of antimicrobial activity, Timentin appears to be an ideal candidate for use in the treatment of skin and soft tissue infections. In this study, we treated patients who were hospitalized for skin and soft tissue infections with either Timentin or moxalactam to evaluate the efficacy and toxicity of this new preparation.

Timentin versus piperacillin in the therapy of serious urinary tract infections

In a comparative study, 47 patients received Timentin, a combination of ticarcillin plus clavulanic acid, or piperacillin to treat serious urinary tract infections. Thirty-nine infections in 38 patients were clinically evaluable (21 in the Timentin-treated group and 18 in the piperacillin-treated group). These included pyelonephritis (10 in the Timentin-treated group and five in the piperacillin-treated group), bladder infections with sepsis (11 in the Timentin-treated group and 11 in the piperacillin-treated group) and bladder infections without fever (two in the piperacillin-treated group). The addition of clavulanic acid to ticarcillin greatly enhanced the susceptibility of five of the 28 evaluable pathogens in the Timentin-treated group (two Escherichia coli isolates, two Staphylococcus aureus isolates, and one Klebsiella pneumoniae isolate). The minimal inhibitory concentrations at which 50 and 90 percent of the bacterial growth was inhibited were 4 and 64 micrograms/ml, respectively, for Timentin, and 4 and 32 micrograms/ml, respectively, for piperacillin. All evaluable patients had a satisfactory symptomatic response at the end of the trial. Of 28 evaluable pathogens treated with Timentin, 18 were eradicated up through the one-week post-therapy evaluation period; of 27 evaluable pathogens treated with piperacillin, 18 were eradicated up through the same time period. Eradicated pathogens included E. coli (six of 13 in the Timentin-treated group and six of 11 in the piperacillin-treated group), other Enterobacteriaceae (three of three in the Timentin-treated group and eight of 10 in the piperacillin-treated group), Pseudomonas aeruginosa (two of four in the piperacillin-treated group), enterococcus (two of three in the Timentin-treated group and two of two in the piperacillin-treated group), staphylococcal species (four of five in the Timentin-treated group), and other organisms (three of four in the Timentin-treated group). Resistance did not develop in any of the persisting pathogens. Adverse effects thought possibly to be related to the study drugs were minimal and included rash in one Timentin-treated patient and diarrhea in another.

In vitro susceptibility of the Bacteroides fragilis group in community hospitals

The antimicrobial susceptibility of clinical isolates of the Bacteroides fragilis group was determined at six community hospitals (one large, greater than 600 beds; and five smaller, 96-325 beds). Imipenem was the most active beta-lactam with 100% of isolates being sensitive at 4 micrograms/ml. The percentage of isolates inhibited at 16 micrograms/ml (and 32 micrograms/ml) for the 7-alpha-methoxy antibiotics was: cefoxitin 66 (90); moxalactam 73 (85); cefotetan 68 (72); cefmetazole 40 (61). Metronidazole, chloramphenicol, and clindamycin were active against 100%, 100%, and 89% at breakpoints of 8 micrograms/ml, 8 micrograms/ml, and 4 micrograms/ml, respectively. The activity of several beta-lactams in our report differed slightly from that reported from university teaching hospitals. There were differences at many of the breakpoints for activity of some of the beta-lactam antibiotics for isolates from the large community hospital as compared with the combined isolates from the smaller community hospitals. Interestingly, the pattern was one of more resistance at the smaller community hospitals.

Canine model for the simultaneous measurement of antibiotic levels in tissues and bacterial killing rate.

Antibiotic levels in serum are commonly used to guide antibiotic therapy. The antibiotic levels in interstitial fluid are a more accurate reflection of the efficacy of antibiotic penetration into the tissues. Although there are experimental models for determining interstitial fluid levels, there is no model for measuring the in vivo killing of bacteria, which is the endpoint of antibiotic therapy. We developed an accurate, reliable animal model which allows measurement of the in vivo killing of bacteria along with a determination of antibiotic levels in tissues. Modified Sykes-Moore chambers were applied to the dissected external oblique muscle of 14 dogs. The chambers were inoculated with clinical isolates of Staphylococcus aureus or Escherichia coli. The dogs were treated with cefoxitin or gentamicin. Quantitative cultures were performed, and the antibiotic levels in interstitial fluid were determined. Images

Levels of amdinocillin in human plasma and interstitial fluid following intravenous administration

Amdinocillin levels in human plasma and interstitial fluid were studied in 12 human volunteers. The results showed that relatively high levels of amdinocillin were detected in the interstitial fluid. The fluid to plasma ratio of the area under the curve was 0.25. This is consistent with high diffusibility as seen in drugs with a low percentage of protein binding.

Pharmacokinetics of intravenous cefmetazole with emphasis on comparison between predicted theoretical levels in tissue and actual skin window fluid levels.

Cefmetazole is a cephamycin antibiotic which is resistant to hydrolysis by various beta-lactamases. This study evaluated the pharmacokinetics of cefmetazole, including its intravascular and interstitial fluid distribution, by using the skin window (SW) technique. A 2-g dose of cefmetazole was given intravenously over 30 min to each of 12 healthy adult male volunteers every 6 h for nine doses. Plasma levels were assayed at predetermined intervals after doses 1, 5, and 9. Interstitial fluid levels were determined by the SW technique. Antibiotic levels were assayed by the agar well bioassay technique. A concentration-versus-time plot indicates that cefmetazole is rapidly distributed, with mean peak levels in plasma equal to 126 micrograms/ml at the end of the half-hour infusion. The mean plasma half-life was 1.1 h. Plasma and tissue distribution constants permitted calculation of theoretical levels in tissue. Parallel elimination slopes for SW and theoretical tissue level showed that the SW model distribution kinetics are closely related. The area under the curve for the SW was 73.9 mg.h/liter. This was comparable to the theoretical level in tissue, which was 96 mg.h/liter. Furthermore, the area under the curve of theoretical tissue level/plasma was 0.6 and that of SW/plasma was 0.47. These results demonstrate that the SW technique yielded a result quite close to the theoretical tissue level. Ultrafiltration analysis indicated that as cefmetazole levels in plasma increased from 10 to 250 micrograms/ml, plasma protein binding of the antibiotic dropped from 85 to 65%. Finally, 60 to 70% of the drug was recovered from the urine as biologically active drug over 6 h postinfusion.