Continuing Education Activity

Cefotaxime is a medication used to manage and treat cervicitis/urethritis and pneumonia. Cefotaxime is a beta-lactam antibiotic classified as a third-generation cephalosporin. Its broad-spectrum antibacterial activity is useful in treating the susceptible strains of bacteria affecting the lower respiratory tract, genito-urinary tract, central nervous system, intra-abdominal infections, bone and joint infections, skin infections, gynecologic infections, and septicemia. This activity outlines the indications, mechanism of action, and contraindications for cefotaxime is a valuable agent in treating and managing bacterial infections. This activity will highlight the mechanism of action, adverse event profile, resistance, and other key factors pertinent to healthcare team members in the care of patients with pneumonia and urethritis/cervicitis and related conditions.

Objectives:

• Describe the pathophysiology of cefotaxime resistance.
• Identify the most common adverse events associated with cefotaxime therapy.
• Outline the mechanism of action of cefotaxime.
• Review some interprofessional team strategies for improving care coordination and communication to advance cefotaxime and improve outcomes.

Indications

Cefotaxime is a beta-lactam antibiotic classified as a third-generation cephalosporin, which was first synthesized in 1976 and is FDA approved to treat gram-positive, gram-negative, and anaerobic bacteria.[1] Its broad-spectrum antibacterial activity is useful in treating the susceptible strains of bacteria affecting the lower respiratory tract, genito-urinary tract, central nervous system, intra-abdominal infections, bone and joint infections, skin infections, gynecologic infections, and septicemia.[2] Cefotaxime may also be used prophylactically prior to surgery to prevent surgical infections.

Among the susceptible strains, Enterobacteriaceae is particularly sensitive to cefotaxime and may treat multi-drug resistant strains of Enterobacteriaceae.[3] Although it has a broad spectrum of bactericidal activity, it is not as effective against pseudomonas aeruginosa infections compared to other third-generation antibiotics and is not recommended as monotherapy.[3] Intramuscular treatment with cefotaxime for sexually transmitted infections with Neisseria gonorrhoeae has shown a positive outcome in both men and women. Cefotaxime has beneficial therapeutic activity treating pneumonia affecting the lower respiratory tract primarily caused by Gram-negative bacilli, and the bactericidal agent has shown significant efficacy in treating complicated infections affecting the urinary tract.[4] 

Compared with the other cephalosporins, a favorable characteristic of cefotaxime is that it does not cause a notable occurrence of coagulopathies and pseudocholelithiasis.[4] Trials comparing cefotaxime with the third-generation cephalosporin ceftriaxone have exhibited similar clinical efficiency.[4] Clinical trials have also shown 75% to 100% resolution in hospitalized patients with moderate to severe infections.[5][4] Cefotaxime may also be interchangeable with ceftriaxone as off-label use for the treatment of endocarditis by Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae (HACEK) organisms.[6] Cefotaxime can readily cross the blood-brain barrier when administered intravenously and may treat gram-negative infections resistant to previous generations of cephalosporins.[7]

Susceptible Organisms

Gram-positive bacteria

• Enterococcus spp
• Staphylococcus aureus
• Staphylococcus epidermidis
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Streptococcus viridans spp

Anaerobic bacteria

• Bacteroides spp.
• Clostridium spp
• Fusobacterium spp
• Peptococcus spp
• Peptostreptococcus spp

Gram-negative bacteria

• Acinetobacter spp.
• Citrobacter spp
• Enterobacter spp
• Escherichia coli
• Haemophilus influenzae
• Haemophilus parainfluenzae
• Klebsiella spp.
• Morganella morganii
• Neisseria gonorrhoeae 
• Neisseria meningitidis
• Proteus mirabilis
• Proteus vulgaris
• Providencia rettgeri
• Providencia stuartii
• Serratia marcescens

Mechanism of Action

Cefotaxime is a bactericidal agent that exerts its mechanism of action by binding penicillin-binding proteins (PBPs) via beta-lactam rings and inhibiting the definitive activity of transpeptidation in peptidoglycan cell wall synthesis of susceptible bacterial organisms.[8][9] Its action demonstrates a great affinity for PBP Ib and PBP III cell wall proteins.

The inability to form a bacterial cell wall further causes the autolysis of the bacteria.[7] Similarly to other third-generation cephalosporins, its broad spectrum action makes it efficacious against gram-positive and gram-negative bacteria.

Resistance

Beta-lactamases can cause hydrolysis to cefotaxime, further hindering its bactericidal effects. Although susceptive, cefotaxime is quite durable against the activity of most β-lactamases.

Metabolism

Once administered, cefotaxime undergoes metabolism within the liver, and the majority of it is excreted renally. In the liver, cefotaxime converts to desacetylcefotaxime, which is further converted to desacetylcefotaxime lactone and then to M metabolites.[10] More than 80% is recovered in the urine, with one-third being in the form of desacetylcefotaxime (des-CTX). Although desacetylcefotaxime (des-CTX) is the major metabolite of cefotaxime, its activity is eight-fold weaker than cefotaxime.[11]

Administration

Cefotaxime is available and distributed in powder form and as a premixed solution for intramuscular and intervenous administration. The powder form is available in 500 mg, 1 g, 2 g, and 10 g vials. The premixed solution is available as 1g and 2g for injection.

Gonococcal Infections

• Urethritis (Males): 0.5 g intramuscular injection (can be administered as a single dose)
• Cervicitis (Females): 0.5 g intramuscular injection (can be administered as a single dose)
• Rectal infection (Males): 1 g intramuscular injection (can be administered as a single dose)
• Rectal infection( Females): 0.5 g intramuscular injection (can be administered as a single dose)

Cefotaxime has no coverage for Chlamydia trachomatis, and treatment should be added if this organism is suspected.

Septicemia

• 2 g I.V. every 6 to 8 hours. (Daily dose of 6 to 8 grams)

Spontaneous Bacterial Peritonitis (SBP)

• Cefotaxime is the drug of choice in patients with SBP due to its ability to achieve excellent levels in the blood and ascitic fluid. The typical dose in SBP would be 2 g intravenous every 8 hours.  

Uncomplicated Infections

• 1 g intramuscular or IV every 12 hours. (Daily dose of 2 grams)

Moderate to Severe Infections

• 1 to 2 g intramuscular or IV every 8 hours. (Daily dose of 3 to 6 grams)

Life-threatening Infections

• 2 g intramuscular or IV every 4 hours. (Daily dose of 12 grams)

Cesarean Section

• First dose: 1 g IV (Umbilical cord should be clamped)
• Second dose: 1 g intramuscular or IV (six hours after the first dose)
• Third dose: 1 g intramuscular or IV (twelve hours after the first dose)

Surgery Prophylaxis

• 1 g intramuscular or IV 30 minutes before surgery.

Neonates (age 0 to 4 weeks)

• (Age 0 to 1 week) 50 mg/kg per dose IV every 12 hours
• (Age 1 to 4 weeks) 50 mg/kg per dose IV every 8 hours

Infants and Children (age 1 month to 12 years old)

• 50 to 180 mg/kg intramuscular or IV every 6 to 8 hours (for individuals with body weight <50kg)
• 1 to 2 grams intramuscular or IV every 8 hours. (for individuals with body weight >50kg)

Individuals with a body weight>50 kg should follow adult dosing. The daily dosage should not exceed 12 grams for infants and children.

Adverse Effects

• Local reaction: pain, swelling
• Hypersensitivity: rash, pruritis, anaphylaxis
• Gastrointestinal effects: nausea, vomiting, diarrhea
• Pseudomembranous Colitis
• Headache
• Elevation in liver enzymes
• Elevation in BUN and creatinine
• Hematologic: Neutropenia, leukopenia, agranulocytosis

Local reactions such as pain, swelling, and rash are the most common adverse effects following cefotaxime administration. Like other cephalosporins, cefotaxime does not cause disulfiram-like reactions. Cefotaxime used concurrently with nephrotoxic agents may promote nephrotoxic effects on the kidney, and such use requires caution. Patients with hypersensitivity to the cephalosporin or penicillin group may result in an anaphylactic reaction and are manageable with epinephrine, antihistamines, vasopressors, or corticosteroids.

Contraindications

Hypersensitivity to cefotaxime is an absolute contraindication to its use. Patients with known allergies to penicillin or other cephalosporins should also avoid cefotaxime.

Monitoring

Cefotaxime administration and dosing require adjusting in geriatric populations, patients with decreased renal function, and hepatic dysfunction. Renal function and liver enzymes require routine monitoring. The half-life of cefotaxime is generally one hour, and severe kidney dysfunction may prolong the half-life of cefotaxime and its metabolite desacetylcefotaxime.[9] CBC should also be monitored with cefotaxime use as there are reports of hematologic changes such as neutropenia, leukopenia, and agranulocytosis. Cefotaxime, like other cephalosporins, may also cause a false positive direct coombs test.

Cefotaxime is an FDA Pregnancy Category B drug. Cefotaxime use in pregnancy has not been studied clearly and should be used cautiously. Cefotaxime is reported to cross the placenta during pregnancy. It is also present in low concentrations in breast milk during lactation. 

Toxicity

Cefotaxime is metabolized by the liver and excreted through the kidneys, and dysfunctions may result in decreased drug clearance leading to increased plasma concentrations. About 50 to 60% of the agent is excreted unchanged, and 15 to 20% is excreted as a desacetyl metabolite desacetylcefotaxime.[9] Toxicity may result in convulsions, dyspnea, hypothermia, cyanosis, reversible encephalopathy, and death. Mortality has occurred with dosages of 6000 mg/kg/day. Treatment for cefotaxime toxicity requires supportive management.

Enhancing Healthcare Team Outcomes

Cefotaxime is a broad-spectrum antibiotic that is FDA-approved and indicated to treat gram-positive, gram-negative, and anaerobic organisms of susceptible strains causing pneumonia, urinary tract infections, cervicitis, endometritis, urethritis, and sepsis. The care for patients suffering from infectious diseases prompts critical care from an interprofessional team of healthcare professionals, as preventable contagious disorders can lead to medication resistance, complications, and mortality. These healthcare professionals include a primary care physician, an internist, an infectious disease specialist, critical care, a gynecologist, a nurse, and a pharmacist.

Primary care clinicians, internists, and specialists should educate the patients about the consequences of non-compliance with therapy for the full duration and how resistance to treatment can further cause complications and result in mortality. The primary care physician should routinely monitor renal function, liver enzymes, and CBC as cefotaxime is metabolized and cleared in the liver and kidneys, respectively, and has also been shown to cause hematologic adverse effects. Cefotaxime should be renally dosed in patients with compromised renal function, such as CKD or ESRD, and patients receiving hemodialysis. 

Patients developing diarrhea while receiving treatment with antibiotics should be assessed for Clostridium difficile infection. Colonic flora is changed when receiving treatment with antibiotics, making it susceptible to Clostridium difficile infection resulting in mild to severe forms of diarrhea. Diagnostics and treatment focused on Clostridium difficile, electrolyte, and volume depletion should be initiated, and discontinuing management with cefotaxime should be considered.

Counseling and careful monitoring are necessary during pregnancy, as clinical studies during its use in pregnancy are limited, and cefotaxime FDA pregnancy category B. Cefotaxime is reported to also be present in breastmilk in low amounts, and infants should be monitored accordingly.[12] Physicians should be up to date with the newly FDA-approved cefotaxime indications dosing, and their effects in the event drug resistance does develop.

During the treatment of gonorrhea causing urethritis or cervicitis, treatment for chlamydia should be added as cefotaxime does not have coverage for this organism. An interprofessional healthcare team approach to antimicrobial care with cefotaxime involving collaborative interventions and communication is key to building patient rapport and developing a therapeutic alliance so the patients comply with therapy adequately to eradicate the bacteria and prevent further spread. Continued communication and teamwork between healthcare professionals will improve antimicrobial stewardship, improve patient outcomes, limit microbial resistance, and lower the incidence of multidrug-resistant organisms.