Pharmacokinetics and bioavailability of sultamicillin estimated by high performance liquid chromatography

Infusions of 50 mg of sulbactam per kg per day and 400 mg of ampicillin per kg per day in divided doses to infants and children with bacterial meningitis produced levels in cerebrospinal fluid approximately one-third those in serum. Concentrations in cerebrospinal fluid of 5.5 ,ug of sulbactam per ml and 16.0 ,ug of ampicillin per ml declined within a few days of therapy to 1.9 ,g of sulbactam per ml and 5.2 ,ug of ampicillin per ml.Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae are the leading pathogens causing bacterial meningitis in children (16,22). For years, ampicillin was the mainstay of therapy (4). However, its effectiveness was compromised by the emergence (9, 11, 21) and increasing incidence (8,16,18,19,21) of strains of H. influenzae which produce 1-lactamase enzymes that hydrolyze ampicillin, destroying its activity.Sulbactam, a ,-lactamase inhibitor which combines with ,-lactamases to destroy their activity (10) and prevent the destruction of P-lactams, is under clinical development for coadministration with ampicillin for treatment of infections. The activity of sulbactam plus ampicillin against ampicillinresistant strains of H. influenzae and S. pneumoniae (1,3,12,13,23) and the enhanced penetration of sulbactam through inflamed meninges (7,17) suggested that this combination might be useful in the treatment of bacterial meningitis in children.Therefore, we examined the efficacy of ampicillin plus sulbactam in the treatment of meningitis in infants and young children and compared this therapy with the standard therapy of ampicillin plus chloramphenicol. The results (reported previously on 41 of 53 patients receiving sulbactam plus ampicillin [14]) showed eradication of bacteria, including four ampicillin-resistant pathogens, from cerebrospinal fluid (CSF) from 34 of 35 evaluable patients during therapy with ampicillin plus sulbactam. As a part of this study, we also examined the penetration of sulbactam and ampicillin into CSF. range, 1 to 13 doses]). Sample set 2 was obtained 1 to 5 (median, 3) days later and sample set 3 was obtained 6 to 11 (median, 8) days after sample set 1. Serum samples were also obtained at the time of the first sampling. Because of the nature of the patient population, sufficient volume to run the desired assays was sometimes not available. The samples were frozen until assays for ampicillin by bioassay (6) and for sulbactam by gas chromatography (5, 6) were done. Each assay was free from interference by the coadministered drug and had a coefficient of variation of less than 10% for quadruplicate assays. The few CSF samples with unusually high drug concentrations were correlated with very high concentrations in serum, suggesting that the high concentrations in CSF were not due to contamination. MATERIALS AND METHODSComparisons were made by means of paired t tests, whenever possible, to reduce the extensive variability expected from this patient population. Group t tests were used otherwise.

“…As shown elsewhere for other kinetic parameters (2,5,6,15) (14) indicate that this combination is highly effective in the treatment of meningitis in infants and children.…”

Section: Resultssupporting

confidence: 70%

Penetration of sulbactam and ampicillin into cerebrospinal fluid of infants and young children with meningitis

Foulds

Mcbride

Knirsch

et al. 1987

“…Sulbactam was extracted from 0.5 ml of serum by ether phase as previously described by Rogers et al (18). Sulbactam levels in vegetations were determined by assay in supernatants of vegetation samples homogenized in 0.3 ml of 0.1 M phosphate buffer, as previously described (9,14).…”

mentioning

confidence: 99%

“…Sulbactam levels in vegetations were determined by assay in supernatants of vegetation samples homogenized in 0.3 ml of 0.1 M phosphate buffer, as previously described (9,14). A solution of 0.05 M ammonium phosphate-methanol-phosphoric acid (95:5:0.1) was used as the mobile phase with a flow rate of 1.5 ml/min (18). The detector was operating at a wavelength of 214 nm.…”

mentioning

confidence: 99%

Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase

Fantin

Pangon

Potel

et al. 1990

We studied the efficacy of sulbactam, a j8-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum ,-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 ,ug/ml with 5 x 105 and 5 x i07 CFU of inoculum per ml, respectively). Sulbactam inhibited the P-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log1o CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactani-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 loglo CFU/g of vegetation greater than that produced by single-drug therapy (P < 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P < 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 ,ug/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.The therapeutic use of broad-spectrum cephalosporins that are relatively resistant to hydrolysis by P-lactamases such as ceftriaxone has been initially associated with the emergence of resistant clinical isolates with an overproduction of chromosomal ,B-lactamase among members of the family Enterobacteriaceae (Enterobacter cloacae, Proteus vulgaris, Citrobacterfreundii, and Serratia marcescens) (19,20). The mechanism of resistance, involving the overproduction of class 1 P-lactamase as a result of mutation, is spontaneously nontransferable. More recently, strains of Klebsiella pneumoniae and Escherichia coli resistant to cefotaxime and ceftriaxone have been reported (2,22). The mechanism of ,-lactam resistance involved is a new, plasmid-mediated P-lactamase called SHV-2 (10). A similar type of resistance, related to another new, plasmid-mediated ,-lactamase called CTX-1 or TEM-3, has been described in multiresistant K. pneumoniae causing outbreaks of nosocomial infections (3, 23 However, no in vivo data are available on the activity of a P-lactamase inhibitor in combination with a broad-spectrum cephalosporin for the treatment of an infect...

“…Coadministration of sulbactam appears to have very little effect on the pharmacokinetics of ampicillin, suggesting that coadministration of the sulbactam will not affect the usual dosing regimens for ampicillin (5). The pharmacokinetics of sulbactam are very similar to those of ampicillin in subjects with normal renal function (2,4,5,11,14). The purposes of this study were to evaluate the pharmacokinetics of ampicillin-sulbactam in subjects with various degrees of renal function to evolve dosage guidelines and to determine the effect of hemodialysis on the clearances of ampicillin and sulbactam.…”

mentioning

confidence: 99%

Pharmacokinetics of ampicillin (2.0 grams) and sulbactam (1.0 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis

Blum

Kohli

Harrison

et al. 1989

The single-dose pharmacokinetics of intravenously administered ampicillin (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects (CLCR, >60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, <7 ml/min) were studied. The terminal half-lives for ampicillin and sulbactam more than doubled in patients with severe renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly correlated with ampicillin (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of distribution and nonrenal clearance for ampicillin and sulbactam were not affected by renal function. Hemodialysis approximately doubled the ampicillin and sulbactam total body clearance. Mean totals of 34.8 4.0% of the ampicillin dose and 44.7 + 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In hemodialysis patients, the ampicillin half-life was 17.4 8.0 h and the sulbactam half-life was 13.4 + 7.4 h. The ampicillin and sulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3 h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal clearance remaining relatively constant, suggests that the same ratio of ampicillin to sulbactam is appropriate regardless of renal function. An adjustment of the ampicillin (2.0 g) and sulbactam (1.0 g) dose to twice daily would be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.Ampicillin-sulbactam is a broad-spectrum, bactericidal, P-lactamase-resistant antimicrobial combination with potent activity against Haemophilus influenzae, Branhamella catarrhalis, Neisseria species, and most gram-positive and anaerobic pathogens (3,9,10,13). Coadministration of sulbactam appears to have very little effect on the pharmacokinetics of ampicillin, suggesting that coadministration of the sulbactam will not affect the usual dosing regimens for ampicillin (5). The pharmacokinetics of sulbactam are very similar to those of ampicillin in subjects with normal renal function (2,4,5,11,14). The purposes of this study were to evaluate the pharmacokinetics of ampicillin-sulbactam in subjects with various degrees of renal function to evolve dosage guidelines and to determine the effect of hemodialysis on the clearances of ampicillin and sulbactam.