Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. B), 193-195

Intravenous cefoxitin sodium in the treatment of urinary tract infections C. E. Cox

Cefoxitin sodium, a new antibiotic, is a highly effective, broad-spectrum, semisynthetic cephamycin. Ninety-three patients hospitalized with urinary tract infections, 63 of whom had undergone a urological operative procedure, were treated with intravenous cefoxitin (1 g every 8 h in 100 ml of 5% dextrose and water) for 5 to 14 days. Many of these patients had underlying urological problems that caused re-infection to occur irrespective of initial therapy. Eighty-seven per cent of the patients had negative urine cultures following therapy and 90% had negative urine cultures 4 to 6 weeks after therapy. Adverse reactions were minimal. Because of the unique, broad antibacterial spectrum of cefoxitin, it is a significant addition to the currently available therapeutic field. Introduction Cefoxitin sodium is a new semi-synthetic cephamycin antibiotic developed by Merck Sharp & Dohme Research Laboratories. Its structure closely resembles that of the semisynthetic cephalosporin antibiotic cephalothin, with significant differences: a methoxy group (rather than a hydrogen atom) in the 7-a position; and a carbamoyloxy (rather than acetoxy) substituent at the 3-methyl position. Possession of the 7-a methoxy substituent confers upon cefoxitin a high degree of resistance to inactivation by bacterial cephalosporinases, the class of /Mactamase enzymes that constitutes a major mechanism of bacterial resistance to the cephalosporin antibiotics. As a result, the antibacterial spectrum of cefoxitin is considerably broader in vitro and in vivo than that of any known marketed or experimental cephalosporin. Active against virtually all strains of bacterial species that are sensitive to the cephalosporins, cefoxitin is also highly active against bacterial species that, by virtue of cephalosporinase production, have characteristically been cephalosporin-resistant: Serratia marcescens, indole-positive Proteus, Provideneia, and anaerobic Gram-negative rods such as Bacteroidesfragilis. Moreover, cefoxitin is active against the large majority of cephalosporinase-producing, cephalosporin-resistant strains of common pathogenic species of Gram-negative rods—Escherichia coli, Klebsiella, indole-negative Proteus, Salmonella, and Shigella—strains whose prevalence has been steadily rising in the past decade. Like existing cephalosponns, cefoxitin is essentially inactive against Pseudomonas aervginosa and enterococci. Parenterally administered cefoxitin is well tolerated in animals in high doses, with a 193

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Department of Urology, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee, U.S.A.

194

C. E. Cox

degree of safety comparable to that of cephalothin; unlike cephaloridine, cefoxitin is free of nephrotoxic properties in the animal species studied (monkeys, rats, mice, and rabbits). Methods

Results As noted, laboratory studies indicated some degree of toxicity in most of the patients. This toxicity was manifested by one or by a combination of the following factors: leukocytosis, fever, severe upper urinary tract symptoms and, on occasion, positive blood cultures. All patients had normal BUN and/or serum creatinine pre-therapy; results of these studies weTe also normal post-therapy. Studies of renal, hepatic, and haematopoietic function were carried out in the course of therapy. Bacteriological studies included a pre-treatment urine culture, a during-treatment urine culture, a post-therapy urine culture and, in most instances, a urine culture 4 to 6 weeks afteT therapy. This 4- to 6-weeks post-therapy culture was not obtained from those patients who had a positive urine culture at the termination of therapy. All bacterial isolates underwent sensitivity testing with the standard antimicrobial agents as well as a cephalothin disc and a cefoxitin disc. Twenty-eight of the 93 patients had a pre-treatment organism that was sensitive to cefoxitin but resistant to cephalothin. However, the results in those patients who had cephalothin-resistant organisms pre-treatment are not segregated in the data subsequently presented because theTe was no statistical difference between results in patients with cephalothin-resistant organisms and those with cephalothin-sensitive organisms. Two of the 3 pre-treatment Providencia cultures were resistant to cephalothin; all 14 indolepositive Proteus isolates were resistant to cephalothin pre-therapy; and, significantly, 12 of the 56 E. coli and Klebsiella isolates were resistant to cephalothin pre-treatment. Bacteriological results of this study were most gratifying (Table I). Forty patients had E. coli before starting therapy; 36 (90 %) of these patients had a negative urine culture post-theTapy. Sixteen of the pre-therapy cultures gTew Klebsiella, and 14 (88%) revealed a negative post-therapy urine culture. Most encouraging weTe the results from the indolepositive Proteus patients, in whom 11 of the 14 pre-therapy cultures weTe negative posttheTapy. In view of the fact that no other cephalosporin is capable of eradicating indolepositive Proteus, this finding is clearly significant. Two of the 3 Providencia infections

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During 1975 to 1976, 105 urological patients were treated with i.v. cefoxitin at the University of Tennessee Center for the Health Sciences. Of these 105 patients, 93 fulfilled the standard, multi-institutional protocol requirements. Sixty-six of the 93 patients were male; 27 were female. The age range was 19 to 75 years, with a median age of 58. Urinary tract infection was present in all patients, as evidenced by a urine culture revealing > 100,000 colonies of bacteria per millilitre of urine. All patients were hospitalized, and 63 patients underwent a urological procedure immediately prior to or during the course of cefoxitin therapy. All patients were considered to be toxic or potentially toxic, as evidenced by fever, elevated leukocyte count, or underlying urological disease. A few patients had positive blood cultures; all cultures became negative subsequent to cefoxitin therapy. All patients received 1 g of cefoxitin i.v. every 8 h in 100 ml of 5% dextrose and water. Treatment was carried out for 5 to 14 days, with an average of 7-6 days per patient.

Urinary tract infections

195

were eradicated in this study. Overall, 81 of 93 cultures (87%) that were positive pretreatment were eradicated post-therapy. Culture results, 4 to 6 weeks after therapy, are also displayed in Table I. However, little significance is placed on these results, because many of these patients had underlying urological problems that caused re-infection to occur, irrespective of the results following cefoxitin therapy. Nevertheless, 90% of the patients with a negative posttreatment urine culture were free of infection 4 to 6 weeks after therapy.

Pre-therapy* Escherichia coli Klebsiella Proteus mirabilis P. rettgeri P. vulgaris P. morgana Providencia Totals

Post-therapyt (90%) (88%) (90%) (75%) (83%) (75%) (67%)

40 16 20 4 6 4 3

36 14 18 3 5 3 2

93

81/93 (87%)

4 to 6 weeks post-therapy 3O/32J 9/11 14/15 2/3 5/5 2/3 1/1 63/70(90%)

'Number of patients with positive urine cultures pre-therapy. fNumber of patients with negative urine cultures following therapy. ^Number of patients (less those lost to follow-up and those with post-therapy infection) with negative urine cultures 4 to 6 weeks after therapy.

Side effects Side effects and toxicity in this study were minimal. Five patients complained of or demonstrated mild phlebitis during i.v. theTapy with cefoxitin. This phlebitis was transient and did not require discontinuation of therapy. In all instances, the phlebitis resolved upon termination of therapy. Allergic manifestations were not encountered. There was no evidence of hematopoietic toxicity. Transient changes in renal function were noted in 6 patients, but function returned to normal either during therapy or immediately thereafter. Transient changes in hepatic function were noted during therapy, but function here also returned to normal, either during or after therapy. Discussion The antibacterial spectrum of cefoxitin is clearly superior to that of the other available cephalosporins. Cefoxitin has antibacterial activity against indole-positive Proteus, Providencia and cephalothin-resistant E. coli and Klebsiella. In addition, studies in vitro indicate that cefoxitin is effective against Serratia and some species of Enterobacter. Cefoxitin provides higher blood levels and has a longer half-life than does cephalothin. Cefoxitin sodium appears to represent a valuable addition to the therapeutic armamentarium and significantly complements the currently available cephalosporin antibiotics.

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Table I. Bacteriological results of i.v. cefoxitin treatment of urinary tract infections

Intravenous cefoxitin sodium in the treatment of urinary tract infections.

Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. B), 193-195 Intravenous cefoxitin sodium in the treatment of urinary tract infections C. E. Co...
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