REVIEWS OF INFECTIOUS DISEASES. VOL. 1, NO.1. JANUARY-FEBRUARY 1979 © 1979 by The University of Chicago. 0162-0886179/0101-0034$00.75
Cefoxitin: An Overview of Clinical Studies in the United States Harold C. N eu
From the Division of Infectious Diseases, College of Physicians and Surgeons, Columbia University, New York, New York
Although the number of available antimicrobial agents has tripled in the past two decades, major problems in the chemotherapy of infectious diseases still confront the clinician. The increased number of .infections due to gram-negative aerobic bacteria in hospitalized patients, the increase in plasmid-mediated resistance to antibiotics, and the increasing awareness of the importance of anaerobic pathogens are three major factors in infectious diseases that have prompted recent molecular modifications of antibiotics [1-4]. Cefoxitin, a cephamycin antibiotic closely related to the cephalosporin antibiotics, is one such agent which has been shown in in vitro and in vivo experiments to offer great promise as a chemotherapeutic agent [5-81. Cefoxitin is a J3-lactam antibiotic that is produced by chemical modification of cephamycin C, which is produced naturally by Streptomyces lactam.durans. Cefoxitin contains a methoxy group at position 7 of the J3-lactam ring; this group conveys resistance to J3-lactamases of both gram-positive and gram-negative bacteria, whether of an aerobic or anaerobic species [7, 8]. Cefoxitin binds to all of the J3-lactam-binding pro-
teins and thus inhibits cell wall biosynthesis [9]. Like other J3-lactam compounds, cefoxitin is a bactericidal agent that inhibits both gram-positive cocci, such as Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, and gram-negative bacilli, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis [6-8]. By virtue of its resistance to hydrolysis by J3-lactamase, cefoxitin inhibits many organisms characteristically resistant to the cephalosporins, namely, Serratia marcescens, Proteus oulgaris, Prooidencia, and Bacteroides fragilis [4, 10-13]. It lacks in vitro activity, however, against Enterobacter cloacae and Pseudomonas aeruginosa [13]. Pharmacologic studies have shown that, unlike those cephalosporins that contain an acetoxy side chain at position 3 of the ring [14], ccfoxitin is not metabolized in humans, and it is excreted unchanged by the kidneys [15]. The serum t~ of cefoxitin after iv administration is 40-60 min, and the compound is distributed widely in most body tissues [15, 16]. In view of the excellent microbiologic and pharmacokinetic properties of cefoxitin, extensive clinical studies of the efficacy of this antibiotic in therapy of various infections were undertaken in the United States. This report is a review of these studies.
Please address requests for reprints to Dr. Harold C. Neu, Division of Infectious Diseases, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032.
233
Downloaded from http://cid.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Cefoxitin, a new cephamycin antibiotic that is active against aerobic and anaerobic bacteria, was studied by 35 investigators in the United States. Of 657 patients eligible for evaluation of efficacy of the compound, 69% were cured and 92% were cured or improved on clinical grounds. Bacteriologic response to therapy with cefoxitin was equally good for infections due to gram-positive cocci (94% cured), gram-negative bacilli (87% cured), and anaerobes (95% cured). Cefoxitin was effective clinically and bacteriologically in the eradication of infections due to organisms resistant to ampicillin, cephalothin, chloramphenicol, tetracycline, and aminoglycosides. Overall rates of favorable response to cefoxitin therapy by disease were: lower respiratory tract infections, 90%; urinary tract infections, 87%; intraabdominal infections, 90%; gynecologic infections, 94%; and septicemia, 84%. Cefoxitin was tolerated well, and major abnormalities of hematologic, hepatic, renal, or central nervous system function were encountered rarely. Resistance to cefoxitin did not develop among gram-negative cocci, anaerobes, or gram-negative bacilli in the medical centers in which the antibiotic was used.
Neu
234
Materials and Methods
Results
A total of 920 patients were treated with cefoxitin by 35 investigators in the United States during the years 1975-1977. There were 208 genitourinary infections, 101 gynecologic infections, 195 lower respiratory tract infections, 187 ~kin a.nd soft tissue infections, 39 bone and joint infections, 67 gastrointestinal infections, and various other diagnoses. All patients were considered for evaluation of the safety of cefoxitin, but only 657 (71 %) met the criteria for consideration for evaluation of the efficacy of the drug. In any in-
Table 1.
Comparative activities of cefoxitin and bacteria isolated from patients III clinical studies of the efficacy of cefoxitin. ce'p~alothin. against
Characteristic Susceptible to both Suscep tible to cefoxitin only Susceptible to cephalothin only Resistant to both
Percentage of isolates GramGrampositive negative Anaerobes cocci bacilli (n = 369) (n = 543) (n = 202) 89
3
7
65
68
22
22
1 12
3
7
Downloaded from http://cid.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Patients were treated with cefoxitin if they had an acute infection due to an infectious agent that was presumed or proven to be susceptible to cefoxitin. Cefoxitin was administered by the iv route in doses of 3-12 g per day, depending on the severity of the infection. Individuals with markedly reduced renal function (i.e., creatinine clearance of
Cefoxitin: An Overview of Clinical Studies in the United States Harold C. N eu
From the Division of Infectious Diseases, College of Physicians and Surgeons, Columbia University, New York, New York
Although the number of available antimicrobial agents has tripled in the past two decades, major problems in the chemotherapy of infectious diseases still confront the clinician. The increased number of .infections due to gram-negative aerobic bacteria in hospitalized patients, the increase in plasmid-mediated resistance to antibiotics, and the increasing awareness of the importance of anaerobic pathogens are three major factors in infectious diseases that have prompted recent molecular modifications of antibiotics [1-4]. Cefoxitin, a cephamycin antibiotic closely related to the cephalosporin antibiotics, is one such agent which has been shown in in vitro and in vivo experiments to offer great promise as a chemotherapeutic agent [5-81. Cefoxitin is a J3-lactam antibiotic that is produced by chemical modification of cephamycin C, which is produced naturally by Streptomyces lactam.durans. Cefoxitin contains a methoxy group at position 7 of the J3-lactam ring; this group conveys resistance to J3-lactamases of both gram-positive and gram-negative bacteria, whether of an aerobic or anaerobic species [7, 8]. Cefoxitin binds to all of the J3-lactam-binding pro-
teins and thus inhibits cell wall biosynthesis [9]. Like other J3-lactam compounds, cefoxitin is a bactericidal agent that inhibits both gram-positive cocci, such as Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, and gram-negative bacilli, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis [6-8]. By virtue of its resistance to hydrolysis by J3-lactamase, cefoxitin inhibits many organisms characteristically resistant to the cephalosporins, namely, Serratia marcescens, Proteus oulgaris, Prooidencia, and Bacteroides fragilis [4, 10-13]. It lacks in vitro activity, however, against Enterobacter cloacae and Pseudomonas aeruginosa [13]. Pharmacologic studies have shown that, unlike those cephalosporins that contain an acetoxy side chain at position 3 of the ring [14], ccfoxitin is not metabolized in humans, and it is excreted unchanged by the kidneys [15]. The serum t~ of cefoxitin after iv administration is 40-60 min, and the compound is distributed widely in most body tissues [15, 16]. In view of the excellent microbiologic and pharmacokinetic properties of cefoxitin, extensive clinical studies of the efficacy of this antibiotic in therapy of various infections were undertaken in the United States. This report is a review of these studies.
Please address requests for reprints to Dr. Harold C. Neu, Division of Infectious Diseases, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032.
233
Downloaded from http://cid.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Cefoxitin, a new cephamycin antibiotic that is active against aerobic and anaerobic bacteria, was studied by 35 investigators in the United States. Of 657 patients eligible for evaluation of efficacy of the compound, 69% were cured and 92% were cured or improved on clinical grounds. Bacteriologic response to therapy with cefoxitin was equally good for infections due to gram-positive cocci (94% cured), gram-negative bacilli (87% cured), and anaerobes (95% cured). Cefoxitin was effective clinically and bacteriologically in the eradication of infections due to organisms resistant to ampicillin, cephalothin, chloramphenicol, tetracycline, and aminoglycosides. Overall rates of favorable response to cefoxitin therapy by disease were: lower respiratory tract infections, 90%; urinary tract infections, 87%; intraabdominal infections, 90%; gynecologic infections, 94%; and septicemia, 84%. Cefoxitin was tolerated well, and major abnormalities of hematologic, hepatic, renal, or central nervous system function were encountered rarely. Resistance to cefoxitin did not develop among gram-negative cocci, anaerobes, or gram-negative bacilli in the medical centers in which the antibiotic was used.
Neu
234
Materials and Methods
Results
A total of 920 patients were treated with cefoxitin by 35 investigators in the United States during the years 1975-1977. There were 208 genitourinary infections, 101 gynecologic infections, 195 lower respiratory tract infections, 187 ~kin a.nd soft tissue infections, 39 bone and joint infections, 67 gastrointestinal infections, and various other diagnoses. All patients were considered for evaluation of the safety of cefoxitin, but only 657 (71 %) met the criteria for consideration for evaluation of the efficacy of the drug. In any in-
Table 1.
Comparative activities of cefoxitin and bacteria isolated from patients III clinical studies of the efficacy of cefoxitin. ce'p~alothin. against
Characteristic Susceptible to both Suscep tible to cefoxitin only Susceptible to cephalothin only Resistant to both
Percentage of isolates GramGrampositive negative Anaerobes cocci bacilli (n = 369) (n = 543) (n = 202) 89
3
7
65
68
22
22
1 12
3
7
Downloaded from http://cid.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Patients were treated with cefoxitin if they had an acute infection due to an infectious agent that was presumed or proven to be susceptible to cefoxitin. Cefoxitin was administered by the iv route in doses of 3-12 g per day, depending on the severity of the infection. Individuals with markedly reduced renal function (i.e., creatinine clearance of
