AHFS Class:

• Cephamycins 8:12.07.12

Generic Name(s):

• cefoTEtan Disodium

Chemical Name:

• [6 R -(6α,7α)]-7-[[[4-(2-Amino-1-carboxy-2-oxoethylidene)-1,3-dithietan-2-yl]carbonyl]amino]-7-methoxy-3-[[(1-methyl-1 H -tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid disodium salt

Cefotetan is a semisynthetic cephamycin β-lactam antibiotic.1,2,3,4,5,16,26,37,62,64,110,157

Cefotetan is used for treatment of urinary tract, lower respiratory tract, skin and skin structure, bone and joint, gynecologic, and intra-abdominal infections caused by susceptible bacteria1,2,51,52,53,64,66,110,157 and also is used for perioperative prophylaxis.1,2,64,67,68,69,70,71,72,110,157,360 Cefotetan should not be used for treatment of meningitis or other CNS infections.2

Prior to initiation of cefotetan therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests.1,110,157 Cefotetan therapy may be started pending results of susceptibility tests, but should be discontinued if the organism is found to be resistant to the drug.1,110,157 In certain serious infections, including confirmed or suspected gram-positive or gram-negative sepsis, when the causative organism is unknown, cefotetan and concomitant therapy with an aminoglycoside may be indicated initially pending results of susceptibility tests.1,17,110,157 If an aminoglycoside is used concomitantly with cefotetan, renal function should be monitored.1,110,157 (See Drug Interactions: Aminoglycosides.)

Gram-positive Aerobic Bacterial Infections

Cefotetan is used in adults for treatment of lower respiratory tract infections caused by susceptible Streptococcus pneumoniae or Staphylococcus aureus ;1,2,53,64,110,157 gynecologic infections caused by susceptible S. aureus , S. epidermidis , streptococci (except enterococci);1,2,64,110,157 skin and skin structure infections caused by susceptible S. aureus , S. epidermidis , S. pyogenes (group A β-hemolytic streptococci), other streptococci (except enterococci);1,110,157 intra-abdominal infections caused by susceptible streptococci (except enterococci);1,64,110,157 and bone and joint infections caused by susceptible S. aureus .1,2,110,157 The drug also has been used effectively in a limited number of adults for treatment of urinary tract infections caused by susceptible S. aureus † or S epidermidis †.51

Cefotetan, like second and third generation cephalosporins, generally is not a drug of choice for treatment of infections caused by gram-positive bacteria and should not be used for treatment of infections caused by these organisms when a penicillin or a first generation cephalosporin could be used.37,88

Gram-negative Aerobic Bacterial Infections

Cefotetan is used in adults for treatment of urinary tract infections caused by susceptible Escherichia coli , Klebsiella , Proteus mirabilis , P. vulgaris , Providencia rettgeri , or Morganella morganii ;1,2,51,52,64,110,157 lower respiratory tract infections caused by susceptible Haemophilus influenzae , E. coli , Klebsiella , P. mirabilis , or Serratia marcescens ;1,2,53,64,110,157 and skin and skin structure infections caused by susceptible E. coli or K. pneumoniae .1,64,110,157 The drug is also used in adults for treatment of intra-abdominal infections caused by susceptible E. coli or Klebsiella 1,2,64,110,157 and for treatment of gynecologic infections caused by susceptible E. coli , P. mirabilis , or N. gonorrhoeae .1,2,64,66,110,157

Cefotetan generally has been as effective as cefoxitin or cefotaxime for treatment of urinary tract infections caused by susceptible gram-negative bacteria.2,64 Because Pseudomonas aeruginosa generally are resistant to cefotetan, the drug should not be used for treatment of any infection where Ps. aeruginosa may be the causative organism.2,88

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Cefotetan is used for treatment of gynecologic infections caused by susceptible gram-positive anaerobic cocci, including Peptococcus and Peptostreptococcus , or susceptible Fusobacterium and skin and skin structure infections caused by Peptococcus and Peptostreptococcus .1,66,110,157 The drug also is used for treatment of gynecologic and intra-abdominal infections caused by susceptible Bacteroides or Clostridium .1,64,110,157

Cefotetan generally has been effective when used for treatment of mixed aerobic-anaerobic bacterial infections, including peritonitis and gynecologic infections (see Uses: Pelvic Inflammatory Disease).2,66,111,129 Cefotetan has been used effectively for treatment of mild to moderate infections caused by B. fragilis ;88 however, other anti-infectives (e.g., metronidazole, clindamycin) usually are preferred,88,97 especially for treatment of severe or life-threatening B. fragilis infections.88

Because of the increasing prevalence of B. fragilis resistant to cefotetan, the Infectious Diseases Society of America (IDSA) states that the drug is not recommended for empiric treatment of intra-abdominal infections.161 In addition, B. distasonis , B. ovatus , and B. thetaiotaomicron generally are resistant to cefotetan, and the drug is unlikely to be effective in infections caused by these anaerobes.1,110,157

Pelvic Inflammatory Disease

Cefotetan is used for treatment of pelvic inflammatory disease (PID).344,346,419 Cefotetan, like cephalosporins, generally is inactive against C. trachomatis and should not be used alone for treatment of PID.1,110,157,344

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.344,417 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.344,346,417,418 PID is treated with an empiric regimen that provides broad spectrum coverage.344,346,417,418 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.344,346,417,418 The optimum empiric regimen for treatment of PID has not been identified.344 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;344,418,419 however, only limited data are available 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).344,419

Parenteral Regimens for PID

When a parenteral regimen is indicated for treatment of PID, the US Centers for Disease Control and Prevention (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).344,346 While certain parenteral cephalosporins (e.g., cefotaxime, ceftriaxone) also have been used and may be effective for treatment of PID,344,417,418 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.344 CDC states that only limited data are available to support the use of other parenteral regimens for treatment of acute PID, although a regimen of IV ampicillin and sulbactam given with oral or IV doxycycline may be effective against C. trachomatis , N. gonorrhoeae , and anaerobes in women with tubo-ovarian abscess.344

CDC states that a transition to oral therapy usually can be initiated within 24-48 hours after the patient demonstrates clinical improvement and decisions regarding such a transition should be guided by clinical experience.344 At least 24 hours of direct inpatient observation is recommended for patients with tubo-ovarian abscesses.344

Oral Regimens for PID

When acute PID that is mild to moderately severe is treated with an oral regimen, CDC recommends a regimen that consists of a single dose of IM ceftriaxone, IM cefoxitin (with oral probenecid), or IM cefotaxime given in conjunction with a 14-day regimen of oral doxycycline (100 mg twice daily) with or without oral metronidazole (500 mg twice daily).344 The optimal parenteral cephalosporin or cephamycin for this outpatient regimen is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae .344

For additional information regarding treatment of PID, the current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.344

Perioperative Prophylaxis

Cefotetan has been effective when used perioperatively to reduce the incidence of infection in patients undergoing cesarean section,1,2,68,110,130,149,157 abdominal or vaginal hysterectomy,1,2,67,110,157 or transurethral,1,2,71,110,157 biliary tract,1,2,70,110,157 or GI surgery.1,2,69,72,110,157 Perioperative prophylaxis with an appropriate anti-infective agent can decrease the incidence of infection, particularly surgical site infection, after certain procedures.360

GI Surgery

Biliary Tract Surgery

Perioperative prophylaxis is recommended for patients undergoing biliary tract surgery who are at high risk of infection (e.g., those older than 70 years of age or those with acute cholecystitis, a nonfunctioning gallbladder, obstructive jaundice, or common duct stones).360 In high-risk patients undergoing endoscopic retrograde cholangiopancreatography (ERCP), perioperative prophylaxis is recommended only if complete biliary drainage is unlikely to be achieved.360 Perioperative prophylaxis is not considered necessary for low-risk patients undergoing elective laparoscopic cholecystectomy.360,374

For perioperative prophylaxis in high-risk patients undergoing open biliary tract surgery, many clinicians recommend IV cefazolin as the drug of choice.360,374 Alternatives include IV cefotetan, IV cefoxitin, or IV ampicillin and sulbactam.360,374 In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with an aminoglycoside (gentamicin or tobramycin), a fluoroquinolone (ciprofloxacin or levofloxacin), or aztreonam;360,374 some clinicians suggest metronidazole and an aminoglycoside (gentamicin or tobramycin) or fluoroquinolone (ciprofloxacin or levofloxacin) as another alternative.374

Colorectal Surgery

There is evidence that perioperative prophylaxis can decrease the incidence of infection after colorectal surgery, and such prophylaxis is recommended.360,374

For perioperative prophylaxis in patients undergoing colorectal surgery, many clinicians recommend a parenteral regimen of IV cefotetan, IV cefoxitin, IV cefazolin (used in conjunction with IV metronidazole), IV ampicillin and sulbactam, or IV ertapenem.360,374 In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with an aminoglycoside (gentamicin or tobramycin), a fluoroquinolone (ciprofloxacin or levofloxacin), or aztreonam;360,374 some clinicians suggest metronidazole and an aminoglycoside (gentamicin or tobramycin) or fluoroquinolone (ciprofloxacin or levofloxacin) as another alternative.374

Alternatively, an oral regimen of oral neomycin with either oral erythromycin or oral metronidazole can be used in conjunction with mechanical bowel preparation for perioperative prophylaxis in patients undergoing colorectal surgery.360,374 Many clinicians recommend using both an oral regimen and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery,153,360,374 and there is some evidence that use of an oral regimen (with mechanical bowel preparation) in conjunction with a parenteral regimen is more effective than use of a parenteral regimen alone.151,158,360,374

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 (14.6%) than in those who received the combined oral and parenteral regimen (5%).151

A single dose of cefotetan has been as effective as multiple doses of cefoxitin for perioperative prophylaxis in patients undergoing colorectal surgery.72

Appendectomy

There is evidence that perioperative prophylaxis can reduce the incidence of infection after surgery for acute appendicitis, and such prophylaxis is recommended.360,374

For perioperative prophylaxis in patients undergoing uncomplicated (nonperforated) appendectomy, many clinicians recommend IV cefoxitin, IV cefotetan, or IV cefazolin (used in conjunction with IV metronidazole).360 In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with an aminoglycoside (gentamicin or tobramycin), a fluoroquinolone (ciprofloxacin or levofloxacin), or aztreonam;360,374 some clinicians suggest metronidazole and an aminoglycoside (gentamicin or tobramycin) or fluoroquinolone (ciprofloxacin or levofloxacin) as another alternative.374

If perforation has occurred, anti-infectives are continued postoperatively for about 5 days.360

Genitourinary Surgery

Cefotetan has been used for perioperative prophylaxis in patients undergoing transurethral surgery;1,2,71,110,157 however, the drug is not included in recommendations for perioperative prophylaxis in patients undergoing urinary tract surgery.360,374

Gynecologic and Obstetric Surgery

Perioperative prophylaxis decreases the incidence of infection after vaginal or abdominal hysterectomy and also is used for laparoscopic hysterectomies.360,374 In addition, there is evidence that perioperative prophylaxis can prevent infection after elective and nonelective cesarean section,360,374 and also can prevent infection after elective abortions.150,360 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 by 42% compared with placebo.150

Many clinicians suggest that the preferred agents for perioperative prophylaxis in women undergoing vaginal, abdominal, or laparoscopic hysterectomy are IV cefoxitin, IV cefotetan, IV cefazolin, or IV ampicillin and sulbactam.360,374 In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with an aminoglycoside (gentamicin or tobramycin), a fluoroquinolone (ciprofloxacin or levofloxacin), or aztreonam;374 some clinicians suggest metronidazole and an aminoglycoside (gentamicin or tobramycin) or fluoroquinolone (ciprofloxacin or levofloxacin) as another alternative.374

IV cefazolin generally is the preferred agent for prophylaxis in women undergoing cesarean section;360,374 oral doxycycline is recommended for prophylaxis in those undergoing abortion.360

In a limited number of patients, a single dose of cefotetan appeared to be at least as effective as multiple doses of cefoxitin for perioperative prophylaxis in patients undergoing vaginal or abdominal hysterectomy67 and at least as effective as multiple doses of cefoxitin or cefazolin in patients undergoing cesarean section.68,130 Results of a prospective, randomized study indicate that single-dose regimens of cefazolin, cefotetan, or ampicillin sodium and sulbactam sodium are equally effective in decreasing the incidence of postpartum infections in women undergoing high-risk cesarean section; postpartum endomyometritis was reported in 14.3% of those who received cefazolin, 11.1% of those who received cefotetan, and 7.4% of those who received ampicillin sodium and sulbactam sodium.149

Timing and Number of Doses

When perioperative prophylaxis is indicated in patients undergoing surgery, administration of an appropriate 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;360,374 therapeutic concentrations of the drug should then be maintained in serum and tissues for the duration of the procedure.374

An IV dose of an appropriate anti-infective should be administered within 60 minutes before the initial incision.360,374 If cefotetan is used prophylactically, the manufacturers recommend that the drug be given 30-60 minutes before surgery.1,110,157

A single preoperative dose usually is sufficient for perioperative prophylaxis.374 However, if surgery is prolonged (more than 3-4 hours), major blood loss occurs, or other factors are present that shorten the half-life of the drug (e.g., extensive burns), additional doses should be administered during the procedure to ensure adequate serum and tissue concentrations of the anti-infective throughout the procedure.360,374 For prolonged procedures in patients with normal renal function, some clinicians suggest that intraoperative doses be given during the procedure at intervals that correspond to 1-2 times the half-life of the drug (e.g., every 6 hours for cefotetan, measured from the time the preoperative dose is initiated).360,374 Intraoperative doses may not be warranted if there are factors that prolong the half-life of the drug (e.g., renal impairment).374

For most procedures, the duration of prophylaxis should be less than 24 hours.360,374 There is no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.360,374

Reconstitution and Administration

Cefotetan disodium is administered by IV injection1 or infusion1,110,157 or by deep IM injection.1

The IV route is the preferred route in patients with bacteremia, septicemia, or other severe or life-threatening infections and in patients with lowered resistance resulting from debilitating conditions (e.g., malnutrition, trauma, surgery, diabetes, heart failure, malignancy), particularly if shock is present or impending.1,110,157

If an aminoglycoside is administered concomitantly with cefotetan disodium, the drugs should be administered at separately and should not be admixed.1,110,157

Cefotetan disodium solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1,110,157

Intermittent IV Injection

For direct intermittent IV injection, the contents of a vial labeled as containing 1 or 2 g of cefotetan should be reconstituted with 10 or 10-20 mL, respectively, of sterile water for injection to provide solutions containing approximately 95 or 95-182 mg/mL, respectively.1 The vial should be shaken until the drug is dissolved, and then allowed to stand until the solution is clear.1

The appropriate dose of reconstituted solution may then be injected directly into a vein over a 3- to 5-minute period.1

Intermittent IV Infusion

IV infusions of cefotetan disodium solutions should preferably be given using butterfly or scalp vein-type needles.1,110,157 Other IV solutions flowing through a common administration tubing or set should be discontinued while cefotetan disodium is being infused.1,110,157

For direct intermittent IV infusion, the contents of a vial labeled as containing 1 or 2 g of cefotetan should be reconstituted with 10 or 10-20 mL, respectively, of sterile water for injection to provide solutions containing approximately 95 or 95-182 mg/mL, respectively.1 The vial should be shaken until the drug is dissolved, and then allowed to stand until the solution is clear.1

Commercially available pharmacy bulk package vials containing 10 g of cefotetan should be reconstituted with 50 or 100 mL of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection to provide solutions containing approximately 180 or 95 mg/mL, respectively.110 The vial should be shaken until the drug is dissolved and allowed to stand until the solution is clear.110 Reconstituted solutions in pharmacy bulk package vials should not be used for direct IV infusion; the reconstituted solution must be further diluted in a compatible IV infusion solution within 4 hours after reconstitution.110 (See Chemistry and Stability: Stability.) A suitable sterile transfer device or dispensing set should be used to transfer the contents of the reconstituted bulk package vial to a compatible IV solution;110 a syringe with a needle is not recommended since leakage could occur during transfer.110 The manufacturer's directions should be consulted for additional information.110

Alternatively, the commercially available Duplex^® drug delivery system containing 1 or 2 g of cefotetan disodium powder and 50 mL of 3.58 or 2.08% dextrose injection, respectively, in separate chambers should be reconstituted (activated) according to the manufacturer's directions and administered by IV infusion.157 If stored in the refrigerator after reconstitution (see Chemistry and Stability: Stability), the solution should be allowed to reach room temperature prior to administration.157

Rate of Administration

Cefotetan may be administered by IV infusion over 20-60 minutes.1,2,52,53,110

IM Injection

For IM injection, vials labeled as containing 1 or 2 g of cefotetan should be reconstituted by adding 2 or 3 mL of sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or 0.5 or 1% lidocaine hydrochloride injection, respectively, to provide solutions containing approximately 400 or 500 mg/mL, respectively.1 The vial should be shaken until the drug is dissolved, and then allowed to stand until the solution is clear.1

IM injections of cefotetan disodium should be made deeply into a large muscle, such as the upper outer quadrant of the gluteus maximus, using usual techniques and precautions.1 The plunger of the syringe should be drawn back before IM injection to ensure that the needle is not in a blood vessel.1

Dosage

Dosage of cefotetan disodium is expressed in terms of cefotetan.1,110,157

Adult Dosage

The usual adult dosage of cefotetan is 1 or 2 g IV or IM every 12 hours; however, the dosage and route of administration should be determined by the type and severity of infection, the susceptibility of the causative organism, and the condition and renal function of the patient.1,110,157 The maximum adult dosage of cefotetan recommended by the manufacturers is 6 g daily.1,110,157

For treatment of infections at sites other than the urinary tract, skin, or skin structure, the usual adult dosage is 1 or 2 g IV or IM every 12 hours.1,110,157 However, severe infections in adults may require 2 g IV every 12 hours and life-threatening infections may require 3 g IV every 12 hours.1,64,110,157

Skin and Skin Structure Infections

For treatment of mild to moderate skin and skin structure infections, the manufacturers recommend that adults receive 2 g of cefotetan IV every 24 hours or 1 g IV or IM every 12 hours.1,110,157 For mild to moderate infections caused by Klebsiella pneumoniae , the manufacturers recommend 1 or 2 g IV or IM every 12 hours.1,110,157

For treatment of severe skin and skin structure infections, the manufacturers recommend 2 g IV every 12 hours.1,110,157

Urinary Tract Infections

For treatment of urinary tract infections, the manufacturers recommend that adults receive 500 mg of cefotetan IV or IM every 12 hours or 1 or 2 g IV or IM every 12 or every 24 hours. 1,110,157

Pelvic Inflammatory Disease

For treatment of acute pelvic inflammatory disease (PID), adults and adolescents should receive IV cefotetan in a dosage of 2 g every 12 hours given in conjunction with IV or oral doxycycline (100 mg every 12 hours).344,346 The initial parenteral regimen may be discontinued 24-48 hours after there is clinical improvement and oral doxycycline (100 mg twice daily) continued to complete 14 days of therapy.344,346

Perioperative Prophylaxis

For perioperative prophylaxis in women undergoing abdominal, vaginal, or laparoscopic hysterectomy or undergoing cesarean section, 1 or 2 g of cefotetan should be given IV within 30-60 minutes prior to incision.1,110,157,360,374 For cesarean section, the manufacturers recommend giving the dose as soon as the umbilical cord is clamped;1,110,157 however, there is some evidence that giving the dose prior to incision may be more effective than giving it after clamping.360,374

For perioperative prophylaxis in adults undergoing colorectal surgery, appendectomy (nonperforated), biliary tract, or other GI surgery, 1 or 2 g of cefotetan should be given IV 30-60 minutes prior to incision.1,110,157,360,374

If cefotetan is used for perioperative prophylaxis in adults undergoing transurethral surgery, the manufacturers recommend that 1 or 2 g of the drug be given IV 30-60 minutes prior to surgery.1,110,157

During prolonged procedures (longer than 3-4 hours), if major blood loss occurs, or if other factors are present that shorten the half-life of the drug, additional doses should be given during the procedure (e.g., every 6 hours, measured from time the preoperative dose is initiated).360,374

The duration of prophylaxis should be less than 24 hours for most procedures;360,374 there is no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.360,374

Pediatric Dosage

General Pediatric Dosage

Although safety and efficacy of cefotetan in children have not been established,1,110,157 the American Academy of Pediatrics (AAP) suggests that children beyond the neonatal period† may receive IM or IV cefotetan in a dosage of 60 mg/kg daily given in 2 divided doses for treatment of mild to moderate infections or a dosage of 100 mg/kg daily given in 2 divided doses for treatment of severe infections.292

Perioperative Prophylaxis

If cefotetan is used for perioperative prophylaxis in children 1 year of age or older† undergoing colorectal surgery or appendectomy, some clinicians recommend that 40 mg/kg of cefotetan be given within 60 minutes prior to incision.374

During prolonged procedures (longer than 3-4 hours), if major blood loss occurs, or if other factors are present that shorten the half-life of the drug, additional doses should be given during the procedure.374

The duration of prophylaxis should be less than 24 hours for most procedures;360,374 there is no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.360,374

Dosage in Renal Impairment

In patients with renal impairment, doses and/or frequency of administration of cefotetan should be modified in response to the degree of renal impairment, type and severity of the infection, and susceptibility of the causative organisms.1,2,37,39,43,110,157

The manufacturers and some clinicians recommend that adults with impaired renal function receive the following dosage of cefotetan given at dosage intervals based on the patient's creatinine clearance.1,39,110,157 (See Table 1.)

Adverse effects reported with cefotetan are similar to those reported with cephalosporins.64 For information on adverse effects reported with cephalosporins, see Cautions in the Cephalosporins General Statement and other monographs in 8:12.06. Cefotetan generally is well tolerated; adverse effects have been reported in less than 5% of patients receiving the drug and have required discontinuance of the drug in less than 3% of patients.64

Hematologic Effects

Adverse hematologic effects, including eosinophilia,1,2,52,64,110,157 thrombocytosis,1,64,157 thrombocytopenia,1,2,110,157 neutropenia,2,64 leukopenia,1,2,110,157 agranulocytosis,1,110,157 hemolytic anemia,1,110,114,157 and positive indirect64 or direct1,2,64,110,157 antiglobulin (Coombs') test results, have been reported in up to 1.4% of patients receiving cefotetan.1,110,157

Severe hemolytic anemia, including some fatalities, have been reported rarely in association with cefotetan therapy.1,110,114,117,118,119,120,127,157 Hemolytic anemia has been reported in a few women undergoing obstetric and gynecologic procedures who received a single dose of cefotetan for perioperative prophylaxis.127 Similar cases of immune-mediated hemolytic anemia have been reported rarely in patients receiving cephalosporins (e.g., cefotaxime, ceftizoxime [no longer commercially available in the US], ceftriaxone).1,110,146,147,148,157 If a patient develops hemolytic anemia within 2-3 weeks after initiation of cefotetan therapy, the diagnosis of immune-mediated hemolytic anemia should be considered and the drug discontinued until the etiology of the anemia is determined.1,110,157 (See Cautions: Precautions and Contraindications.)

Prolongation of bleeding time or prothrombin time (PT), with or without bleeding, has been reported rarely in patients receiving cefotetan1,2,64,76,77,78,110,131,132,133,157 (i.e., in 0.14% of patients).64 Monitor PT in patients at risk, including geriatric patients and those with renal or hepatic impairment, malnutrition, or cancer.1,110,132,133,157 Administer vitamin K when indicated.1,76,110,132,133,157 Hypoprothrombinemia also has been reported with other β-lactam antibiotics that contain an N -methylthiotetrazole (NMTT) side chain like that contained in cefotetan (e.g., cefamandole, cefoperazone; drugs no longer commercially available),126,128,135,136 and it has been suggested that the NMTT side chain may interfere with hepatic synthesis of vitamin K-dependent clotting factors.132,135 Cefotetan does not interfere with adenosine diphosphate-induced, collagen-induced, or arachidonic acid- and epinephrine-induced platelet aggregation.2,64,76,77

GI Effects

Adverse GI effects, including diarrhea1,2,38,40,42,52,53,64,110,157 and nausea,1,2,52,53,64,110,157 have been reported in up to 1.5% of patients receiving cefotetan.1,2,110,157 Hiccups also have been reported.116

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,110,157,302,303,304 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including cefotetan, and may range in severity from mild diarrhea to fatal colitis.1,110,157,302,303,304 C. difficile produces toxins A and B, which contribute to development of CDAD;1,110,157,302 hypertoxin producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1,110,157

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,110,157,302,303,304 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1,110,157

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,110,157,302 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,110,157,302,303,304

Sensitivity Reactions

Rash,1,2,51,64,110,157 pruritus,1,2,52,64,109,110,157 anaphylaxis,1,109,110,157 urticaria,1,110,157 and fever or chills1,2,64,110,157 have been reported in up to 1.5% of patients receiving cefotetan.1,2,110,157 Erythema multiforme (e.g., Stevens-Johnson syndrome) and toxic epidermal necrolysis have been reported in patients receiving cephalosporin therapy.1,110,157 If a hypersensitivity reaction occurs during cefotetan therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., IV fluids, IV antihistamines, corticosteroids, vasopressors, and maintenance of an adequate airway and oxygen) as indicated.1,110,157

Hepatic Effects

Increased serum concentrations of AST (SGOT),1,2,52,64,110,157 ALT (SGPT),1,2,53,64,110,157 alkaline phosphatase,1,2,51,52,53,64,110,157 and LDH1,52,53,64,110,157 have been reported in up to 1.2% of patients receiving cefotetan.1,110,157 Hepatic dysfunction, including cholestasis, and increased serum bilirubin concentrations have been reported in patients receiving cephalosporin therapy.1,110,157

Local Effects

Adverse local effects have been reported in less than 1% of patients receiving cefotetan,1,64,110,157 and include phlebitis,1,2,64,110,157 pain,2,52,64 inflammation,2,52,53,64 discomfort,1,42,64,110,157 and swelling52,53,64 at the site of administration. Swelling of the forearm also has been reported.64

Renal Effects

Cefotetan does not appear to be nephrotoxic.64,83,84 Although a transient increase in urinary concentrations of total protein occurred in healthy adults who received usual dosages of cefotetan for 3 days, urinary albumin concentrations and excretion of thermophilic aminopeptidase (alanine aminopeptidase), an enzyme originating from renal proximal tubular cells, were generally unaffected, suggesting that the drug does not adversely affect these cells.83 Nephrotoxicity and increases in BUN and serum creatinine concentrations have been reported in patients receiving cefotetan.1,110,157 Impairment of renal function and toxic nephropathy have been reported in patients receiving cephalosporin therapy.1,110,157

Although a causal relationship to cefotetan has not been established, interstitial nephritis manifested by fever, rash, pruritus, eosinophilia, hematuria, proteinuria, and azotemia have been reported in at least one patient receiving cefotetan.115 The nephritis resembled that reported with other anti-infective agents and appeared to be a hypersensitivity reaction to the drug.115 For more information on anti-infective-induced acute interstitial nephritis, see Cautions: Renal Effects, in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

Other Adverse Effects

Several cephalosporins have been associated with seizures, generally when usual dosages of the drugs were not reduced in patients with renal impairment.1,110,157 If seizures occur during cefotetan therapy, the drug should be discontinued and appropriate anticonvulsant therapy administered as indicated.1,110,157

Superinfection, vaginitis, and vaginal candidiasis have been reported in patients receiving cephalosporin therapy.1,110,157

Precautions and Contraindications

Prior to initiation of cefotetan therapy, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics, including cephalosporins and penicillins, or to other drugs.1,110,157 There is clinical and laboratory evidence of partial cross-allergenicity among β-lactam antibiotics including penicillins, cephalosporins, and cephamycins.1,37,60,110,157 Cefotetan is contraindicated in patients who are hypersensitive to the drug or to cephalosporins and should be used with caution in patients hypersensitive to penicillins.1,2,110,157

Because potentially fatal, severe hemolytic anemia has been reported rarely in association with cefotetan therapy,1,110,114,117,118,119,120,157 patients should be monitored periodically for signs and symptoms of hemolytic anemia, including assessment of hematologic parameters, where appropriate.1,110,157 If a patient develops anemia anytime within 2-3 weeks after administration of cefotetan, the diagnosis of cephalosporin-associated anemia should be considered and the drug stopped until the etiology is determined with certainty.1,110,157 Blood transfusions may be considered as needed.1,110,157 Cefotetan is contraindicated in individuals who have experienced cephalosporin-associated hemolytic anemia.1,110,157

As with other anti-infective agents, prolonged use of cefotetan may result in overgrowth of nonsusceptible organisms (e.g., enterococci, Pseudomonas , Acinetobacter , Candida ).1,51,88,110,157 Careful observation of the patient during cefotetan therapy is essential.1,110,157 If superinfection occurs, appropriate therapy should be initiated.1,110,157

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1,110,157 Cefotetan should be used with caution in patients with a history of GI disease, especially colitis.1,110,157 (See Clostridium difficile-associated Diarrhea and Colitis under Cautions: GI Effects.)

Although prolonged prothrombin time (PT) has been reported rarely in patients receiving cefotetan (see Cautions: Hematologic Effects), the PT should be monitored when the drug is used in patients at increased risk (e.g., patients with renal or hepatic impairment, malnutrition, geriatric patients, patients with cancer),1,2,88,110,132,133,157 and vitamin K should be administered when indicated.1,76,110,132,133,157

Patients should be warned to avoid ingestion of alcohol during and for 72 hours after cefotetan therapy because of the possibility that a disulfiram-like reaction may occur.1,2,108,110,157 (See Drug Interactions: Alcohol.)

Like other dextrose-containing solutions, the commercially available Duplex^® delivery system containing 1 or 2 g of cefotetan powder and 50 mL of 3.58 or 2.08% dextrose injection, respectively, should be used with caution in patients with overt or known subclinical diabetes mellitus or in patients with carbohydrate intolerance for any reason.157

To reduce development of drug-resistant bacteria and maintain effectiveness of cefotetan and other antibacterials, the drug should be used only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1,110,157 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1,110,157 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1,110,157

Patients should be advised that antibacterials (including cefotetan) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1,110,157 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefotetan or other antibacterials in the future.1,110,157

Because serum concentrations of cefotetan are higher and more prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of the drug should be decreased in patients with impaired renal function.1,2,37,39,43,110,157 (See Dosage and Administration: Dosage in Renal Impairment.)

Pediatric Precautions

The manufacturer states that the safety and efficacy of cefotetan in children have not been established.1,110,157 However, the American Academy of Pediatrics (AAP) suggests that the drug may be used for treatment of infections in children beyond the neonatal period†.292 (See Pediatric Dosage under Dosage and Administration: Dosage.)

Geriatric Precautions

In clinical studies, safety and efficacy of cefotetan in geriatric adults 60 years of age or older have been similar to those observed in younger adults.1,110,157 Although other clinical experience has revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1,110,157

Cefotetan is substantially eliminated in urine and the risk of toxicity may be increased in patients with impaired renal function.1,110,157 Because geriatric patients are more likely to have decreased renal function, use caution when selecting dosage for such patients and consider monitoring renal function.1,110,157 (See Dosage in Renal Impairment under Dosage and Administration: Dosage.)

Mutagenicity and Carcinogenicity

In vitro studies have not shown cefotetan to be mutagenic.1,110,157 Long-term studies have not been performed to date to evaluate the carcinogenic potential of the drug.1,110,157

Pregnancy, Fertility, and Lactation

Safe use of cefotetan during pregnancy has not been definitely established.1,110,157 Reproduction studies in rats and monkeys using cefotetan dosages up to 20 times the usual human dosage have not revealed evidence of impaired fertility or harm to the fetus.1,110,157 There are no adequate or controlled studies using cefotetan in pregnant women, and the drug should be used during pregnancy only when clearly needed.1,110,157

Cefotetan has caused adverse effects on the testes of prepubertal rats at high dosages.1,64,110,157 Reduced testicular weight and seminiferous tubule degeneration occurred in all rats tested following subcutaneous administration of cefotetan in a dosage of 500 mg/kg daily (8-16 times the usual human adult dosage).1,64,110,157 The drug was given to the rats on days 6-35 of life, the days thought to be developmentally analogous to late childhood and prepuberty in humans.1,110,157 Spermatogonia and spermatocytes were affected, but Sertoli and Leydig cells were unaffected.1,110,157 The incidence and severity of lesions appeared to be dose dependent since a dosage of 120 mg/kg daily (2-4 times the usual human adult dosage) resulted in only mild degeneration in 1 of 10 rats.1,64,110,157 Adverse effects on testicular development did not occur in rats 7 weeks of age following subcutaneous administration of cefotetan in a dosage up to 1 g/kg daily for 5 weeks or in dogs 3 weeks of age following IV administration of the drug in a dosage up to 300 mg/kg daily for 5 weeks.1,64,110,157 Adverse testicular effects (e.g., reduced testicular weight, seminiferous tubule degeneration, delayed maturity of germinal epithelium) have occurred in prepubertal rats receiving other β-lactam antibiotics that contain an N -methylthiotetrazole (NMTT) side chain like that contained in cefotetan (e.g., cefamandole, cefoperazone; drugs no longer commercially available).126,128 The relevance of these findings to humans is unknown.1,64,157

Because cefotetan is distributed into milk, the drug should be used with caution in nursing women.1,110,157

Alcohol

Disulfiram-like reactions characterized by flushing, sweating, headache, and tachycardia may occur if alcohol is ingested within 72 hours after administration of cefotetan.1,108,110,157 These reactions have been reported with other β-lactam antibiotics that contain an N -methylthiotetrazole (NMTT) side chain similar to that contained in cefotetan (e.g., cefamandole, cefoperazone; drugs no longer commercially available)126,128,136 and appear to result from accumulation of acetaldehyde.2,73,74,75

Aminoglycosides

In vitro studies indicate that the antibacterial activity of cefotetan and an aminoglycoside may be additive or synergistic against Staphylococcus aureus ,2,5,64 Citrobacter , Klebsiella , Enterobacter , Escherichia coli , and Serratia .2,5,17,24,64,96 The combination of cefotetan and an aminoglycoside is generally only additive against Proteus mirabilis and P. vulgaris .5,64 The combination of cefotetan and amikacin reportedly does not result in a synergistic effect in vitro against Pseudomonas aeruginosa .2,64,96

Concomitant use of an aminoglycoside and certain cephalosporins reportedly may increase the risk of nephrotoxicity during therapy.1,61,110,157 Although cefotetan did not potentiate the nephrotoxicity of gentamicin in rats84 and this effect has not been reported to date in humans, the manufacturers state that nephrotoxicity may be potentiated if the drug is used concomitantly with an aminoglycoside and that renal function should be monitored.1,110,157

-Lactam Antibiotics

An additive or synergistic effect has occurred in vitro against some strains of E. coli , E. aerogenes , and Proteus mirabilis when cefotetan was used concomitantly with cefotaxime or piperacillin.5 The combination of cefotetan and piperacillin reportedly has been antagonistic in vitro against some gram-negative bacteria.2,64

Probenecid

Concomitant administration of oral probenecid does not appear to affect the pharmacokinetics of cefotetan, presumably because cefotetan is eliminated principally by glomerular filtration and nonrenal mechanisms.87

Laboratory Test Interferences

Tests for Urinary Glucose

Cefotetan may cause false-positive results in urinary glucose determinations using cupric sulfate solutions (e.g., Benedict's solution, Clinitest^®);1,110,157 glucose oxidase methods (e.g., Clinistix^®) should be used in patients receiving cefotetan therapy.1,110,157

Tests for Creatinine

High concentrations of cefotetan may cause falsely elevated serum or urinary creatinine values when the Jaffé reaction is used.1,110,157

Acute Toxicity

No information is available on acute overdosage of cefotetan in humans.1,110,157 If acute overdosage of cefotetan occurs, symptomatic treatment should be initiated and hemodialysis considered, especially in patients with renal impairment.1,110,157

Mechanism of Action

Cefotetan usually is bactericidal in action.1,2,3,5,13,64,110,157 Like other β-lactam antibiotics, the antibacterial activity of cefotetan results from inhibition of mucopeptide synthesis in the bacterial cell wall.1,64,110,157 Studies evaluating the binding of cefotetan to penicillin-binding proteins (PBPs), the target enzymes of β-lactam antibiotics, indicate that the drug has an affinity for and binds to most PBPs of gram-positive bacteria.13 Cefotetan also has an affinity for and binds to most PBPs of gram-negative bacteria, except PBP 2.5,13,64 Because cefotetan has the highest affinity for PBP 3, the drug usually causes the formation of filamentous forms in susceptible gram-negative bacteria.5,13,64 Cell lysis and death then occur since cefotetan also has an affinity for PBPs 1a and 1b.5,13,64,87

Spectrum

Although cefotetan is a cephamycin antibiotic, some clinicians classify the drug as a third generation cephalosporin based on its spectrum of activity.2,9,17,37,57,88 Like third generation cephalosporins, cefotetan usually is less active in vitro against susceptible staphylococci than first generation cephalosporins but has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.2,17,37,64,85,88 However, most clinicians classify cefotetan as a second generation cephalosporin since the drug generally is less active in vitro on a weight basis than many third generation cephalosporins against gram-negative bacteria and, unlike some currently available third generation cephalosporins, cefotetan generally is inactive against Pseudomonas aeruginosa .62,87,88 For information on the classification of cephalosporins and closely related β-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

In vitro on a weight basis, cefotetan generally is less active than cefotaxime or ceftriaxone against most susceptible organisms including gram-positive cocci, Haemophilus , Neisseria , and Enterobacteriaceae.2,4,11,18,26,85 Cefotetan generally is less active in vitro on a weight basis than cefoxitin against susceptible gram-positive cocci, but generally is more active than cefoxitin against Enterobacteriaceae.2,3,4,5,6,11,15,16,18,26,64,85 The in vitro activity of cefotetan against Bacteroides fragilis is equal to or slightly less than that of cefoxitin.7,15,16,26,27,30,62,64

In Vitro Susceptibility Testing

Inoculum size does not generally affect susceptibility to cefotetan,2,64,89 and MICs for most organisms are generally only 2-4 times greater when the size of the inoculum is increased from 10³ to 10⁸ colony-forming units (CFU) per mL.2,3,4,5,18,26,64,89 However, MICs for some strains of Morganella , Proteus , and Providencia may be 8 times greater when the inoculum is increased from 10³ to 10⁷ CFU/mL.2,3,4,18 Results of cefotetan in vitro susceptibility tests are generally unaffected by media,5,18,89 pH,2,5,89 or presence of serum.5,26,89

Strains of staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant [methicillin-resistant] staphylococci) should be considered resistant to cefotetan, although routine in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.123

For information on interpreting results of in vitro susceptibility testing (disk susceptibility tests, dilution susceptibility tests) when cefotetan susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]),123 see Spectrum: In Vitro Susceptibility Testing, in the Cephalosporins General Statement 8:12.06.

Gram-positive Aerobic Bacteria

Cefotetan's activity against gram-positive aerobic bacteria generally is similar to that of cefoxitin.64 Cefotetan generally is active in vitro against penicillinase- and nonpenicillinase-producing strains of Staphylococcus aureus .1,2,3,4,5,6,11,15,17,18,26,64,110,157 In addition, most strains of S. pyogenes (group A β-hemolytic streptococci),1,2,3,4,5,11,15,64,110,157 group B streptococci (e.g., S. agalactiae ),1,2,3,4,15,20,64,110,157 and groups C and G streptococci are susceptible to the drug.4 Cefotetan also is active in vitro against some strains of S. epidermidis 1,2,3,4,11,17,110,157 and Streptococcus pneumoniae .1,2,4,64,110,157 Enterococci, including E. faecalis (formerly S. faecalis ), generally are resistant to the drug.1,2,3,4,5,6,11,17,18,64,110,157

The MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of cefotetan for penicillinase- and nonpenicillinase-producing S. aureus is 7.5-16 mcg/mL.2,3,4,5,6,11,15,17,18,26,64,85 The MIC₉₀ of the drug for S. pyogenes 2,3,4,5,11,15,64 and groups B,2,3,4,15,20,64 C, or G streptococci4 is 2-8 mcg/mL. The MIC₅₀ of cefotetan for S. epidermidis and S. pneumoniae is 1-11.2 mcg/mL, but the MIC₉₀ of the drug for these organisms ranges from 8-64 mcg/mL or greater and some strains are considered resistant to the drug.2,3,4,11,17,64

Gram-negative Aerobic Bacteria

Neisseria

Cefotetan is active in vitro against Neisseria meningitidis 2 and most strains of penicillinase- and nonpenicillinase-producing Neisseria gonorrhoeae .1,2,3,4,20,26,64,110,157 The MIC₉₀ of cefotetan for N. meningitidis is 0.12 mcg/mL,2 and the MIC₉₀ of the drug for nonpenicillinase- or penicillinase-producing N. gonorrhoeae is 0.5-4 mcg/mL.2,3,4,20,26,64

Haemophilus

Cefotetan is active in vitro against most β-lactamase- and non-β-lactamase-producing strains of Haemophilus influenzae .1,2,3,4,15,16,26,64,110,157 Cefotetan generally is more active in vitro than cefamandole against β-lactamase-producing (ampicillin-resistant) strains of H. influenzae .3,64 The MIC₉₀ of cefotetan reported for H. influenzae is 1-4 mcg/mL.2,3,4,15,26

Enterobacteriaceae

Cefotetan generally is active in vitro against the following Enterobacteriaceae: Citrobacter diversus ,1,2,3,64,157 C. freundii ,1,2,3,4,11,17,64,110,157 Escherichia coli ,1,2,3,4,5,6,11,15,17,18,20,22,64,110,157 Hafnia alvei ,3 Klebsiella oxytoca ,1,3,110,157 K. ozaenae ,2,4 K. pneumoniae ,1,2,3,5,15,26,64,110,157 Morganella morganii (formerly Proteus morganii ),1,2,3,4,6,18,64,110,157 Proteus mirabilis ,1,2,3,4,5,6,11,15,17,18,26,64,110,157 P. vulgaris ,1,2,3,4,5,6,17,18,64,110,157 Providencia rettgeri (formerly Proteus rettgeri ),1,2,3,4,5,6,17,18,64,110,157 P. stuartii ,2,3,4,15,17,26,64 Serratia marcescens ,1,2,3,4,5,11,15,17,64,110,157 Salmonella ,1,2,3,6,11,14,15,110,157 Shigella ,1,2,3,6,15,110,157 and Yersinia enterocolitica .1,2,6,28,110,157

The MIC₉₀ of cefotetan for E. coli ,2,3,4,6,11,14,15,17,18,20,22,64,85 H. alvei ,3 K. oxytoca ,3 K. ozaenae ,4 K. pneumoniae ,2,3,15,26,64,85 P. mirabilis ,2,3,4,5,6,11,15,17,18,26,64 and P. vulgaris 2,3,4,5,6,17,18,64,85 is 0.12-4 mcg/mL. The MIC₉₀ of cefotetan for M. morganii ,2,3,4,6,18,64 P. rettgeri ,3,4,5,6,17,64 P. stuartii ,2,3,4,15,17,26,64 and Y. enterocolitica 2,6,28 is 0.25-12 mcg/mL. Although the MIC₉₀ for C. diversus is 0.12-0.5 mcg/mL, the MIC₉₀ for C. freundii is usually 1-32 mcg/mL.2,3,4,11,17,64 The MIC₅₀ of the drug for Serratia , including S. marcescens , is 0.5-4 mcg/mL, but the MIC₉₀ ranges from 0.5-32 mcg/mL.2,3,4,5,6,11,15,17,18,26,64

The in vitro activity of cefotetan against Enterobacter varies considerably, and many strains (approximately 50% of E. aerogenes or E. cloacae ) are considered resistant to the drug.1,2,3,4,18,110,157 The MIC₉₀ of cefotetan for E. agglomerans is 0.5-32 mcg/mL, but the MIC₉₀ for E. aerogenes or E. cloacae is usually 32 mcg/mL or greater.3,4,5,18,64,85

The MIC₉₀ of cefotetan reported for Salmonella , including S. typhi and S. enteritidis , is 0.05-12.5 mcg/mL.2,3,6,11,14,15 The MIC₉₀ of cefotetan reported for Shigella , including Sh. sonnei , is 0.06-0.5 mcg/mL.2,3,6,15

Pseudomonas

Most strains of Pseudomonas aeruginosa are resistant to cefotetan.1,4,6,11,15,17,18,26,64,85,110,157 Cefotetan has some activity in vitro against Ps. acidovorans , and Ps. stutzeri , and the MIC₉₀ of the drug reported for these organisms is 4-32 mcg/mL.2,22,85 Other Pseudomonas , including Ps. fluorescens , and Ps. putida generally are resistant to cefotetan.3,22,85

Other Gram-negative Aerobic Bacteria

Cefotetan is active in vitro against some strains of Alcaligenes faecalis (formerly A. odorans ) and Moraxella , but Acinetobacter , Achromobacter , and Flavobacterium generally are resistant to the drug.2,22

Stenotrophomonas maltophilia (formerly Ps. maltophilia ) generally is resistant to cefotetan.3,22,85

Anaerobic Bacteria

Cefotetan is active in vitro against some gram-positive anaerobic bacteria including Actinomyces ,8 Clostridium ,1,2,4,5,7,8,9,29,64,110,157 Peptococcus ,1,2,4,8,29,64,110,157 Peptostreptococcus ,1,2,4,5,8,9,20,29,64,110,157 and Propionibacterium .1,2,8,32,110,157 The MIC₉₀ of cefotetan reported for most of these gram-positive anaerobes, including Clostridium perfringens and C. botulinum , is 0.06-8 mcg/mL.2,5,7,8,9,29,64 The MIC₉₀ reported for C. difficile is 16-32 mcg/mL,7,8,9,29,32,64 but many strains of this organism are resistant to the drug.1,2,157

Cefotetan is active in vitro against gram-negative anaerobic bacteria including some strains of Bacteroides ,1,2,4,7,8,9,10,18,20,29,30,64,110,157 Fusobacterium ,1,2,4,8,10,20,29,64,110,157 and Veillonella .1,2,20,29,64,110,157 The MIC₉₀ of cefotetan reported for Fusobacterium is 0.13-8 mcg/mL,4,8,10,20,29,64 and the MIC₉₀ for Veillonella is 1-2 mcg/mL.2,20,29,64 The MIC₉₀ for B. fragilis ,4,7,8,9,10,18,25,27,29,30,64 B. uniformis ,2,7 and B. vulgatus 2,4,7,10,29 is 2-32 mcg/mL. Most strains of B. asaccharolyticus , B. distasonis , B. ovatus , and B. thetaiotaomicron are resistant to cefotetan.1,2,4,7,8,9,10,29,30,64,110,157

Prevotella bivia , P. disiens , and P. melaninogenica (formerly B. bivius , B. disiens , and B. melaninogenicus ) may be inhibited in vitro by cefotetan concentrations of 2-32 mcg/mL.2,4,9,10,20,30,64

Other Organisms

Cefotetan has some activity in vitro against Mycobacterium fortuitum , but the clinical importance of this in vitro activity has not been determined to date.34,35 In one study, 1113 isolates of M. fortuitum were inhibited in vitro by cefotetan concentrations of 50 mcg/mL.35

Resistance

Because cefotetan contains a 7 α-methoxy group on the β-lactam ring, the drug is generally stable against hydrolysis by penicillinases and most cephalosporinases.1,2,3,11,16,19,26,64,110,157 Cefotetan is stable against hydrolysis by β-lactamases classified as Richmond-Sykes types I, III (TEM types), IV, and V.2,3,11,26,64 The drug is hydrolyzed by PSE 2 β-lactamases produced by Pseudomonas aeruginosa 2,3,11 and by some β-lactamases produced by Bacteroides fragilis .16 Cefotetan is also hydrolyzed by some β-lactamases produced by Enterobacter 2,4 but is generally more stable than cefoxitin against hydrolysis by cephalosporinases produced by E. coli and E. cloacae .19

Resistance to cefotetan in some gram-negative bacteria, including Citrobacter , Enterobacter , and Pseudomonas , apparently is related to permeability factors.5,16 Resistance in Bacteroides probably results from nonspecific binding of PBPs and permeability factors.3,4,26

In vitro studies indicate that cefotetan, like cefoxitin, is a potent inducer of β-lactamases and can derepress inducible, chromosomally mediated enzymes in gram-negative bacteria that possess these enzymes.19,21,91 Cefotetan appears to be active against some strains of Morganella morganii , Providencia stuartii , and Serratia marcescens following derepression of inducible β-lactamases, but Enterobacter and Citrobacter were generally resistant to the drug following derepression.91

Pharmacokinetics

In all studies described in the Pharmacokinetics section, cefotetan was administered as cefotetan disodium; dosages and concentrations of the drug are expressed in terms of cefotetan.

Total body clearance and mean volume of distribution of cefotetan in geriatric patients (older than 65 years of age) with normal renal function generally are similar to pharmacokinetics reported in younger healthy adults.1,110,157

Absorption

Cefotetan disodium is not absorbed from the GI tract and must be given parenterally.46

Following IV infusion over 30 minutes of a single 1-g dose of cefotetan in healthy adults with normal renal function, peak plasma cefotetan concentrations immediately following completion of the infusion averaged 126-158 mcg/mL and plasma concentrations 11-12 hours later averaged 6.5-9 mcg/mL.1,39,64,110,157

Distribution

Cefotetan is widely distributed into body tissues and fluids including gallbladder,2,64,80 skin,1,64,80,110,157 muscle,1,64,80,110,157 fat,1,64,80,110,157 myometrium,1,48,64,110,157 endometrium,1,48,64,79,110,157 fallopian tube,48,64,79 cervix,1,110,157 ovary,1,64,110,157 uterus and adnexa,64,81 prostatic tissue,2,64 kidney,1,64,110,157 ureter,1,64,110,157 bladder,1,64,110,157 maxillary sinus mucosa,1,110,157 tonsils,1,2,64,110,157 sputum,2,64 bile,1,2,37,46,64,110,157 and wound,2,80 prostatic,64 and peritoneal fluids.1,2,49,64,80,110,157

The apparent volume of distribution of cefotetan is 8-14.8 L in healthy adults.2,38,41,57,64 In one study in healthy adults, the volume of distribution of cefotetan in the central compartment was 0.136 L/kg and the volume of distribution at steady state was 0.194 L/kg.39 The volume of distribution of cefotetan reported for adults with impaired renal function does not differ substantially from that reported for patients with normal renal function.2,45

Information on the distribution of cefotetan into CSF is limited, but only low concentrations of the drug are probably attained in CSF after IV administration.2,88

Cefotetan is generally distributed into bile, and concentrations in common duct bile are 2-21 times higher than concurrent serum concentrations;2,37,46,64 concentrations of the drug in gallbladder bile depend on the functional state of the gallbladder.2,46,64 In patients with good gallbladder function who received a single 1-g IV dose of cefotetan, concentrations of the drug in gallbladder bile ranged from 1.3-1.96 mcg/mL and concentrations in common duct bile ranged from 548 mcg/mL to 1.59 mg/mL in samples obtained 1-4 hours after the dose.46,64 Biliary concentrations of the drug are low in patients with poor or absent gallbladder function.46,64 Cefotetan distributes into prostatic fluid in relatively low concentrations, averaging 0.8 mcg/mL after a 1-g IV dose.64

Cefotetan is 76-91% bound to serum proteins.1,2,5,26,37,38,57,64,110,157 The drug is 87.4% bound at a concentration of 50 mcg/mL and 76.3% bound at a concentration of 400 mcg/mL.26

Cefotetan crosses the placenta and is distributed into cord blood and amniotic fluid.1,2,64,81,157 Peak cefotetan concentrations in umbilical cord serum and amniotic fluid have been reported to be 29 and 8.6 mcg/mL, respectively, following a 1-g IV dose64,81 and were attained approximately 3 hours after the dose.81 The drug is distributed into milk in low concentrations,1,2,64,110,157 averaging 0.22, 0.34, and 0.28 mcg/mL 1, 4, and 6 hours, respectively, after a 1-g IV dose.64

Elimination

In adults with normal renal function, the distribution half-life of cefotetan (t_½α) is 0.2-1.1 hours39,41,45,47 and the elimination half-life (t_½β) is 2.8-4.6 hours.1,2,37,38,39,41,42,45,47,57,64,82,157

Cefotetan does not appear to be metabolized;1,2,38,157 however, 1-10% of a cefotetan dose is present in plasma1,2,40,64,82,110,157 and urine as a tautomer of the drug.1,2,39,40,45,47,64,82,110,157 This tautomer has microbiologic activity and pharmacokinetic properties similar to those of cefotetan.1,39,44,64,82,110,157

Following parenteral administration of a single 0.5- to 2-g dose of cefotetan in adults with normal renal function, 49-81% of the dose is excreted unchanged in urine within 18-24 hours.1,2,37,38,39,40,41,42,47,64,82,110,157 Urinary concentrations of the drug are generally highest during the first 1-4 hours following a dose.1,2,38,39,41,47,110,157 Cefotetan concentrations average 1.4-2 or 3.5-4 mg/mL in urine collected over the first hour following a single 1- or 2-g dose of the drug, respectively, in healthy adults with normal renal function.1,38,39,64,110,157 Following a single 0.5- or 1-g dose of cefotetan in healthy adults with normal renal function, concentrations of the drug in urine collected over the 12th to 24th hours after the dose average 36-77 mcg/mL.2,41 Cefotetan is excreted in urine principally by glomerular filtration, although some renal tubular secretion also occurs.37,39,57 The principal nonrenal route of elimination of cefotetan is biliary excretion;39,57,64 approximately 20% of a dose is reportedly excreted in bile.57,64

Total body clearance of cefotetan from plasma in adults with normal renal function ranges from 29.2-49.7 mL/minute per 1.73 m².39,41,64 Total body clearance and mean volume of distribution of cefotetan in geriatric patients (older than 65 years of age) with normal renal function generally are similar to pharmacokinetics reported in younger healthy adults.1,157

Serum concentrations of cefotetan are higher and the serum half-life of the drug is prolonged in patients with impaired renal function.1,2,39,43,45,64,110,157 In patients with creatinine clearances of 31-94 mL/minute per 1.73 m², the t_½β of cefotetan is 3.7-9.1 hours and, in patients with creatinine clearances less than 15 mL/minute per 1.73 m², the t_½β is 13.1-35.1 hours.2,45 Renal elimination of cefotetan is substantially reduced in patients with impaired renal function; only 5, 8, or 65% of a single 500-mg dose is excreted in urine within 24 hours in patients with creatinine clearances of 0-5, 6-14, or 15-50 mL/minute, respectively.43,64 Systemic clearance of cefotetan decreases linearly with decreases in creatinine clearance.1,110,157

Cefotetan is removed by hemodialysis2,45,64 and peritoneal dialysis.2,90 In patients with renal failure undergoing continuous ambulatory peritoneal dialysis who received a single 1-g IV dose of cefotetan, 5-9% of the dose was removed into the dialysate over the 24-hour period immediately following the dose.90

Chemistry and Stability

Chemistry

Cefotetan is a semisynthetic cephamycin antibiotic1,2,3,4,5,16,26,37,62,64,110,157 derived from oganomycin G, a substance produced by Streptomyces oganonensis .2,64 Cephamycins are β-lactam antibiotics that contain a methoxy group rather than a hydrogen at the 7α-position on the β-lactam ring of the cephalosporin nucleus.2,17,37,62,64 The methoxy group imparts stability against hydrolysis by many penicillinases and some cephalosporinases.1,2,3,11,37,64,110,157 Cefotetan also contains an N -methylthiotetrazole (NMTT) side chain at position 3 of the cephalosporin nucleus similar to that contained in cefamandole and cefoperazone (drugs no longer commercially available in the US).35,57,62,64 The NMTT side chain enhances antibacterial activity, helps to prevent metabolism of the drug, and also may be associated with certain adverse effects (e.g., hypoprothrombinemia, disulfiram-like reactions).57,62,64,135,136

Cefotetan is commercially available as the disodium salt.1,64,65,86,110,157 Potency of cefotetan disodium is expressed in terms of cefotetan, calculated on the anhydrous basis.1,64,86,110,157 Commercially available cefotetan disodium is a mixture of the R - and S -epimers of the drug;2,3,39,44,87 in vivo and in weakly alkaline solutions, a tautomer may be present.2,44,87 The isomers and tautomer have equivalent antibacterial activity.1,2,39,44,87,110,157

Cefotetan disodium occurs as a white to pale yellow powder1,64,65,86,110,157 and is very soluble in water1 and slightly soluble in alcohol,65 having solubilities of 769 and 1.4 mg/mL in water and alcohol, respectively, at 20°C.87 The drug has pK_as of 2.58 and 3.19.37

When the commercially available Duplex^® delivery system containing 1 or 2 g of cefotetan powder and 50 mL of 3.58 or 2.08% dextrose injection, respectively, in separate chambers is reconstituted (activated) according to the manufacturer's directions, the resultant solution is iso-osmotic and has an osmolality of approximately 290 mOsm/kg.157

Stability

Commercially available vials containing 1 or 2 g of cefotetan should be stored at a temperature of 22°C or cooler and protected from light.1 Commercially available pharmacy bulk package vials containing 10 g of cefotetan should be stored at 20-25°C and protected from light.110

Following reconstitution of 1- or 2-g vials of cefotetan with sterile water for injection, IV solutions containing 95-182 mg/mL are colorless to yellow in color and are stable for 24 hours at room temperature (25°C), 96 hours when refrigerated at 5°C, or at least 1 week when frozen at -20°C.1,64,65 Reconstituted solutions have a pH of approximately 4.5-6.5.1

Following reconstitution of 1- or 2-g vials of cefotetan with sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or 0.5 or 1% lidocaine hydrochloride, IM solutions containing 400 or 500 mg/mL are stable for 24 hours at room temperature (25°C), 96 hours when refrigerated at 5°C, or at least 1 week when frozen at -20°C.1,64

Following reconstitution of 10-g pharmacy bulk package vials of cefotetan with sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, doses should be promptly withdrawn from the container and further diluted in a compatible IV solution within 4 hours.110 Any unused portion of the reconstituted pharmacy bulk package should be discarded 4 hours after the vial was originally entered.110 Reconstituted and diluted solutions should be used within 24 hours if stored at room temperature, within 96 hours if stored in a refrigerator at 5°C, or within 1 week if frozen.110

The commercially available Duplex^® drug delivery system containing 1 or 2 g of cefotetan powder and 50 mL of dextrose injection in separate chambers should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.157 Following reconstitution (activation), these IV solutions must be used within 12 hours if stored at room temperature or within 5 days if stored in a refrigerator and should not be frozen.157

Cefotetan disodium powder and reconstituted solutions may darken to a deeper yellow; however, such discoloration does not indicate loss of potency.64,87,157

Cefotetan disodium is physically incompatible with aminoglycosides.1,64,65,87,110,157

1. APP Pharmaceuticals, LLC. Cefotetan for injection prescribing information. Schaumburg, IL; 2010 Sep.

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