P&T News: January 1995, Vol. 15, No. 7

Cefotetan to Become UIHC's New Formulary Second-Generation Cephalosporin

Karen M. Sedlacek, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Bradley E. Britigan, M.D., Professor and Director, Division of Infectious Diseases Department of Internal Medicine

1) Cefotetan and cefoxitin are essentially therapeutically equivalent due to their similar antimicrobial spectrums;1

2) Cefotetan is dosed twice daily as opposed to three to four times daily for cefoxitin; and

3) Cefotetan has a lower cost-per-day of therapy than cefoxitin.

This conversion has been approved by the Antibiotic Advisory Subcommittee and the Pharmacy and Therapeutics Subcommittee.

Spectrum of Activity
Cefotetan is, like cefoxitin, a semi-synthetic cephamycin antibiotic. Cephamycins are beta-lactam antibiotics that contain a methoxy group rather than a hydrogen at the 7a position on the beta-lactam ring of the cephalosporin nucleus. The methoxy group imparts stability against hydrolysis by most penicillinases and some cephalosporinases. 1,3 Cefotetan has in vitro activity against a wide range of aerobic and anaerobic gram-positive and gram-negative organisms and is resistant to the activity of most beta-lactamases.

Like the other cephamycins, cefotetan is active against many aerobic gram-negative bacteria including Escherichia coli, Klebsiella, Proteus, Morganella, Providencia, Neiserria, and Haemophilus species.3,6 The minimum inhibitory concentrations for 90% of these gram-negative aerobic bacteria (MIC90) range from 0.12 to 4 ug/ml.1,3 Similar to cefoxitin, cefotetan has little activity against Pseudomonas aeruginosa and other Pseudomonas or Acinetobacter species. Cefotetan displays modest activity (MIC90 = 2 to 16 ug/ ml) against most gram-positive bacteria (streptococci and staphylococci) while enterococci, including Enterococcus faecalis and methicillin-resistant Staphylococcus species, show marked resistance.3

Cefotetan is active in vitro against some gram-positive anaerobic bacteria including Actinomyces, Clostridium, Peptococcus, Peptostreptococcus, and Propionbacteriun. The MIC90 of cefotetan reported for most of these gram positive anaerobes is 0.06 to 8ug/ml. Cefotetan is also active in vitro against gram-negative anaerobic bacteria including some strains of Bacteroides, Fusobacterium, and Veillonella.1

Organisms with an MIC of 16 ug/ml or less are considered to be susceptible to cefotetan, while those with an MIC of 64 ug/ml or greater are considered to be resistant. Organisms with an MIC greater than 16 ug/ml but less than 64 ug/ml are generally considered only moderately susceptible to cefotetan and may be susceptible if the infection is confined to tissues and fluids where high concentrations of the drug are attained.1 Concentrations of cefotetan in excess of the MIC for most pathogens have been found in most body fluids and tissues, including urine, bile, peritoneal fluid, soft tissues, and the female reproductive tract.3.4 However, cefotetan has poor cerebrospinal fluid (CSF) penetration, and should not be used for central nervous system (CNS) infections.

Cefotetan, like cefoxitin, is used for the treatment of urinary tract, lower respiratory tract, skin and skin structure, bone and joint, gynecologic and intra-abdominal infections caused by susceptible organisms. Cefotetan is also used in perioperative prophylaxis, although in most situations it is not significantly better than cefazolin.

Pharmacokinetic Properties
Cefotetan has a half-life of 2.8 to 4.2 hours3 after IV or IM administration as opposed to cefoxitin with a half-life of approximately 1 hour;l therefore, cefotetan can be dosed every 12 hours instead of every 6 to 8 hours. Cefotetan is 88% plasma protein bound and is 51 to 81% excreted unchanged by the kidneys over a 24-hour period.2 The principal nonrenal route of elimination is biliary excretion; approximately 20% of a dose is reportedly excreted in the bile.1

In healthy adults with normal renal function, IV infusion of a single 1 gram dose of cefotetan over 30 minutes results in peak plasma concentrations averaging 126 to 158 ug/ml immediately following completion of the infusion, and plasma concentrations 11 to 12 hours later averaging 6.5 to 9 ug/ml.

Adverse Drug Reactions
Adverse reactions to cefotetan and cefoxitin are similar. The most common adverse effects related to cefotetan use are gastrointestinal symptoms (diarrhea and nausea) in 1.5% of patients, hematologic laboratory abnormalities in 1.4% of patients, hepatic enzyme elevations in 1.2% of patients, and hypersensitivity (including rash and itching) in 1.2% of patients.l,2

Dosing Guidelines
The usual adult dose is 1 or 2 grams of cefotetan administered IV or IM every 12 hours. Table 1 provides the Antibiotic Advisory Subcommittee and the Pharmacy and Therapeutics Subcommittee approved dosing equivalents for cefoxitin to cefotetan. The usual maximum daily dose of cefotetan is 4 grams. Up to 6 grams a day may be used in life-threatening infections.l,2,4

TABLE 1. Dosage Conversions: Cefoxitin to Cefotetan
Ordered		Dispensed
Drug	Dose	Drug	Dose
Cefoxitin	1 g q 6 hr 1 g q 8 hr	Cefotetan	1 g q 12 hr
Cefoxitin	2 g q 6 hr 2 g q 8 hr	Cefotetan	2 g q 12 hr

The dosage of cefotetan should be adjusted in patients with renal impairment. Table 2 describes two methods for dosing adjustments in renally impaired patients. 1,2,5

TABLE 2. Cefotetan Dosing in Renal Dysfunction
Drug	Normal Dose	Clcr greater than 30 ml/min	Clcr 10-30 ml/min	Clcr less than 10 ml/min
Cefotetan *Cefotetan	1 to 2 g q 12 hr 1 to 2 g q 12 hr	1 to 2 g q 12 hr 1 to 2 g q 12 hr	1 to 2 g q 24 hr 0.5 to 1 g q 12 hr (1/2 usual dose)	1 to 2 g q 48 hr 0.25 to 0.5 g q 12 hr (1/4 usual dose)
Clcr = Creatinine Clearance *Dose reduction method

Summary
The Pharmacy and Therapeutics Subcommittee considers cefoxitin and cefotetan to be therapeutically equivalent and interchangeable antibiotics. Cefotetan is a cost effective alternative to cefoxitin due to a similar antimicrobial spectrum, favorable pharmacokinetic profile, and lower cost per day of therapy.7 Therefore, cefotetan will replace cefoxitin as the second-generation cephalosporin on the UIHC formulary. A similar conversion has been in effect for some time at the Iowa City VA Hospital and has provided cost effective therapy without compromise in patient care or increased incidence of adverse drug reactions. The conversion at UIHC will begin on March 1, 1995. After a 30-day transition period, cefoxitin will be deleted from stock.

References

1. American Hospital Formulary Service. Bethesda: ASHP;1994: 173-82.

2. Physicians' Desk Reference. Montvale: Medical Economics; 1994:2325-7.

3. Drugs. 1985;30:382-426.

4. Pharmacotherapy. 1991;11(1 Pt 2):27S-31S.

5. Pocketbook of Infectious Disease Therapy. Baltimore: Williams & Wilkins; 1994.

6. Am J Hosp Pharm. 1991;48:2146-50.

7. Am J Hosp Pharm. 1993;50:446. Letter.

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Ampicillin/Sulbactam to be Designated a Nonprotocol Antibiotic

Rebecca Brannan, R.Ph.
Peer Review Status: Internally Peer Reviewed by Bradley E. Britigan, M.D., Professor and Director, Division of Infectious Diseases, Department of Internal Medicine

Ampicillin/sulbactam (Unasyn(R)) is a combination antibiotic consisting of ampicillin (a beta-lactam penicillin) and sulbactam (an irreversible beta-lactamase inhibitor). Ampicillin is the active antimicrobial component of this combination antibiotic. Sulbactam has limited antimicrobial activity, but is effective at preventing the inactivation of ampicillin by beta-lactamase producing bacteria. Ampicillin/sulbactam has a broad spectrum of activity covering many gram-positive, gram-negative, and anaerobic organisms.

The Pharmacy and Therapeutics Subcommittee has recommended the removal of ampicillin/ sulbactam from protocol status. This change is occurring because antimicrobial resistance to ampicillin/sulbactam has not developed at UIHC and because usage has been for appropriate indications. It is anticipated that continued adherence to prescribing will occur despite removal of the drug from protocol status. Therefore, effective March 1, 1995, ampicillin/sulbactam will become a nonprotocol antibiotic.

Spectrum of Activity and Place in Therapy
In vitro data collected at UIHC shows the following susceptibility profile of ampicillin/sulbactam against gram-positive organisms: methicillin-sensitive Staphylococcus agrees (97%), methicillin-sensitive Staphylococcus epidermidis (100%), Streptococcus sp. (100%), and Enterococcus faecalis (99.1%).6 The gram-negative susceptibility patterns are: Proteus vulgaris (100%), Proteus mirabilis (99%), Klebsiella pneumoniae (89%), Escherichia coil (79%), Enterobacter (61%), Citrobacter freundii (60%), Pseudomonas sp. (33%), and Serratia (16%).6 Table 1 summarizes the spectrum of activity of ampicillin/sulbactam. Table 2 summarizes the appropriate indications for ampicillin/sulbactam.

TABLE 1. Spectrum of Activity of Ampicillin/Sulbactam[3-5]
Gram-Positive Coverage
Sensitive	Resistant
Stephylococcus aureus (MSSA) Coagulase-negative Staphylococcus Streptococcus sp. Enterococcus sp. Listeria sp.	Methicillin-resistant Staphylococcus sp.
Gram-Negative Coverage
Haemophilus influenzae Neisseria meningitis Acinetobacter sp. Moraxella catarrhalis	Pseudomonas sp. Citrobacter sp. Serratia sp. Enterobacter sp.
Anaerobic Coverage
Bacteroides fragilis Bacteroides sp. Fusobacterium Clostridium sp. Peptostreptococcus sp. Peptococcus

TABLE 2: Clinical Uses of Ampicillin/Sulbactam

Appropriate Clinical Uses of Ampicillin/Sulbactam Polymicrobial skin/soft tissue infections, such as those seen in diabetic patients Bite-wound infections Sinusitis Intra-abdominal and pelvic infections Community-acquired pneumonias (i.e., beta-lactamase producting Haemophilis influenzae) As an alternative to surgical prophylaxis with a second-generation cephalosporin Pediatric patients with cellulitis Inappropriate Uses of Ampicillin/Sulbactam Penicillin-sensitive cellulitis infections Uncomplicated urinary tract infections Nosocomial gram-negative pneumonias Other gram negative infections involving Pseudomonas, Citrobacter, Serratia, or Enterobacter, which are not usually susceptible to this agent

Pharmacokinetic Properties
Protein binding is minimal for both ampicillin (28%) and sulbactam (38%), therefore allowing extensive distribution into tissues. Following the intravenous injection of a 1.5 gram dose and 3 gram dose, peak serum concentrations of 58 ug/ml (ampicillin) and 124 ug/ml (ampicillin) were attained, respectively. Serum concentrations in healthy volunteers were approximately 1 ug/ml six hours after the administration of the dose. Similar concentrations can be detected in peritoneal fluid, bile, puss, and abscesses shortly after administration. Penetration into the cerebral spinal fluid (CSF) is extensive in the presence of inflamed meninges; otherwise, CSF penetration is minimal. Both ampicillin and sulbactam are eliminated virtually unchanged in the urine. The elimination half-life is approximately one hour, but may be prolonged in neonates, the elderly, or patients with renal dysfunction.2-4,6

Adverse Drug Reactions
As with most penicillins, hypersensitivity reactions are the most common adverse effect. Rashes, itching, and erythema (1.5%); pain at the injection site (3.2%); and diarrhea (1.7%) have been noted. Increases in ALT (6.9%) and AST (6.2%) are laboratory abnormalities which have been associated with ampicillin/sulbactam therapy.2-4

Dosing Guidelines
Ampicillin/sulbactam is available in two dosage strengths -- 1.5 gram (1 gram ampicillin/0.5 gram sulbactam) and 3 gram (2 gram ampicillin/l gram sulbactam) -- and should be dosed according to the guidelines outlined in Table 3.3,7

TABLE 3: Ampicillin/Sulbactam Dosing Guidelines

Adult Dosing 1.5 g every six hours for mild/moderate infections without systemic signs and for surgical prophylaxis. 3.0 g every six hours for severe infections with systemic signs. Renal Dysfunction The following dosage intervals (using the above doses) should be followed according to the degree of renal dysfunction. Clcr Dosing Interval 49 to 30 ml/min every 6 to 8 hr 29 to 10 ml/min every 12 hr less than 10 ml/min every 24 hr Pediatric Dosing* 50 to 100 mg/kg/24hr divided every 6 hours for mild/moderate infections. 200 to 400 mg/kg/24hr divided every 6 hours for severe infections. ________ *Based on the ampicillin component[7] Clcr = Creatinine Clearance

Conclusion
Ampicillin/sulbactam is a useful broad-spectrum antibiotic with coverage against many gram-positive, gram-negative and anaerobic organisms. If used appropriately, ampicillin/sulbactam can also be cost effective therapy. Because antimicrobial resistance to this product has not developed at UIHC and usage of the drug has been for appropriate indications, effective March 1, 1995, ampicillin/sulbactam (Unasyn (R)) will be removed from protocol status at UIHC. However, it is believed that only with continued diligence in prescribing ampicillin/sulbactam in the most clinically efficacious situations will the drug continue to display its clinical efficacy with minimal adverse effects and acceptable sensitivity patterns.

References

1. University of Iowa Hospitals and Clinics. Department of Pathology, Medical Microbiology Division (Data on file).

2. Unasyn. Mod Lett Drug Ther. 1987;29:79-81.

3. Roerig. Ampicillin/sulbactam product information and package insert. New York, 1987.

4. Rev Inf Dis. 1986;8(Suppl 5):S528-S534.

5. Drugs. 1988;35(Suppl 7):17-26.

6. Am J Med Sci. 1991;301(6):406-11.

7. The Harriet Lane Handbook. 13th ed. St. Louis: Mosby; 1993:338-9.

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