Cefotetan Disodium

Class: Cephamycins
Chemical Name: [6R - (6α,7α)] - 7 - [[[4 - (2 - Amino - 1 - carboxy - 2 - oxoethylidene) - 1,3 - dithietan - 2 - yl]carbonyl]amino] - 7 - methoxy - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo - [4.2.0]oct - 2 - ene - 2 - carboxylic acid disodium salt
CAS Number: 74356-00-6

Introduction

Antibacterial; β-lactam antibiotic; cephamycin.^{1 2 3 4 5 26 62 110 157}

Uses for Cefotetan Disodium

Bone and Joint Infections

Treatment of bone and joint infections caused by Staphylococcus aureus.^{1 2 110 157}

Gynecologic Infections

Treatment of gynecologic infections caused by susceptible S. aureus (including penicillinase-producing strains), S. epidermidis, Streptococcus agalactiae (group B streptococci), other streptococci (except enterococci), Escherichia coli, Neisseria gonorrhoeae, Proteus mirabilis, Bacteroides (except B. distasonis, B. ovatus, B. thetaiotaomicron), Fusobacterium, and gram-positive anaerobic cocci (including Peptococcus and Peptostreptococcus).^{1 2 66 110 157}

Treatment of pelvic inflammatory disease (PID).^{113 121 155} Cefotetan (or cefoxitin) in conjunction with doxycycline considered a regimen of choice by CDC and others when a parenteral regimen is indicated for PID.^{113 121 155} Because cefotetan (like cephalosporins) is not active against Chlamydia, concomitant use of a drug active against Chlamydia (e.g., doxycycline) is necessary when these organisms are suspected pathogens.^{1 110 121 157}

Intra-abdominal Infections

Treatment of intra-abdominal infections caused by susceptible Streptococcus (except enterococci), E. coli, Klebsiella (including K. pneumoniae), Bacteroides (except B. distasonis, B. ovatus, B. thetaiotaomicron), or Clostridium.^{1 2 110 157}

May be effective for mild to moderate infections caused by B. fragilis,^{87 88} but other anti-infectives (e.g., metronidazole, clindamycin) preferred,^{88 97} especially for severe or life-threatening B. fragilis infections.⁸⁸

Respiratory Tract Infections

Treatment of lower respiratory tract infections caused by susceptible S. pneumoniae, S. aureus (including penicillinase-producing strains), Haemophilus influenzae (including ampicillin-resistant strains), E. coli, Klebsiella (including K. pneumoniae), P. mirabilis, or Serratia marcescens.^{1 2 53 110 157}

Skin and Skin Structure Infections

Treatment of skin and skin structure infections caused by susceptible S. aureus (including penicillinase-producing strains), S. epidermidis, S. pyogenes (group A β-hemolytic streptococci), other streptococci (except enterococci), E. coli, K. pneumoniae, Peptococcus niger, or Peptostreptococcus.^{1 110 157}

Urinary Tract Infections (UTIs)

Treatment of UTIs caused by susceptible E. coli, Klebsiella (including K. pneumoniae), P. mirabilis, P. vulgaris, Providencia rettgeri, or Morganella morganii.^{1 2 51 52 110 157}

Should not be used alone for UTIs if Pseudomonas aeruginosa is a possible pathogen since most strains are resistant.^{2 88}

Gonorrhea

Has been used for treatment of uncomplicated gonorrhea†.⁹⁸ Not included in CDC recommendations for treatment of Neisseria gonorrhoeae infections.^{121 155}

Perioperative Prophylaxis

Perioperative prophylaxis in women undergoing cesarean section^{1 2 68 130 149 157} or abdominal or vaginal hysterectomy.^{1 2 67 110 125 157} A preferred agent for vaginal, abdominal, or laparoscopic hysterectomy.⁶³ Cefazolin generally preferred for perioperative prophylaxis in cesarean section;^{63 125} doxycycline recommended for perioperative prophylaxis in abortion.⁶³

Perioperative prophylaxis in patients undergoing biliary tract^{1 2 70 157} or GI surgery.^{1 2 69 72 110 125 157} A preferred agent for colorectal surgery^{63 125} and nonperforated appendectomy.^{63 125} Cefazolin usually recommended for biliary tract surgery.⁶³

Perioperative prophylaxis in patients undergoing transurethral surgery.^{1 2 71 110 157} Not a preferred agent for genitourinary surgery.⁶³

Cefotetan Disodium Dosage and Administration

Administration

Administer by IV injection¹ or infusion^{1 110 157} or by deep IM injection.¹

IV route preferred for treatment of 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}

For solution and drug compatibility information, see Compatibility under Stability.

IV Injection

Reconstitution

Vials containing 1 or 2 g of cefotetan: Reconstitute 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 Shake to dissolve; let stand until clear.¹

Rate of Administration

Inject appropriate dose of reconstituted solution directly into a vein over a 3- to 5-minute period or slowly into the tubing of a compatible IV solution.¹

IV Infusion

Other IV solutions flowing through a common administration tubing or set should be discontinued while cefotetan is infused.^{1 157}

Reconstitution

Vials containing 1 or 2 g of cefotetan: Reconstitute 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 Shake to dissolve; let stand until clear.¹

Pharmacy bulk package vial containing 10 g of cefotetan: Reconstitute 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 Shake to dissolve; let stand until clear.¹¹⁰ The pharmacy bulk package of the drug is not intended for direct IV infusion; prior to administration, doses from the reconstituted pharmacy bulk package must be further diluted in a compatible IV infusion solution.¹¹⁰ As soon as possible following reconstitution (within 4 hours), transfer individual doses to a compatible IV solution (see Solution Compatibility under Stability).¹¹⁰ Consult manufacturer's directions for additional information.¹¹⁰

Duplex drug delivery system containing 1 or 2 g of cefotetan and 50 mL of dextrose injection in separate chambers: Reconstitute (activate) according to the manufacturer's directions.¹⁵⁷

Rate of Administration

Administer by IV infusion over 20–60 minutes.^{1 2 52 53 87}

IM Administration

Administer IM injections deeply into a large muscle, such as the upper outer quadrant of the gluteus maximus.¹ Use aspiration to ensure needle is not in a blood vessel.¹

Reconstitution

Prepare IM injections 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 to vials containing 1 or 2 g of cefotetan, respectively, to provide solutions containing approximately 400 or 500 mg/mL, respectively.¹ Shake to dissolve; let stand until clear.¹

Dosage

Available as cefotetan disodium; dosage expressed in terms of cefotetan.^{1 110 157}

Pediatric Patients

Treatment of Severe Infections in Children ≥1 Month of Age†

IV or IM

AAP recommends 40–80 mg/kg daily given in 2 equally divided doses.¹¹² AAP states drug is inappropriate in mild to moderate infections.¹¹²

Perioperative Prophylaxis†

Children Undergoing Colorectal Surgery

IV

30–40 mg/kg given at induction of anesthesia (within 0.5–1 hour prior to incision).¹²⁵

Some clinicians recommend additional doses during the procedure (e.g., every 3–6 hours) if surgery is prolonged >4 hours or major blood loss occurs.^{63 154} Postoperative doses usually unnecessary and may increase risk of bacterial resistance.⁶³

Children Undergoing Appendectomy

IV

20–40 mg/kg given at induction of anesthesia (within 0.5–1 hour prior to incision).¹²⁵

Some clinicians recommend additional doses during the procedure (e.g., every 3–6 hours) if surgery is prolonged >4 hours or major blood loss occurs.^{63 154} Postoperative doses usually unnecessary and may increase risk of bacterial resistance.⁶³

Adults

General Adult Dosage

Less Severe Infections

IV or IM

1 or 2 g every 12 hours.^{1 110 157}

Severe Infections

IV

2 g every 12 hours.^{1 110 157}

Life-threatening Infections

IV

3 g every 12 hours.^{1 110 157}

Gynecologic Infections

Pelvic Inflammatory Disease (PID)

IV

2 g every 12 hours;^{113 121 155} used in conjunction with IV or oral doxycycline (100 mg every 12 hours).^{113 121 155} Cefotetan may be discontinued 24 hours after clinical improvement occurs and oral doxycycline (100 mg every 12 hours) continued to complete 14 days of treatment.^{113 121}

Skin and Skin Structure Infections

Mild to Moderate Infections

IV

1 g every 12 hours or 2 g every 24 hours.^{1 110 157} For infections caused by K. pneumoniae, 1 or 2 g every 12 hours.^{1 110 157}

IM

1 g every 12 hours.¹ For infections caused by K. pneumoniae, 1 or 2 g every 12 hours.¹

Severe Infections

IV

2 g every 12 hours.^{1 110 157}

Urinary Tract Infections (UTIs)

IV or IM

500 mg every 12 hours; 1 or 2 g every 12 hours; or 1 or 2 g every 24 hours.^{1 110 157}

Perioperative Prophylaxis

Gynecologic and Obstetric Surgery

IV

Hysterectomy (vaginal, abdominal, laparoscopic): Single 1- or 2- g dose given within 0.5–1 hour prior to incision.^{1 63 110 125 157}

Cesarean section: Single 1- or 2-g dose given within 0.5–1 hour prior to incision.^{1 63 110 125 157} Manufacturers recommend giving the dose as soon as the umbilical cord is clamped for cesarean section,¹ but there is some evidence that giving dose prior to skin incision is more effective than after clamping.⁶³

Some clinicians recommend additional doses during the procedure (e.g., every 3–6 hours) if surgery is prolonged >4 hours or major blood loss occurs.^{63 154} Postoperative doses usually unnecessary and may increase risk of bacterial resistance.⁶³

Colorectal Surgery, Appendectomy (Nonperforated), or Other GI Surgery

IV

Single 1- or 2-g dose given within 0.5–1 hour prior to incision.^{1 63 110 125 157}

Some clinicians recommend additional doses during the procedure (e.g., every 3–6 hours) if surgery is prolonged >4 hours or major blood loss occurs.^{63 154} Postoperative doses usually unnecessary and may increase risk of bacterial resistance.^{63 152}

Transurethral Surgery

IV

Single 1- or 2-g dose given within 0.5–1 hour prior to incision.^{1 110 125 157}

Some clinicians recommend additional doses during the procedure if surgery is prolonged >4 hours or major blood loss occurs.⁶³ Postoperative doses usually unnecessary and may increase risk of bacterial resistance.^{63 152}

Prescribing Limits

Adults

Maximum 6 g daily.^{1 110 157}

Special Populations

Renal Impairment

Dosage adjustments required based on Cl_cr.^{1 2 37 39 43 110 157}

Table 1. Dosage for Adults with Renal Impairment139110157

Clcr (mL/min)	Dosage
>30	Usual dose every 12 hours
10–30	Usual dose every 24 hours or 50% of usual dose every 12 hours
<10	Usual dose every 48 hours or 25% of usual dose every 12 hours
Hemodialysis patients	25% of usual dose every 24 hours on days between dialysis and 50% of usual dose on the day of dialysis

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal function.^{1 110 157} (See Renal Impairment under Dosage and Administration.)

Cautions for Cefotetan Disodium

Contraindications

• 
  

  Known hypersensitivity to cefotetan or cephalosporins.^{1 110 157}

  
  


• 
  

  History of cephalosporin-associated hemolytic anemia.^{1 110 157}

  
  

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.^{1 110 157} Careful observation of the patient is essential.^{1 110 157} Institute appropriate therapy if superinfection occurs.^{1 110 157}

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.^{1 110 141 142 143 144 145 157} C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including cefotetan, and may range in severity from mild diarrhea to fatal colitis.^{1 110 141 142 143 144 145 157} 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}

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.^{1 110 141 142 143 144 145 157} 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.^{1 110 141 142 143 144 145 157}

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile may need to be discontinued.^{1 110 141 142 143 144 145 157} Some mild cases may respond to discontinuance alone.^{141 142 143 144 145} Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.^{1 110 141 142 143 144 145 157}

Hemolytic Anemia

Severe hemolytic anemia (including fatalities) reported rarely with cefotetan;^{1 110 114 117 118 119 120 127 157} hemolytic anemia reported in a few women undergoing obstetric and gynecologic procedures who received a single dose of cefotetan for perioperative prophylaxis.¹²⁷ Similar immune-mediated hemolytic anemia reported with some cephalosporins (e.g., cefotaxime, ceftizoxime [no longer commercially available in the US], ceftriaxone).^{1 110 146 147 148 157}

Periodically monitor for signs and symptoms of hemolytic anemia; assess hematologic parameters when appropriate.^{1 110 157}

If hemolytic anemia develops within 2–3 weeks after initiation of cefotetan, the diagnosis of immune-mediated hemolytic anemia should be considered and the drug discontinued until the etiology of anemia is determined.^{1 110 157} Consider blood transfusions as needed.^{1 110 157}

Prolonged PT

Prolonged PT (with or without bleeding) reported rarely.^{1 2 76 77 78 110 131 132 133 157}

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}

Sensitivity Reactions

Hypersensitivity Reactions

Possible hypersensitivity reactions, including rash (maculopapular or erythematous), pruritus, fever, eosinophilia, urticaria, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.^{1 110 157 a}

If an allergic reaction occurs, discontinue cefotetan and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).^{1 110 157}

Cross-hypersensitivity

Partial cross-allergenicity among β-lactam antibiotics, including penicillins, cephalosporins, and cephamycins.^{1 37 60 110 157}

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cefotetan, cephalosporins, penicillins, or other drugs.^{1 110 157 a} Cautious use recommended in individuals hypersensitive to penicillins;^{1 110 157 a} avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.^a

General Precautions

History of GI Disease

Use with caution in patients with a history of GI disease, particularly colitis.^{1 110 157} (See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions.)

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefotetan and other antibacterials, use 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}

In certain serious infections when the causative organism is unknown and in cases of confirmed or suspected gram-positive or -negative sepsis, concomitant use of an aminoglycoside may be indicated pending results of in vitro susceptibility tests.^{1 110 157} (See Aminoglycosides under Interactions.)

Patients with Diabetes

The commercially available Duplex delivery system containing 1 or 2 g of cefotetan and 50 mL of dextrose injection should be used with caution in patients with overt or known subclinical diabetes mellitus or in patients with carbohydrate intolerance for any reason.¹⁵⁷

Sodium Content

Contains approximately 80 mg (3.5 mEq) of sodium per g of cefotetan.^{1 110 157}

Specific Populations

Pregnancy

Category B.^{1 110 157}

Lactation

Distributed into milk in low concentrations; use with caution.^{1 110 157}

Pediatric Use

Safety and efficacy not established in children.^{1 110 157} (See Pediatric Patients under Dosage and Administration.)

Geriatric Use

Safety and efficacy in those ≥60 years of age similar to that in younger adults, but possibility exists of greater sensitivity to the drug in some geriatric patients.^{1 110 157}

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.^{1 110 157} Select dosage with caution and consider monitoring renal function because of age-related decreases in renal function.^{1 110 157} (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance and increased half-life.^{1 110 157}

Reduce dosage in those with renal impairment.^{1 110 157} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects, hematologic effects (eosinophilia, positive direct Coombs test, thrombocytosis), elevated hepatic enzymes, hypersensitivity reactions, local reactions at administration site.^{1 110 157}

Interactions for Cefotetan Disodium

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Alcohol	Possibility of disulfiram-like reactions (flushing, sweating, headache, tachycardia) if alcohol ingested within 72 hours after cefotetan1 2 108 110 157	Avoid ingesting alcohol during and for 72 hours after cefotetan1 2 108 110 Appears to result from accumulation of acetaldehyde2 73 74 75
Aminoglycosides	Possible increased risk of nephrotoxicity1 61 110 157 In vitro evidence of additive or synergistic antibacterial activity against S. aureus and some gram-negative bacilli2 5 17 24 96	Closely monitor renal function if used concomitantly1 110 157 Administer separately; do not admix1 110 157
Probenecid	Concomitant probenecid does not appear to affect pharmacokinetics of cefotetan since the drug is excreted principally by glomerular filtration and nonrenal mechanisms87
Tests for creatinine	High concentrations may cause falsely elevated serum or urine creatinine values when the Jaffe reaction is used1 110 157
Tests for glucose	Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1 110 157	Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix)1 110 157

Cefotetan Disodium Pharmacokinetics

Absorption

Bioavailability

Not absorbed from the GI tract; must be given parenterally.⁴⁶

Appears to be completely absorbed following IM administration;^{2 41} peak plasma concentrations attained 1.5–4 hours after a dose.^{2 41 42 64}

Distribution

Extent

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 93 110 157} sputum,^{2 64 92} bile,^{1 2 37 46 64 110 157} and wound,^{2 80} prostatic,⁶⁴ and peritoneal fluids.^{1 2 49 64 80 110 157}

Only low concentrations attained in CSF.^{2 88}

Crosses the placenta^{1 2 64 81 110 157} and is distributed into milk in low concentrations.^{1 2 64 110 157}

Plasma Protein Binding

76–91%.^{1 2 5 26 37 38 57 64 110 157}

Elimination

Metabolism

Does not appear to be metabolized,^{1 2 38 110 157} but 1–10% of a dose is present in plasma and urine as a tautomer of the drug.^{1 2 39 40 45 47 64 82 110 157} This tautomer has microbiologic activity and pharmacokinetics similar to cefotetan.^{1 39 44 64 82 110 157}

Elimination Route

Eliminated principally in urine by glomerular filtration;^{1 2 37 38 39 40 41 42 47 64 82 110 157} also eliminated by biliary excretion.^{39 57 64}

49–81% of a dose eliminated unchanged in urine;^{1 2 37 38 39 40 41 42 47 64 82 110 157} approximately 20% excreted in bile.^{57 64}

Half-life

Adults with normal renal function: Distribution half-life 0.2–1.1 hours^{39 41 45 47} and elimination half-life 2.8–4.6 hours.^{1 2 37 38 39 41 42 45 47 57 64 82 110 157}

Special Populations

Patients with impaired renal function: Renal elimination decreased and serum concentrations higher and half-life prolonged.^{1 2 39 43 45 64 110 157} Half-life may be 10 hours in those with moderate renal impairment.^{1 110 157}

Stability

Storage

Parenteral

Powder for Injection or IV Infusion

Vials containing 1 or 2 g of cefotetan: ≤22° C;¹ protect from light.¹

Pharmacy bulk package vial containing 10 g of cefotetan: 20–25°C;¹¹⁰ protect from light.¹¹⁰ Discard any unused portion of reconstituted pharmacy bulk package 4 hours after the vial was originally entered.¹¹⁰

Powder and reconstituted solutions may darken to a deeper yellow; this does not indicate loss of potency.^{64 87}

IV solutions containing 95–182 mg of cefotetan/mL prepared using sterile water are stable for 24 hours at 25°C, 96 hours when refrigerated at 5°C, or at least 1 week when frozen at -20°C.^{1 64 65 87}

IM solutions containing 400 or 500 mg/mL prepared using sterile or bacteriostatic water, 0.9% sodium chloride, or 0.5 or 1% lidocaine hydrochloride are stable for 24 hours at 25°C, 96 hours when refrigerated at 5°C, or at least 1 week when frozen at -20°C.^{1 64 87} Reconstituted solutions transferred to disposable glass or plastic syringes are stable for 24 hours at room temperature or 96 hours when refrigerated.¹

Powder For Injection, for IV Infusion

Duplex drug delivery system containing 1 or 2 g of cefotetan and 50 mL of dextrose injection: 20–25°C (may be exposed to 15–30°C).¹⁵⁷ Following reconstitution (activation), use within 12 hours if stored at room temperature or within 5 days if stored in a refrigerator; do not freeze.¹⁵⁷

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility¹⁵⁶

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Y-site Compatibility156

Compatible
Allopurinol sodium
Amifostine
Aztreonam
Bivalirudin
Dexmedetomidine HCl
Diltiazem HCl
Docetaxel
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Filgrastim
Fluconazole
Fludarabine phosphate
Gatifloxacin
Gemcitabine HCl
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Insulin, regular