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Cefoxitin Sodium

Cefoxitin is a semisynthetic cephamycin b-lactam antibiotic.

Uses

Cefoxitin is used in the treatment of serious infections of the lower respiratory tract, skin and skin structure, bone and joint, and urinary tract; septicemia; gynecologic infections (including endometritis, pelvic cellulitis, and pelvic inflammatory disease); and intra-abdominal infections (including peritonitis and intra-abdominal abscess) caused by susceptible bacteria. Cefoxitin also has been used in the treatment of uncomplicated gonorrhea and is used for perioperative prophylaxis.

Prior to and during cefoxitin therapy, the causative organism should be cultured and in vitro susceptibility tests conducted. In serious infections, therapy may be initiated pending results of in vitro tests.

Use of cefoxitin does not replace surgical procedures such as incision and drainage when indicated.

Gram-positive Aerobic Bacterial Infections

Cefoxitin is used in the treatment of lower respiratory tract infections (including pneumonia and lung abscess) caused by susceptible Staphylococcus aureus, Streptococcus pneumoniae, or other streptococci (except Enterococcus faecalis [formerly S. faecalis]); septicemia caused by susceptible S. aureus or S. pneumoniae; skin and skin structure infections caused by susceptible S. aureus, S. epidermidis, or streptococci (except E. faecalis); or bone and joint infections caused by susceptible S. aureus. However, cefoxitin generally should not be used in the treatment of infections caused by gram-positive bacteria when a penicillin or a first generation cephalosporin could be used.

Gram-negative Aerobic Bacterial Infections

Cefoxitin is used in the treatment of lower respiratory tract infections (including pneumonia and lung abscess) caused by susceptible Haemophilus influenzae, Escherichia coli, or Klebsiella; urinary tract infections caused by susceptible E. coli, Klebsiella, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, or Providencia rettgeri (formerly Proteus rettgeri); septicemia or intra-abdominal infections (including peritonitis and intra-abdominal abscess) caused by susceptible E. coli or Klebsiella; gynecologic infections (including endometritis, pelvic cellulitis, pelvic inflammatory disease) caused by susceptible E. coli or Neisseria gonorrhoeae; or skin or skin structure infections caused by susceptibleE. coli, Klebsiella, or P. mirabilis.

Mixed Aerobic-Anaerobic Bacterial Infections

Cefoxitin is used in the treatment of lower respiratory tract infections or septicemia caused by susceptible Bacteroides (including B. fragilis); intra-abdominal infections (including peritonitis and intra-abdominal abscess) caused by susceptible Bacteroides or Clostridium; or gynecologic infections (including endometritis, pelvic cellulitis, and pelvic inflammatory disease) and skin and skin structure infections caused by susceptible Bacteroides (including B. fragilis), Clostridium, Peptococcus niger, Peptostreptococcus, or S. agalactiae (group B streptococci).

Cefoxitin has been effective in many mixed aerobic-anaerobic infections which failed to respond to an aminoglycoside and clindamycin. In clinical studies in patients with intra-abdominal infections caused by Bacteroides (i.e.,B. distasonis, B. fragilis, B. ovatus, B. thetaiotaomicron), eradication rates 1-2 weeks after cefoxitin therapy have been reported to be 70-80%.

Gonorrhea and Associated Infections

Cefoxitin has been used in the treatment of uncomplicated gonorrhea in adults and adolescents, but is not considered a drug of choice for gonorrhea. The US Centers for Disease Control and Prevention (CDC) and many clinicians recommend that uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single oral dose of azithromycin or a 7-day regimen of oral doxycycline). However, fluoroquinolones should not be used for the treatment of gonorrhea acquired in Asia or the pacific islands (including Hawaii) and may be inadvisable for infections acquired in other areas where N. gonorrhoeae with quinolone resistance have been reported (including California). (See Uses: Gonorrhea and Associated Infections, in Ciprofloxacin 8:12.18.)

Alternative regimens that are recommended by the CDC for the treatment of uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents include a single IM dose of spectinomycin, a single IM dose of certain cephalosporins (ceftizoxime, cefotaxime, cefoxitin), or a single oral dose of certain fluoroquinolones (gatifloxacin, lomefloxacin, norfloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia.

Although a single 2-g IM dose of cefoxitin (with 1 g of oral probenecid) may be effective for the treatment of uncomplicated gonorrhea, the CDC states that the drug does not appear to offer any advantage over ceftriaxone for the treatment of gonorrhea. For additional information on current recommendations regarding the treatment of gonorrhea and associated infections, see Uses: Gonorrhea and Associated Infections in Ceftriaxone 8:12.06.12.

Pelvic Inflammatory Disease

The CDC and many clinicians currently suggest cefoxitin in combination with doxycycline as one possible regimen for the treatment of acute pelvic inflammatory disease (PID) in hospitalized adult and adolescent patients.

Because cefoxitin (like cephalosporins) is inactive against Chlamydia, the drug should not be used alone in the treatment of PID. PID is an acute or chronic inflammatory disorder in the upper female genital tract and can include any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. PID generally is a polymicrobial infection most frequently caused by N. gonorrhoeae and/or Chlamydia trachomatis; however, organisms that can be part of the normal vaginal flora (e.g., anaerobic bacteria, Gardnerella vaginalis, H. influenzae, enteric gram-negative bacilli, S. agalactiae) or mycoplasma (e.g., Mycoplasma hominis, Ureaplasma urealyticum) also may be involved. PID is treated with an empiric regimen provides broad-spectrum coverage that includes several anti-infectives.

The regimen should be effective against N. gonorrhoeae and C. trachomatis and also probably should be effective against anaerobes, gram-negative facultative bacteria, and streptococci. The optimum empiric regimen for the treatment of PID has not been identified. A wide variety of parenteral and oral regimens have been shown to achieve clinical and microbiologic cure in randomized studies with short-term follow-up; however, only limited data are available to date regarding elimination of infection in the endometrium and fallopian tubes or intermediate or long-term outcomes, including the impact of these regimens on the incidence of long-term sequelae of PID (e.g., tubal infertility, ectopic pregnancy, pain) is unknown.

Although many clinicians previously recommended that all patients with acute PID be hospitalized so that bed rest and supervised treatment with parenteral anti-infectives could be initiated, the CDC currently states that decisions regarding the necessity for hospitalization and whether an oral or parenteral regimen are most appropriate should be made on an individual basis since data are not available to date comparing efficacy of parenteral or oral therapy or inpatient or outpatient.

Based on observational data and theoretical concerns, the CDC states that hospitalization is indicated if surgical emergencies such as appendicitis cannot be excluded; the patient is pregnant; the patient is unable to follow or tolerate an outpatient oral regimen; the patient has severe illness, nausea and vomiting, or high fever; the patient has a tubo-ovarian abscess; the patient is immunodeficient because of HIV infection, immunosuppressive therapy, or other disease; or a clinical response was not obtained with an oral anti-infective regimen.

Parenteral Regimens for PID

When a parenteral regimen is indicated for the treatment of patients with PID, the CDC and other clinicians generally recommend a 2-drug regimen of cefotetan (2 g IV every 12 hours) or cefoxitin (2 g IV every 6 hours) given in conjunction with doxycycline (100 mg IV or orally every 12 hours) or a 2-drug regimen of clindamycin (900 mg IV every 8 hours) and gentamicin (usually a 2-mg/kg IV or IM loading dose followed by 1.5 mg/kg every 8 hours). While there is some evidence that parenteral cephalosporins (e.g., ceftizoxime, cefotaxime, ceftriaxone) also may be effective for the treatment of PID, the CDC states that there is less experience with use of these cephalosporins in patients with PID and these drugs may be less active than cefotetan or cefoxitin against anaerobic bacteria.

The CDC states that limited data support the use of several alternative parenteral regimens for the treatment of acute PID, including IV ofloxacin or IV levofloxacin (with or without IV metronidazole) or IV ampicillin sodium and sulbactam sodium with oral or IV doxycycline. Traditionally, parenteral regimens for the treatment of PID have been continued for at least 48 hours after the patient demonstrates substantial clinical improvement and then an oral regimen is continued to complete a total of 14 days of therapy; however, the CDC states that a transition to oral therapy may occur within 24 hours after the patient demonstrates clinical improvement and that decisions regarding such a transition should be guided by clinical experience. Most clinicians recommend at least 24 hours of direct inpatient observation for patients with tubo-ovarian abscesses, after which time anti-infective therapy at home is adequate.

Oral Regimens for PID

When PID is treated with an oral regimen, the CDC recommends a 14-day regimen that consists of oral ofloxacin (400 mg twice daily) or oral levofloxacin (500 mg once daily) with or without oral metronidazole (500 mg twice daily) or a regimen that consists of a single dose of cefoxitin (with a single oral dose of probenecid) or a parenteral cephalosporin (ceftriaxone, ceftizoxime, cefotaxime) and a 14-day regimen of oral doxycycline with or without oral metronidazole (500 mg twice daily for 14 days). Although ofloxacin is effective against both N. gonorrhoeae and C. trachomatis, the addition of metronidazole to the fluoroquinolone regimen may be necessary to provide adequate coverage against anaerobes. The optimal parenteral cephalosporin for the second regimen is unclear, although cefoxitin or ceftriaxone usually is preferred.

There is evidence from clinical trials that a single 2-g IM dose of cefoxitin (given with a single 1-g oral dose of probenecid) effectively produces a short-term clinical response in women with PID; however, because of theoretical limitations in cefoxitin’s coverage of anaerobes, the addition of metronidazole to the regimen may be necessary. In addition, metronidazole should be effective in the treatment of bacterial vaginosis, which is frequently associated with PID.

There are some data suggesting that use of oral doxycycline and oral metronidazole after primary parenteral therapy is safe and effective.

Patient Follow-up and Management of Sexual Partners

Regardless of whether an oral or parenteral regimen is used, patients with PID should demonstrate substantial clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; reduction in uterine, adnexal, and cervical motion tenderness) within 72 hours after initiation of anti-infective therapy, and patients being treated on an outpatient basis should receive a follow-up examination within this period to ensure that a response is obtained.

Patients who do not respond to therapy within 72 hours usually require hospitalization, additional diagnostic tests, and surgical intervention. In women who had documented infections with N. gonorrhoeae or C. trachomatis, some experts recommend rescreening for these organisms 4-6 weeks after therapy is completed. Sexual partners of women with PID should be examined and treated if they had sexual contact during the 60 days preceding the onset of symptoms in the patients. Evaluation and treatment are imperative because of the risk for reinfection and the strong likelihood of urethral gonococcal or chlamydial infection in the partner.

Male partners of women with PID caused by N. gonorrhoeae or C. trachomatis often are asymptomatic. Sex partners should be treated empirically with regimens effective against these organisms, regardless of the apparent etiology of PID or pathogens isolated from the infected woman.

Perioperative Prophylaxis

Cefoxitin is used perioperatively to reduce the incidence of infections in patients undergoing GI surgery (e.g., colorectal surgery, nonperforated appendectomy) or gynecologic and obstetric surgery (e.g., vaginal or abdominal hysterectomy, cesarean section). There is evidence that perioperative prophylaxis with an appropriate anti-infective agent can decrease the incidence of infection, particularly wound infection, after certain procedures; however, the benefits of prophylaxis must be weighed against the risks of adverse effects (including sensitivity reactions), emergence of resistant bacteria or superinfection, drug interactions, and cost.

Therefore, such prophylaxis usually is recommended only for procedures with a high rate of infection, procedures involving implantation of prosthetic material, and procedures in which the consequences of infection are especially serious.

Gynecologic and Obstetric Surgery

Perioperative prophylaxis decreases the incidence of infection after vaginal or abdominal hysterectomy. In addition, there also is evidence that perioperative prophylaxis can prevent infection after emergency cesarean section in high-risk situations (e.g., active labor or premature rupture of membranes), after second trimester abortions, or after first trimester abortion in high-risk women. A pooled analysis of results of randomized, placebo-controlled studies in women who underwent therapeutic abortion before 16 weeks’ gestation indicates that perioperative prophylaxis can reduce the overall risk of postabortal infection in these women by 42% compared with placebo. Some clinicians suggest that the preferred agents for perioperative prophylaxis in women undergoing vaginal or abdominal hysterectomy are IV cefazolin, IV cefotetan, or IV cefoxitin; IV cefazolin generally is the preferred agent for prophylaxis in women undergoing high-risk cesarean section or second trimester abortion; and IV penicillin G or oral doxycycline is preferred for high-risk first trimester abortions (previous history of PID or gonorrhea, multiple sexual partners).

Cefoxitin

GI Surgery

There is evidence that perioperative prophylaxis can decrease the incidence of infection after colorectal surgery, and such prophylaxis usually is recommended. For perioperative prophylaxis in patients undergoing colorectal surgery, some clinicians recommend a regimen of IV cefoxitin or IV cefotetan; a regimen of IV cefazolin and IV metronidazole; or a regimen of oral erythromycin and oral neomycin.

It has been suggested that the oral regimen may be as effective as the parenteral regimens. Many clinicians use both the oral regimen and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery; however, it is unclear whether this combined regimen is more effective than use of either an oral or parenteral regimen alone. In a randomized, prospective study in patients undergoing elective colorectal surgery, the overall incidence of intra-abdominal septic complications in those who received mechanical bowel preparation and an oral regimen (erythromycin and neomycin) alone was similar to that in those who received both the oral regimen and a parenteral regimen (cefoxitin); however, the incidence of abdominal wound infection was higher in those who received the oral regimen alone (14.%) than in those who received the combined oral and parenteral regimen (5%).

There is evidence that perioperative prophylaxis can reduce the incidence of infection after surgery for acute appendicitis, and some clinicians recommend use of IV cefoxitin or IV cefotetan for perioperative prophylaxis in patients undergoing appendectomy (nonperforated). If perforation has occurred, anti-infectives are considered treatment rather than prophylaxis and are continued postoperatively for several days. (See Contaminated Surgery under Uses: Perioperative Prophylaxis.)

For perioperative prophylaxis in high-risk patients undergoing esophageal or gastroduodenal surgery (e.g., those who are morbidly obese or have esophageal obstruction, decreased gastric acidity, or decreased GI motility) or high-risk patients undergoing biliary tract surgery (e.g., those older than 70 years of age or those with acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones), many clinicians recommend IV cefazolin as the drug of choice; however, some clinicians prefer cefoxitin in patients undergoing these procedures since it provides better coverage against anaerobic bacteria.

Timing and Number of Doses

When perioperative prophylaxis is indicated in patients undergoing clean-contaminated or potentially contaminated surgery, administration of the anti-infective should be timed to ensure that bactericidal concentrations of the drug are established in serum and tissues by the time the initial surgical incision is made; therapeutic concentrations of the drug should then be maintained in serum and tissues throughout the operation and until, at most, a few hours after the incision is closed. With many anti-infectives (e.g., cefazolin), a single dose given no more than 30 minutes before the incision provides adequate tissue concentrations throughout the procedure. If cefoxitin is used prophylactically, the manufacturer recommends that the drug be given just prior to surgery (approximately 30-60 minutes before the initial incision) to ensure adequate cefoxitin tissue concentrations at the time of surgery. If surgery is prolonged (more than 4 hours), major blood loss occurs, or an anti-infective with a short half-life (e.g., cefoxitin) is used, it may be advisable to administer one or more additional doses during the procedure; for prolonged procedures, some clinicians suggest that intraoperative doses be administered every 4-8 hours for the duration of the procedure.

Although anti-infective prophylaxis regimens reported in published studies often include 1 or 2 postoperative doses in addition to the preoperative dose, many clinicians state that postoperative doses generally are unnecessary. Continuation of prophylaxis after surgery appears to be of no additional value and may increase the risk of toxicity and bacterial superinfection. If signs of infection occur following surgery, specimens should be obtained for identification of the causative organism and appropriate therapy instituted.

Contaminated Surgery

Patients undergoing contaminated or dirty surgery, such as that involving a perforated abdominal viscus, a compound fracture, a traumatic wound, or a laceration due to an animal or human bite are at risk for infection.

When used in patients undergoing these procedures, anti-infective therapy is considered treatment rather than prophylaxis and is continued postoperatively for about 5 days. Some clinicians recommend use of a regimen of IV cefoxitin or IV cefotetan (with or without IV gentamicin) or, alternatively, a regimen of IV clindamycin and IV gentamicin for patients undergoing surgery involving a ruptured viscus; if ruptured viscus occurs in a postoperative setting (dehiscence), anti-infective coverage of nosocomial pathogens should be included. Cefazolin generally is the preferred anti-infective in patients undergoing surgery involving a traumatic wound; some clinicians state that if a bitewound is involved, an anti-infective against anaerobes (e.g., amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium) should be used. For penetrating intracranial wounds, including gunshot injuries, a broad-spectrum anti-infective such as ampicillin sodium and sulbactam sodium is recommended.

Dosage and Administration

Reconstitution and Administration

Cefoxitin sodium is administered by IV injection or infusion. The drug also has been administered by IM injection. Cefoxitin should be given IV in patients with septicemia or other severe or life-threatening infections, or in patients with lowered resistance resulting from debilitating conditions (e.g., malnutrition, trauma, surgery, diabetes, heart failure, malignancy), particularly with shock.

Intermittent IV Injection

For direct IV administration, 1 g of cefoxitin may be dissolved in at least 10 mL, or 2 g of the drug may be dissolved in 10 or 20 mL, of sterile water for injection. The appropriate dose may then be injected directly into a vein over a 3- to 5-minute period or slowly into the tubing of a compatible IV infusion solution.

Intermittent or Continuous IV Infusion

For intermittent or continuous IV infusion, 50 or 100 mL of 5 or 10% dextrose injection, 0.9% sodium chloride injection, or other compatible IV solution may be added to an infusion pack labeled as containing 1 or 2 g of cefoxitin; the solutions should preferably be infused with butterfly or scalp vein type needles. (See Cautions: Local Effects.) Alternatively, reconstituted solutions of the drug may be added to containers containing a compatible IV solution. ADD-Vantage® vials or infusion bottles labeled as containing 1 or 2 g of cefoxitin or the 10-g pharmacy bulk package should be reconstituted according to the manufacturer’s directions.

The pharmacy bulk package is not intended for direct IV infusion; doses of the drug from the reconstituted bulk package must be further diluted in a compatible IV infusion solution prior to administration. Thawed solutions of the commercially available frozen cefoxitin sodium injections are administered by IV infusion. The commercially available frozen cefoxitin sodium in dextrose injections should not be thawed by warming them in a water bath or by exposure to microwave radiation. A precipitate may form while the commercially available injection in dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature.

After thawing at room temperature, the container should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection container. The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete. The manufacturer recommends that other IV solutions flowing through a common administration tubing or site be discontinued while cefoxitin is being infused. If an aminoglycoside is administered concomitantly with cefoxitin, the drugs should be administered at separate sites.

IM Injection

IM injections of cefoxitin have been prepared by adding 2 mL of sterile water for injection or 0.5 or 1% lidocaine hydrochloride injection (without epinephrine) to each g of cefoxitin. The resultant solution contains approximately 400 mg of cefoxitin per mL. IM injections of cefoxitin should be made deeply into a large muscle such as the upper outer quadrant of the gluteus maximus, using usual techniques and precautions. The plunger of the syringe should be drawn back before IM injection to ensure that the needle is not in a blood vessel.

Dosage

Dosage of cefoxitin sodium is expressed in terms of cefoxitin.

Adult Dosage

The usual adult dosage of cefoxitin is 1-2 g every 6-8 hours, depending on the severity of the infection and the susceptibility of the causative organism. In severe, life-threatening infections, up to 12 g daily may be required. The manufacturer suggests that adults with uncomplicated infections (e.g., pneumonia, urinary tract infections, cutaneous infections) receive 1 g IV every 6-8 hours, those with moderately severe or severe infections receive 1 g IV every 4 hours or 2 g IV every 6-8 hours, and those with infections requiring higher dosage receive 2 g IV every 4 hours or 3 g IV every 6 hours.

Gonorrhea and Associated Infections

If cefoxitin is used for the treatment of uncomplicated gonorrhea caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism, the US Centers for Disease Control and Prevention (CDC) recommends that adults and adolescents receive a single 2-g IM dose of the drug (with a single 1 g oral dose of probenecid). Unless the presence of coexisting chlamydial infection has been excluded by appropriate testing, cefoxitin therapy for uncomplicated gonorrhea should be administered in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

Pelvic Inflammatory Disease

For the treatment of acute pelvic inflammatory disease (PID) in hospitalized patients, the CDC and others recommend that adults and adolescents receive an IV cefoxitin dosage of 2 g 4 times daily (every 6 hours) given in conjunction with 100 mg of doxycycline administered IV or orally twice daily for at least 2 days after clinical improvement; doxycycline therapy should be continued after the patient is discharged from the hospital in an oral dosage of 100 mg twice daily to complete 14 days of therapy.

For the treatment of PID when an oral regimen is used, the CDC and others recommend that adults and adolescents receive a single 2-g IM dose of cefoxitin and 1 g of oral probenecid followed by an oral doxycycline dosage of 100 mg twice daily for 14 days.

Perioperative Prophylaxis

For perioperative prophylaxis in patients undergoing uncontaminated GI surgery or vaginal or abdominal hysterectomy, the manufacturer recommends that adults receive 2 g of cefoxitin IV 30-60 minutes prior to surgery and 2 g every 6 hours thereafter for no more than 24 hours. When cefoxitin is used prophylactically in patients undergoing cesarean section, the manufacturer recommends that either a single 2-g dose be given IV as soon as the umbilical cord is clamped or a 3-dose regimen be given that consists of 2 g administered IV as soon as the umbilical cord is clamped followed by 2 g administered 4 hours and 8 hours after the first dose.

However, many clinicians recommend that a 1-g IV dose of cefoxitin be given for perioperative prophylaxis in patients undergoing vaginal or abdominal hysterectomy and that 1- to 2-g IV doses be given for perioperative prophylaxis in patients undergoing colorectal surgery or appendectomy (nonperforated). Perioperative prophylaxis should usually be discontinued within 24 hours after surgery.

While a single dose of an appropriate parenteral anti-infective agent administered 30 minutes or less prior to the skin incision usually provides adequate tissue concentrations of the drug throughout most procedures, cefoxitin has a relatively short plasma half-life and it may be advisable to administer one or more additional doses during surgery. More than one dose during the procedure also may be necessary if the procedure is delayed or prolonged (more than 4 hours) or if major blood loss occurs.

Many clinicians believe that postoperative prophylaxis usually is unnecessary for most clean or clean-contaminated procedures. If cefoxitin is used following contaminated or dirty surgery involving a ruptured abdominal viscus, 1-2 g should be given IV every 6 hours (with or without IV gentamicin in a dosage of 1.5 mg/kg every 8 hours). When used in this situation, the regimen should be continued postoperatively for about 5 days and is considered treatment rather than prophylaxis.

Pediatric Dosage

The usual dosage of cefoxitin for pediatric patients 3 months of age or older is 80-160 mg/kg daily given in 4-6 equally divided doses. The maximum daily dose is 12 g. For perioperative prophylaxis in pediatric patients 3 months of age or older, the manufacturer recommends that a dose of 30-40 mg/kg be given 30-60 minutes prior to surgery and that doses of 30-40 mg/kg be given every 6 hours thereafter for no more than 24 hours. Safe use of cefoxitin in infants younger than 3 months of age has not been established. Duration of Therapy The duration of cefoxitin therapy depends on the type of infection. In infections caused by group A b-hemolytic streptococci, therapy should be continued for at least 10 days.

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration must be modified in response to the degree of impairment, severity of the infection, and susceptibility of the causative organism. The manufacturer recommends a loading dose of 1-2 g in adults with renal impairment and the following maintenance dosage: Creatinine Clearance (mL/minute) Dosage 30-50 1-2 g every 8-12 h 10-29 1-2 g every 12-24 h 5-9 500 mg to 1 g every 12-24 h <5 500 mg to 1 g every 24-48 h In adults with renal impairment undergoing hemodialysis, a loading dose of 1-2 g should be given after each dialysis period followed by maintenance doses based on the patient’s creatinine clearance.

Cautions

Hypersensitivity Reactions

Maculopapular or erythematous rash, exfoliative dermatitis, pruritus, urticaria, eosinophilia, fever, and other hypersensitivity reactions have occurred with cefoxitin. Anaphylaxis and angioedema have been reported rarely in patients who received cefoxitin. If a hypersensitivity reaction occurs during cefoxitin therapy, the drug should be discontinued and the patient given appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

Local Effects

Local reactions are the most frequent adverse effects of cefoxitin. Pain, tenderness, and induration have been reported with IM administration, and thrombophlebitis has occurred with IV administration. The discomfort of IM injections may be minimized by administering the drug in 0.5% or 1% lidocaine hydrochloride solution, and the use of butterfly or scalp vein type needles rather than indwelling polyethylene catheters may decrease the incidence of thrombophlebitis with IV administration.

Renal Effects

Elevations in serum creatinine and/or BUN concentrations have been reported with cefoxitin. Rarely, renal toxicity and oliguria have occurred. These effects are most likely to occur in patients older than 50 years of age, patients with prior renal impairment, or patients who are receiving other nephrotoxic drugs. (See Drug Interactions: Nephrotoxic Drugs.)

Hematologic Effects

Transient leukopenia, neutropenia, granulocytopenia, thrombocytopenia, and bone marrow depression have been reported rarely in patients receiving cefoxitin. Anemia, including hemolytic anemia, has also been reported. Although a definite causal relationship has not been established, bleeding from the GI tract, surgical wounds, or genitourinary tract, and prolonged prothrombin time (PT) and/or activated partial thromboplastin time (APTT) have been reported rarely in patients receiving cefoxitin. Positive direct antiglobulin (Coombs’) test results have been reported during cefoxitin therapy, especially in patients with azotemia.

GI Effects

Rarely, adverse GI effects including nausea, vomiting, and diarrhea have been reported in patients receiving cefoxitin. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by toxin-producing clostridia resistant to cefoxitin, has occurred in patients who received cefoxitin (including patients who received multiple doses of the drug for perioperative prophylaxis). C. difficile and/or its toxin was isolated from the feces of most of these patients.

Mild cases of colitis may respond to discontinuance of cefoxitin alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. If colitis is moderate to severe or is not relieved by discontinuance of cefoxitin, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis should also be considered.

Other Adverse Effects

Transient increases in serum AST (SGOT), ALT (SGPT), LDH, and alkaline phosphatase concentrations and jaundice have occurred in patients receiving cefoxitin. Hypotension has also been reported.

Precautions and Contraindications

Prior to initiation of cefoxitin therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cefoxitin, cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among cephamycins, cephalosporins, and penicillins. Cefoxitin is contraindicated in patients who are hypersensitive to the drug or to cephalosporins and should be used with caution in patients hypersensitive to penicillins.

Although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals, the manufacturer states that cefoxitin should be used with caution in individuals with a history of allergy, particularly to drugs. Prolonged use of cefoxitin may result in overgrowth of nonsusceptible organisms. If superinfection occurs, appropriate therapy should be instituted. Cefoxitin should be used with caution in patients with a history of GI disease, particularly colitis.

Because C. difficile-associated diarrhea and colitis has been reported with cefoxitin, it should be considered in the differential diagnosis of patients who develop diarrhea during or following cefoxitin therapy. As with any potent anti-infective agent, periodic assessment of organ system functions (including renal, hepatic, and hematopoietic) is advisable during prolonged cefoxitin therapy.

Pediatric Precautions

Safety and efficacy of cefoxitin in infants younger than 3 months of age have not been established. In pediatric patients 3 months of age and older, high doses of cefoxitin have been associated with an increased incidence of eosinophilia and elevation of serum AST concentration.

The potential for toxic effects in pediatric patients from chemical components that may leach out of the plastic containers of the commercially available frozen cefoxitin injections has not been determined. Cefoxitin that has been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in infants.

Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates. The manufacturer of cefoxitin states that while this toxicity has not been demonstrated in infants older than 3 months of age, small infants in this age range may also be at risk for benzyl alcohol toxicity.

Mutagenicity and Carcinogenicity

Long-term studies in animals have not been performed to date to evaluate the mutagenic or carcinogenic potential of cefoxitin.

Pregnancy, Fertitlity and Lactation

Reproduction and teratologic studies in mice and rats using parenteral cefoxitin doses 1-7.5 times the maximum recommended human dose have not revealed evidence of impaired fertility or harm to the fetus, although a slight decrease in fetal weight was observed. When used in rabbits, cefoxitin was associated with a high incidence of abortion and maternal death; however, this was considered to be an expected consequence of the rabbit’s unusual sensitivity to antibiotic-induced changes in intestinal flora rather than a teratogenic effect. There are no adequate and controlled studies to date using cefoxitin in pregnant women. Because animal reproduction studies are not always predictive of human response, cefoxitin should be used during pregnancy only when clearly needed. Because cefoxitin is distributed into milk in small amounts, the drug should be used with caution in nursing women.

Drug Interactions

Probenecid

Concomitant administration of oral probenecid competitively inhibits tubular secretion resulting in higher and more prolonged serum concentrations of cefoxitin. The clinical application of this effect is limited mainly to the treatment of gonorrhea.

Nephrotoxic Drugs

Concurrent use of nephrotoxic agents such as aminoglycosides, colistin, polymyxin B, or vancomycin may increase the risk of nephrotoxicity with some cephalosporins. The possibility that this may occur with concurrent use of these nephrotoxic agents and cefoxitin should be considered.

Cefoxitin

Laboratory Test Interferences

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have been reported in patients receiving cefoxitin. This reaction may interfere with hematologic studies or transfusion cross-matching procedures.

Tests for Urinary Glucose

Cefoxitin reportedly causes false-positive results in urine glucose determinations using cupric sulfate solution (Benedict’s reagent, Clinitest®). Glucose oxidase methods (Clinistix®, Tes-Tape®) are unaffected.

Tests for Creatinine

At concentrations greater than 100 mcg/mL, cefoxitin may cause falsely elevated serum or urine creatinine values when the Jaffe reaction is used. Serum samples should not be tested for creatinine by the Jaffe reaction if drawn within 2 hours after drug administration.

Mechanism of Action

Cefoxitin is usually bactericidal in action. Like other b-lactam antibiotics, the antibacterial activity of cefoxitin results from inhibition of mucopeptide synthesis in the bacterial cell wall. Spectrum Although cefoxitin is a cephamycin antibiotic, the spectrum of activity of the drug resembles that of the second generation cephalosporins. Therefore, based on its spectrum of activity, cefoxitin can be classified as a second generation cephalosporin.

For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06. Cefoxitin generally is less active in vitro on a weight basis against susceptible gram-positive cocci than first generation cephalosporins and some second generation cephalosporins; however, the drug may be active against strains of gram-negative bacteria, especially Escherichia coli, Klebsiella, and Proteus, that are resistant to first generation cephalosporins. Unlike other currently available second generation cephalosporins, cefoxitin is active in vitro against many strains of Bacteroides fragilis. Cefoxitin is active against some Mycobacterium, including M. abscessus (formerly M. chelonae ssp. abscessus).

In Vitro Susceptibility Testing

Inoculum size, pH, and test media do not usually influence results of cefoxitin in vitro susceptibility tests. The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to cefoxitin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to cefoxitin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to cefoxitin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials. Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to cefoxitin, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to cefoxitin, a disk containing 30 mcg of cefoxitin should be used. The cephalosporin class disk containing 30 mcg of cephalothin or disks containing any other cephalosporins should not be used for testing susceptibility to cefoxitin. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterobacteriaceae with growth inhibition zones of 18 mm or greater are susceptible to cefoxitin, those with zones of 15-17 mm be have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing is performed according to the NCCLS standardized procedures using GC agar (with 1% defined growth supplement), N. gonorrhoeae with growth inhibition zones of 28 mm or greater are susceptible to cefoxitin, those with zones of 24-27 mm have intermediate susceptibility, and those with zones of 23 mm or less are resistant to the drug.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterobacteriaceae with MICs of 8 mcg/mL or less are susceptible to the drug, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to cefoxitin. When dilution susceptibility testing for N. gonorrhoeae is performed according to the NCCLS standardized procedure using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with MICs of 2 mcg/mL or less are susceptible to cefoxitin, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

In vitro, cefoxitin concentrations of 6.25 mcg/mL or less inhibit most strains of a- and b-hemolytic streptococci, Streptococcus pneumoniae, and staphylococci. The drug is active against most strains of penicillin G-resistant Staphylococcus aureus; however, staphylococci resistant to penicillinase-resistant penicillins (e.g., methicillin [no longer commercially available in the US]) usually are also resistant to cefoxitin. Enterococcus faecalis (formerly S. faecalis) is resistant to cefoxitin concentrations obtainable in serum.

Gram-negative Aerobic Bacteria

Cefoxitin is generally active in vitro against the following Enterobacteriaceae: Escherichia coli, Klebsiella (including K. pneumoniae), Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, Providencia rettgeri (formerly Proteus rettgeri), Salmonella, and Shigella. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of cefoxitin for most of these Enterobacteriaceae is 4-16 mcg/mL.

Cefoxitin is active in vitro against most strains of Haemophilus influenzae and is also active against many strains of N. gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains. However, antibiotic-resistant strains of N. gonorrhoeae are being reported with increasing frequency, and decreased susceptibility to cefoxitin has been reported in strains with chromosomally mediated resistance and in those with plasmid-mediated resistance to tetracycline (TRNG). Pseudomonas aeruginosa is resistant to the drug. Cefoxitin is active in vitro against b-lactamase-negative strains of Eikenella corrodens. In vitro, cefoxitin concentrations of 0.25 mcg/mL or less inhibit most strains of Legionella pneumophila; however, in vivo activity has not been demonstrated to date.

Anaerobic Bacteria

Cefoxitin is active in vitro against certain gram-negative anaerobic bacteria, including some strains of Bacteroides, Fusobacterium, and Prevotella, and certain gram-positive anaerobic bacteria, including some strains of Clostridium, Peptococcus, Peptostreptococcus, and Propionibacterium. The MIC50 of cefoxitin reported for B. fragilis, B. distasonis, B. ovatus, B. thetaiotamicron, B. uniformis, and B. vulgatus is 8-32 mcg/mL; however, the MIC90 of the drug reported for these Bacteroides is 16-64 mcg/mL or greater. The MIC90 of cefoxitin reported for Prevotella bivia, P. disiens, P. oralis, and P. melaninogenica (formerly B. bivius, B. disiens, B. oralis, and B. melaninogenicus) is 2-16 mcg/mL.

Fusobacterium nucleatum, F. necrophorum, F. varium, Peptostreptococcus, and Propionibacterium acnes generally are inhibited in vitro by cefoxitin concentrations of 1-16 mcg/mL. While the MIC90 of cefoxitin reported for C. perfringens is 1 mcg/mL, C. difficile is resistant to the drug. Resistance For information on possible mechanisms of bacterial resistance to b-lactam antibiotics, see Resistance in the Cephalosporins General Statement 8:12.06. Because of the 7a-methoxy group on the b-lactam ring, cefoxitin is generally more resistant than first generation cephalosporins to staphylococcal b-lactamases and most b-lactamases produced by gram-negative aerobic and anaerobic bacteria.

Pharmacokinetics

Absorption

Cefoxitin sodium is not appreciably absorbed from the GI tract and must be given parenterally. Following a single 1-g IM dose of cefoxitin in healthy adults with normal renal function, peak serum cefoxitin concentrations are attained within 20-30 minutes and average 22-24 mcg/mL; serum concentrations of the drug average 6.4 mcg/mL at 2 hours. After a single 1-g IV dose of cefoxitin given over 3 minutes in adults with normal renal function, serum concentrations of the drug average 110-125 mcg/mL at 5 minutes and less than 1-2 mcg/mL at 4 hours. A single 2-g IV dose given over 3 minutes results in average serum cefoxitin concentrations of 221 mcg/mL at 5 minutes and 3.6 mcg/mL at 4 hours. In a group of children 3 months to 6 years of age, 37. mg/kg of cefoxitin administered IV over 5 minutes every 6 hours resulted in average serum drug concentrations of 82 mcg/mL at 15 minutes, 27 mcg/mL at 1 hour, and 1.4 mcg/mL at 4 hours after each dose.

Distribution

Cefoxitin is widely distributed into body tissues and fluids including ascitic, pleural, and synovial fluid. Therapeutic concentrations of the drug may be obtained in bile if biliary obstruction is not present. The drug diffuses poorly into CSF following IM or IV administration, even when meninges are inflamed. Cefoxitin is 50-80% bound to plasma proteins. Cefoxitin readily crosses the placenta, and fetal serum concentrations may be equal to maternal serum concentrations. Small amounts of the drug are distributed into milk.

Elimination

The serum half-life of cefoxitin is 0.7-1.1 hours in adults with normal renal function. Serum concentrations of the drug are higher and the serum half-life is prolonged in patients with renal impairment. Serum half-life is reported to average 6.3 hours and 21.5 hours in adults with creatinine clearances of about 18 mL/minute and 2 mL/minute, respectively. Approximately 2% or less of a dose of cefoxitin is metabolized to descarbamylcefoxitin which is microbiologically inactive. Cefoxitin is rapidly excreted in urine by both glomerular filtration and tubular secretion.

The same system of anion transport is responsible for the tubular secretion of cefoxitin as for other b-lactam antibiotics and probenecid. Oral probenecid administered shortly before, or with cefoxitin usually slows the rate of excretion of cefoxitin and produces higher and more prolonged serum concentrations. In adults with normal renal function, approximately 85% of a single IM or IV dose of cefoxitin is excreted unchanged in the urine within 6 hours. Peak urinary concentrations of the drug may be 3 mg/mL or greater following a single 1-g IM dose in adults. Cefoxitin is removed by hemodialysis, but not by peritoneal dialysis.

Chemistry and Stability

Chemistry

cefoxitin Cefoxitin is a semisynthetic cephamycin antibiotic derived from cephamycin C, a substance produced by Streptomyces lactamdurans. The drug is a b-lactam antibiotic structurally and pharmacologically related to cephalosporins and penicillins.

Cephamycins contain a methoxy group rather than a hydrogen at the 7a-position on the b-lactam ring of the cephalosporin nucleus. Cefoxitin is commercially available as the sodium salt which occurs as a somewhat hygroscopic, white to off-white powder or granules having a slight characteristic odor. Cefoxitin sodium is very soluble in water and slightly soluble in alcohol.

Each gram of cefoxitin as the sodium salt contains 2.3 mEq of sodium. Following reconstitution with sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or 5% dextrose injection, cefoxitin sodium solutions have a pH of 4.2-7 and are colorless to light amber. The commercially available frozen cefoxitin sodium in dextrose injections are colorless to light amber, nonpyrogenic, iso-osmotic, sterile solutions of the drug; about 2 or 1.1 g of dextrose has been added to the 1- or 2-g injections of cefoxitin, respectively, to adjust osmolality. Cefoxitin sodium in dextrose frozen injections also contain sodium bicarbonate and/or hydrochloric acid to adjust pH to 6.5.

Cefoxitin

Stability

Cefoxitin sodium powder for injection should be stored at 2-25°C and not exposed to temperatures exceeding 50°C. The commercially available frozen cefoxitin sodium injection should be stored at a temperature not greater than -20°C. Cefoxitin sodium powder for injection and solutions of the drug may darken; however, this is not an indication of change in potency.

Cefoxitin sodium is most stable at pH 4-8; the free acid may precipitate at pH less than 4, and hydrolysis of the b-lactam ring may occur at pH greater than 8. Solutions of cefoxitin sodium for IM injection containing 400 mg of cefoxitin per mL of sterile or bacteriostatic water for injection, or 0.5% or 1% lidocaine hydrochloride solution (without epinephrine) and solutions for IV administration containing 95 or 180 mg of the drug per mL of sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or 5% dextrose injection are stable for 24 hours at room temperature, 1 week when refrigerated at less than 5°C, or at least 30 weeks when frozen at -20°C.

Once thawed, solutions should not be refrozen. Piggyback units containing 1 or 2 g of cefoxitin that have been reconstituted with 50-100 mL of 5 or 10% dextrose injection or 0.9% sodium chloride injection are stable for 24 hours at room temperature or 1 week when refrigerated at less than 5°C. At concentrations of 1-20 mg/mL, cefoxitin is stable for 18 hours at room temperature or 48 hours at less than 5°C in the following IV infusion fluids: 0.9% sodium chloride; 5 or 10% dextrose; 5% dextrose and 0.2, 0.45, or 0.9% sodium chloride; lactated Ringer’s; 5% dextrose and lactated Ringer’s; 10% invert sugar; 10% invert sugar and 0.9% sodium chloride; 5% sodium bicarbonate; 1/6 M sodium lactate; and 5 or 10% mannitol.

The manufacturer states that cefoxitin is stable in 0.9% sodium chloride injection, lactated Ringer’s injection, and 5% dextrose injection in Viaflex® IV bags for 24 hours at room temperature, 48 hours when refrigerated at less than 5°C, or 26 weeks when frozen; after thawing, these solutions are stable for 24 hours at room temperature. Cefoxitin sodium that has been reconstituted with sterile water for injection and transferred to disposable plastic syringes is stable for 24 hours at room temperature or 48 hours when refrigerated. When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage® vials of the drug are stable for 24 hours at room temperature.

The manufacturer states that commercially available frozen cefoxitin sodium injection are stable for at least 90 days from the date of shipment when stored at -20°C. The frozen injection should be thawed at room temperature (25°C) or under refrigeration (2-8°C); the injection should not be thawed by immersion in water baths or by exposure to microwave radiation. Thawed solutions of the commercially available frozen injection are stable for 24 hours at room temperature (25°C) or 21 days when refrigerated at 2-8°C and should not be refrozen.

The commercially available frozen injection of the drug in dextrose is provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Cefoxitin sodium is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).

Specialized references should be consulted for specific compatibility information. Because of the potential for incompatibility, the manufacturer states that cefoxitin sodium and aminoglycosides should not be admixed.

Preparations

Cefoxitin Sodium Parenteral For injection 1 g (of cefoxitin) Cefoxitin Sodium for Injection , American Pharmaceutical Partners ESI Lederle Mefoxin®, Merck 2 g (of cefoxitin) Cefoxitin Sodium for Injection , American Pharmaceutical Partners ESI Lederle Mefoxin®, Merck 10 g (of cefoxitin) pharmacy Cefoxitin Sodium for Injection bulk package , American Pharmaceutical Partners ESI Lederle Mefoxin®, Merck For injection, for 1 g (of cefoxitin) Mefoxin®, IV infusion Merck Mefoxin® ADD-Vantage®, Merck 2 g (of cefoxitin) Mefoxin®, Merck Mefoxin® ADD-Vantage®, Merck Cefoxitin Sodium in Dextrose Parenteral Injection (frozen) 20 mg (of cefoxitin) per mL Mefoxin® in Iso-osmotic , for IV infusion (1 g) in 4% Dextrose Dextrose Injection, (Galaxy® [Baxter]) Merck 40 mg (of cefoxitin) per mL Mefoxin® in Iso-osmotic (2 g) in 2.2% Dextrose Dextrose Injection, (Galaxy® [Baxter]) Merck

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