Serum Bactericidal Titres After Cefoperazone With and Without Sulbactam

1992

In a randomized crossover trial, six volunteers received 200-and 400-mg doses of loracarbef (LY 163892), a new oral cephalosporin. Mean ± standard error of the mean concentrations in serum obtained after 1.5 and 3 h were 13.2 + 2.8 and 4.3 ± 0.7 mg/liter, respectively, after the 400-mg dose and 6.9 ± 1.0 and 1.7 ± 0.2 mg/liter, respectively, after the 200-mg dose. Bactericidal reciprocal titers measured against respiratory pathogens in serum suggested that loracarbef would be highly effective against Streptococcus pneumoniae and (16, 23). The use of an ex vivo protocol is particularly interesting when drugs are given orally, because it accounts for the between-volunteer variability in absorption, pharmacokinetic properties, and metabolism. A similar experimental design has recently been used to compare two formulations of oral erythromycin (3). Loracarbef (LY 163892) is a new oral carbacephem that is closely related to cefaclor. It has a good in vitro activity against staphylococci (oxacillin susceptible), non-group D streptococci, ,-lactamase-positive and -negative Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. The following bacteria are resistant: P-lactamase-negative ampicillin-resistant Haemophilus influenzae, methicillin-resistant staphylococci, enterococci, Enterobacter spp., Serratia spp., and pseudomonads. Loracarbef is well absorbed (85 to 90%) independently of food intake. The elimination half-life is 1 to 1.1 h. Approximately 90% of the drug is recovered unchanged in the urine within 24 h after administration, and probenecid markedly decreases renal elimination. Its protein binding is 25% (6).The purpose of the present investigation was to assess the relation between dose and pharmacodynamic parameters by measuring the bactericidal activity in serum (17)(18)(19)(20) and the rate of killing in serum (4) in healthy volunteers receiving loracarbef at two different dosages in a randomized crossover trial. The bacteria that are involved in sinusitis, bronchitis, and otitis media, three target diseases for oral cephalosporins, were chosen for testing in this study. MATERUILS AND METHODSThe protocol of the study was approved by the Ethical Committee of the Institut Jules Bordet. Written informed consent was obtained from all volunteers. This randomized crossover study included six healthy volunteers and was performed between June and August 1990. The inclusion criteria were as follows: healthy volunteers of both genders who were receiving no medication; who had a regular professional occupation; whose age ranged from 18 to 50 years; and whose body mass index (weight [in kilograms]/ height2) ranged from 20 to 30. The exclusion criteria were pregnancy and lactation, intolerance or allergy to f3-lactam antibiotics, renal failure (serum creatinine, > 1.5 mg/100 ml), hepatic failure (serum bilirubin, >1 mg/100 ml), antibiotics within the previous 2 months, any medical investigation within 2 months, and recent blood donation.Administrat...

Bactericidal titers of loracarbef (LY 163892) in serum and killing rates in volunteers receiving 400 versus 200 milligrams

1992

Antimicrobial prophylaxis for major head and neck surgery in cancer patients: sulbactam-ampicillin versus clindamycin-amikacin

Phan

Andry

et al. 1992

A total of 99 patients with head and neck cancer who were to undergo surgery were randomized in a prospective comparative study of sulbactam-ampicillin (1:2 ratio; four doses of 3 g of ampicillin and 1.5 g of sulbactam intravenously [i.v.] Wound infections occurred in 14 (33%) sulbactamampicillin-treated patients and 9 (21%) clindamycin-amikacin-treated patients (P = 0.19; not significant). The rates of bacteremia were 2 and 4%, respectively. The rates of bronchopneumonia were 14.3 and 23.2%, respectively (P was not significant). Most infections were polymicrobial, but strict anaerobes were recovered only from patients who received sulbactam-ampicillin. Antimicrobial treatment was required within 20 days after surgery for 42% of the sulbactam-ampicillin-treated patients and 44% of the clindamycin-amikacintreated patients. By comparison with previous studies, we observed a decreased efficacy of antimicrobial prophylaxis in patients with head and neck cancer undergoing surgery because of the increased proportion of patients who were at very high risk for infection (extensive excision and plastic reconstruction in patients with recurrent stage III and IV cancers) and because of the longer durations of surgery.It has been proven and widely accepted that patients with head and neck cancer undergoing surgery (clean contaminated procedures) benefit from preoperative antibiotic prophylaxis once the skin and oropharyngeal cavities are opened (5,17,18,27,30). Simple laryngectomy has been associated with a very low risk of infection (<4%) (5, 20). Placebo-controlled studies are considered unethical in patients undergoing surgery for head and neck cancer (excluding simple laryngectomy), and any new regimen should be compared with an effective regimen, which has been clindamycin plus an aminoglycoside (netilmicin or amikacin), as determined from studies previously performed in our center (11,27). The combination of a P-lactam antibiotic with a 1-lactamase inhibitor has a spectrum of activity very similar to that of the clindamycin-amikacin combination, including strict anaerobes. However, in recent studies, we have documented that a significant number of failures were due to methicillin-resistant staphylococci (11,27). The in vitro activity of the combination ampicillin-sulbactam against methicillin-resistant staphylococci is high (21,23,34), and the combination of amoxicillin-clavulanic acid was found to be effective in a rat model of endocarditis (7). On the other hand, the combination of clindamycin-amikacin is consid-* Corresponding author. t Present address: European Organization for Research and Treatment of Cancer Central Office, 1200 Brussels, Belgium. ered to be ineffective against those bacteria, since methicillin-resistant staphylococci are frequently resistant to clindamycin and should probably be considered to be resistant to amikacin as well.As far as the choice of the ,-lactamase inhibitor is concerned, sulbactam has two advantages over clavulanic acid; it is more potent (up to 100-fold) in inhibiting the cl...

Ex vivo pharmacodynamic study of piperacillin alone and in combination with tazobactam, compared with ticarcillin plus clavulanic acid

Duchateau

Lambert

et al. 1993

Ten volunteers received piperacillin (4 g), piperacillin (4 g) plus tazobactam (0.5 g) (Tazocin), and ticarcillin (3 g) plus clavulanic acid (0.2 g) (Timentin) intravenously over 30 min in a cross-over blinded scheme. Blood samples were obtained 0.5 and 3 h after the end of infusion to measure by (high-pressure liquid chromatography) the concentration and bactericidal titers against 70 gram-negative bacilli. Serum time-kill curves were done against 35 strains to measure killing rates and area under the time-kill curve. Using the measure of serum bactericidal activity, ticarcillin-clavulanic acid and piperacillin-tazobactam were equally effective against Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Serratia marcescens, and Bacteroidesfragilis. Piperacillin-tazobactam was superior to ticarcillin-clavulanic acid against piperacillin-resistant Kiebsiella pneumoniae (4 to 16 times) and S. marcescens (2 to 4 times). By using the area under the time-kill curve, piperacillin-tazobactam was equivalent to ticarcillin-clavulanic acid against piperacillin-susceptible strains; piperacillin-tazobactam was significantly more active than piperacillin against piperacillin-resistant strains and was more active than ticarcillin-clavulanic acid when the sample obtained 3 h after the end of infusion to volunteers was considered. Serum piperacillin concentrations (mean standard error of the mean; in mg/liter) were 115 + 13 at 0.5 h and 7.4 + 1.4 at 3 h after the administration of piperacillin alone and 105.5 12.6 (0.5 h) and 7.7 + 1.6 after the administration of piperacillin-tazobactam. Serum tazobactam concentrations (in milligrams per liter) were 13.1 1.4 at 0.5 h and 1.2 + 0.2 at 3 h. The piperacillin-tazobactam ratio was 8 0.3 at 0.5 h and 6.2 0.5 at 3 h. Piperacillin-tazobactam appears promising against ,3-lactamase-producing gram-negative bacilli.Infections by gram-negative organisms are still a major cause of morbidity in patients with cancer, especially when they are neutropenic (19). Treatment of these infections often consists of the administration of a broad-spectrum ,-lactam antibiotic in combination with an aminoglycoside, although the use of monotherapy with a broad-spectrum cephalosporin or imipenem has been advocated. The increasing incidence of gram-negative bacilli with broad-spectrum ,3-lactamases has caused the empiric use of monotherapy to be questioned. One way to overcome this problem is use of the combination of a broad-spectrum penicillin with an effective ,-lactamase inhibitor. Piperacillin is a broadspectrum penicillin which has a high level of in vitro activity against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Tazobactam is an effective inhibitor of various types of 3-lactamases, especially the penicillinase type of Staphylococcus aureus, the TEM types, and the cephalosporinase of Bacteroides fragilis (2,3,(8)(9)(10)14). In particular, tazobactam is a better inhibitor of the chromosomal cephalosporinases of members of the family Enterobactenaceae (Enterobacter,...