Pharmacology of Cefotaxime

Introduction/Overview

Cefotaxime is a semisynthetic, broad-spectrum antibacterial agent belonging to the third-generation cephalosporin class. Since its introduction in the late 1970s, it has maintained a significant role in the empirical and targeted treatment of serious bacterial infections, particularly those involving Gram-negative organisms. Its development represented a pivotal advancement in antimicrobial therapy, offering enhanced stability against beta-lactamases and improved activity against Enterobacteriaceae compared to earlier cephalosporins. The clinical relevance of cefotaxime persists in hospital settings for managing sepsis, meningitis, and complicated intra-abdominal infections, among others. Its importance is underscored by its inclusion on the World Health Organization’s List of Essential Medicines, reflecting its utility in a wide range of healthcare environments.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Classify cefotaxime within the broader antibiotic schema and describe its chemical structure.
• Explain the detailed molecular mechanism of action, including its interaction with penicillin-binding proteins and bacterial cell wall synthesis.
• Analyze the pharmacokinetic profile of cefotaxime, including its absorption, distribution, metabolism, and excretion characteristics.
• Evaluate the approved therapeutic indications, common off-label uses, and spectrum of antimicrobial activity.
• Identify major adverse effects, drug interactions, and necessary dosage adjustments in special populations such as those with renal impairment or during pregnancy.

Classification

Cefotaxime is systematically categorized within multiple hierarchical classification systems relevant to pharmacology and clinical medicine.

Therapeutic and Pharmacologic Classification

The primary classification places cefotaxime as an antibacterial agent. Within this broad category, it is a member of the beta-lactam antibiotic family, which is characterized by the presence of a beta-lactam ring in their molecular structure. More specifically, cefotaxime is a third-generation cephalosporin. This generational classification is based on the chronological development and spectrum of activity: first-generation agents have good Gram-positive activity, second-generation show improved Gram-negative coverage, and third-generation cephalosporins like cefotaxime possess expanded Gram-negative coverage, including many Enterobacteriaceae, with retained, though somewhat diminished, activity against Gram-positive cocci. They also demonstrate notable penetration into the cerebrospinal fluid.

Chemical Classification

Chemically, cefotaxime sodium is described as the sodium salt of (6R,7R)-3-(acetoxymethyl)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. Its molecular formula is C₁₆H₁₆N₅NaO₇S₂ and it has a molecular weight of 477.45 g/mol. The core structure consists of a dihydrothiazine ring fused to a beta-lactam ring, forming the 7-aminocephalosporanic acid nucleus. Key structural features that confer its pharmacological properties include:

• The aminothiazole-oxime side chain at the 7-position, which is largely responsible for its enhanced beta-lactamase stability and potent activity against Gram-negative bacteria.
• The acetoxymethyl group at the 3-position, which can be metabolized to yield the active metabolite, desacetylcefotaxime.
• The carboxyl group, which is ionized at physiological pH, contributing to its hydrophilic nature and pharmacokinetic behavior.

This specific configuration renders it stable against hydrolysis by many plasmid- and chromosomally-mediated beta-lactamases, particularly those of the TEM and SHV types prevalent among Gram-negative bacteria.

Mechanism of Action

The antibacterial effect of cefotaxime, like other beta-lactam antibiotics, is primarily bactericidal and results from the inhibition of bacterial cell wall synthesis. This action is exerted during the active growth and multiplication phase of susceptible microorganisms.

Molecular and Cellular Mechanism

Cefotaxime exerts its effect by irreversibly binding to specific enzymes known as penicillin-binding proteins (PBPs). PBPs are membrane-bound bacterial enzymes that catalyze the final transpeptidation and carboxypeptidation steps in the biosynthesis of peptidoglycan, the essential, cross-linked polymer that provides structural integrity and rigidity to the bacterial cell wall. The antibiotic’s beta-lactam ring structurally mimics the D-alanyl-D-alanine terminus of the peptidoglycan precursor strand. This molecular mimicry allows cefotaxime to acylate the active serine site of the PBPs, forming a stable, covalent acyl-enzyme complex. This binding inactivates the PBP, halting the cross-linking process.

The consequence of this inhibition is the disruption of peptidoglycan assembly. With the cell wall synthesis machinery incapacitated, the bacterium continues its autolytic processes unchecked. The imbalance between cell wall synthesis and degradation, particularly in the context of high osmotic pressure inside the bacterial cell, leads to cell wall weakening, osmotic instability, cell swelling, and ultimately lysis and death. The bactericidal activity is considered time-dependent, meaning the clinical efficacy correlates with the duration of time the drug concentration remains above the minimum inhibitory concentration (MIC) for the pathogen (T > MIC).

Spectrum of Activity

The spectrum of activity is a direct consequence of its mechanism and its ability to penetrate bacterial structures and resist enzymatic degradation. Cefotaxime displays a broad spectrum, with pronounced activity against aerobic Gram-negative bacilli.

• Gram-Negative Bacteria: Cefotaxime is highly active against members of the Enterobacteriaceae family, including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella and Shigella spp. It is also effective against Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, and Haemophilus influenzae (including beta-lactamase-producing strains). Activity against Pseudomonas aeruginosa is poor and not clinically reliable.
• Gram-Positive Bacteria: It retains activity against many Gram-positive cocci, such as Streptococcus pneumoniae (penicillin-susceptible strains), Streptococcus pyogenes, and Staphylococcus aureus (methicillin-susceptible strains), though it is less potent than first-generation cephalosporins against staphylococci. Activity against enterococci (e.g., Enterococcus faecalis) and Listeria monocytogenes is negligible.
• Anaerobes: It has moderate activity against many anaerobic organisms but is not considered a first-line agent for serious anaerobic infections, as it is less reliable than metronidazole or carbapenems against Bacteroides fragilis.

It is crucial to recognize that bacterial resistance to cefotaxime can develop through several mechanisms: production of extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases that hydrolyze the drug, alterations in PBPs reducing affinity (as seen in penicillin-resistant pneumococci), and decreased permeability of the outer membrane in Gram-negative bacteria via porin channel loss.

Pharmacokinetics

The pharmacokinetic profile of cefotaxime governs its dosing regimens, route of administration, and penetration into target tissues.

Absorption

Cefotaxime is not absorbed appreciably from the gastrointestinal tract due to its high hydrophilicity and instability in gastric acid. Therefore, it must be administered parenterally, either by intravenous (IV) or intramuscular (IM) injection. Following an IV bolus injection of 1 gram, peak serum concentrations (C_max) of approximately 100 mg/L are achieved immediately at the end of the infusion. Intramuscular administration of the same dose results in a C_max of about 20 mg/L, attained within 30 minutes. The bioavailability via the IM route is considered complete, though the rate of absorption is slower. The drug follows linear pharmacokinetics within the therapeutic dose range.

Distribution

Cefotaxime distributes widely into various body tissues and fluids. Its volume of distribution is approximately 0.25–0.4 L/kg, reflecting distribution primarily into the extracellular fluid compartment. Protein binding is relatively low, ranging from 30% to 50%, which allows for a greater proportion of free, active drug. A critical aspect of its distribution is its ability to achieve therapeutic concentrations in the cerebrospinal fluid (CSF), particularly when the meninges are inflamed. CSF concentrations can reach 5–20% of simultaneous serum levels, which is sufficient to treat susceptible pathogens causing meningitis. It also penetrates well into pleural, peritoneal, and synovial fluids, as well as bone tissue.

Metabolism

Cefotaxime undergoes significant hepatic metabolism, which distinguishes it from some other cephalosporins. The primary metabolic pathway is deacetylation at the 3-position, catalyzed by hepatic esterases, to form desacetylcefotaxime. This metabolite retains antibacterial activity, though it is generally 4- to 16-fold less potent than the parent compound against most organisms. However, against certain bacteria like Bacteroides spp., the metabolite may demonstrate synergistic activity with the parent drug. Desacetylcefotaxime is further metabolized to inactive compounds. The parent drug and its metabolites do not inhibit hepatic cytochrome P450 enzymes to a clinically significant degree.

Excretion

Elimination occurs predominantly via renal excretion. Within 24 hours, approximately 50-60% of an administered IV dose is recovered unchanged in the urine. An additional 20-25% is excreted as the desacetyl metabolite. The total renal excretion thus accounts for about 80% of the dose. A small fraction (≈15-20%) is excreted via biliary secretion into the feces. The serum elimination half-life (t_1/2) of cefotaxime is approximately 1.0 to 1.5 hours in adults with normal renal function. The half-life of the desacetyl metabolite is longer, around 1.6 hours. In conditions of renal impairment, the half-life of both compounds is prolonged, necessitating dosage adjustment.

Pharmacokinetic Parameters and Dosing Considerations

Key pharmacokinetic parameters include a clearance rate of about 250 mL/min and renal clearance of approximately 120 mL/min. The area under the concentration-time curve (AUC) increases proportionally with dose. The time above the MIC (T > MIC) is the primary pharmacodynamic index predicting efficacy. For cephalosporins, maintaining free drug concentrations above the MIC for 40-70% of the dosing interval is typically targeted for optimal bactericidal effect. This relationship supports intermittent dosing regimens, commonly every 6 to 12 hours depending on infection severity and pathogen susceptibility. For severe infections like meningitis, higher doses or more frequent administration (e.g., every 4-6 hours) are employed to ensure adequate CSF penetration and time above the MIC.

Therapeutic Uses/Clinical Applications

Cefotaxime is indicated for the treatment of a variety of moderate to severe infections caused by susceptible strains of microorganisms.

Approved Indications

• Lower Respiratory Tract Infections: Pneumonia, bronchitis, and lung abscess caused by Streptococcus pneumoniae, Staphylococcus aureus (non-MRSA), Haemophilus influenzae, Klebsiella spp., and other susceptible Gram-negative rods.
• Genitourinary Infections: Complicated and uncomplicated urinary tract infections, including pyelonephritis, caused by E. coli, Klebsiella, Proteus, and other Enterobacteriaceae.
• Gynecological Infections: Pelvic inflammatory disease (PID), endometritis, and other female pelvic infections, often used in combination with an agent effective against anaerobes (e.g., doxycycline plus metronidazole).
• Bacteremia/Septicemia: Empirical treatment for suspected Gram-negative sepsis, particularly in healthcare-associated settings.
• Central Nervous System Infections: Bacterial meningitis caused by Neisseria meningitidis, Haemophilus influenzae, and susceptible strains of Streptococcus pneumoniae. It has been a mainstay for pediatric meningitis, though local resistance patterns must be considered.
• Skin and Skin Structure Infections: Complicated infections involving susceptible staphylococci, streptococci, and Gram-negative organisms.
• Intra-abdominal Infections: Peritonitis and other infections resulting from bowel perforation, typically used in combination with an anti-anaerobic agent like metronidazole.
• Bone and Joint Infections: Osteomyelitis and septic arthritis caused by susceptible organisms.
• Gonorrhea: Treatment of uncomplicated gonococcal infections, including those caused by penicillinase-producing Neisseria gonorrhoeae (PPNG).

Common Off-Label Uses

While formal indications are specific, cefotaxime is often used in other clinical contexts based on its spectrum and safety profile. These include:

• Empirical therapy for febrile neutropenia in combination with other agents, although fourth-generation cephalosporins or carbapenems may be preferred in high-risk settings.
• Surgical prophylaxis for certain procedures involving the gastrointestinal or genitourinary tract where contamination with Gram-negative flora is likely.
• Treatment of Lyme disease (neurological or late-stage manifestations) in patients intolerant to first-line therapies like doxycycline or penicillin.
• As part of combination regimens for invasive salmonellosis, such as typhoid fever.

The selection of cefotaxime for any indication should be guided by local antimicrobial susceptibility patterns, especially given the global rise of ESBL-producing organisms against which cefotaxime is ineffective.

Adverse Effects

Cefotaxime is generally well-tolerated, with a safety profile consistent with the cephalosporin class. Adverse reactions are typically mild and transient.

Common Side Effects

• Gastrointestinal: Diarrhea is the most frequently reported adverse effect, occurring in a small percentage of patients. Nausea, vomiting, and abdominal discomfort may also occur. Diarrhea is often related to alterations in intestinal flora.
• Hypersensitivity Reactions: Maculopapular rash, urticaria, pruritus, and drug fever are possible. These reactions are more common in patients with a history of allergy to penicillins, reflecting a cross-reactivity rate estimated at 5-10% due to shared beta-lactam structures.
• Local Reactions: Pain, induration, and tenderness at the site of intramuscular injection; phlebitis or thrombophlebitis following intravenous administration.
• Hepatic: Transient elevations in liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) are occasionally observed.

Serious/Rare Adverse Reactions

• Clostridioides difficile-Associated Diarrhea (CDAD): Like nearly all broad-spectrum antibacterial agents, cefotaxime use can result in overgrowth of toxigenic C. difficile, leading to antibiotic-associated colitis, which may range from mild diarrhea to life-threatening pseudomembranous colitis. This can occur during therapy or several weeks after antibiotic discontinuation.
• Severe Hypersensitivity: Anaphylaxis, though rare, is a potentially fatal reaction characterized by bronchospasm, hypotension, angioedema, and cardiovascular collapse.
• Hematologic Effects: Neutropenia, leukopenia, thrombocytopenia, and eosinophilia have been reported infrequently. A positive direct Coombs’ test may occur without evident hemolytic anemia.
• Renal Effects: Acute interstitial nephritis is a rare but serious idiosyncratic reaction.
• CNS Effects: Seizures or encephalopathy are potential neurotoxic effects, particularly when very high doses are used in patients with renal impairment, leading to excessive drug accumulation.

There are no specific black box warnings mandated for cefotaxime by regulatory agencies such as the U.S. Food and Drug Administration. However, warnings are present in prescribing information regarding CDAD and the potential for cross-hypersensitivity with other beta-lactam antibiotics.

Drug Interactions

Cefotaxime has a relatively low potential for pharmacokinetic drug-drug interactions, as it is not a significant substrate, inhibitor, or inducer of the major cytochrome P450 enzyme systems. However, several important interactions and contraindications exist.

Major Drug-Drug Interactions

• Probenecid: Concomitant administration with probenecid competitively inhibits the renal tubular secretion of cefotaxime and its desacetyl metabolite. This interaction leads to increased and prolonged serum concentrations of cefotaxime. While this can be exploited to enhance therapeutic effect in some contexts (e.g., gonorrhea treatment with a single dose), it generally requires monitoring as it may increase the risk of adverse effects, particularly neurotoxicity.
• Other Nephrotoxic Agents: Concurrent use with potent nephrotoxic drugs such as aminoglycosides (e.g., gentamicin), vancomycin, or loop diuretics (e.g., furosemide) may theoretically increase the risk of renal dysfunction. While the risk with cephalosporins is lower than with aminoglycosides alone, renal function should be monitored closely during combination therapy.
• Alcohol (Disulfiram-like Reaction): Although more characteristic of cephalosporins containing a methyltetrazolethiol (MTT) side chain (e.g., cefamandole, cefoperazone), isolated cases of a disulfiram-like reaction (flushing, tachycardia, nausea) have been reported with cefotaxime. Patients are generally advised to avoid alcohol during and for up to 72 hours after therapy.

Contraindications

The primary contraindication to cefotaxime therapy is a history of serious hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to cefotaxime itself or to any other cephalosporin antibiotic. Caution is warranted in patients with a history of severe penicillin allergy, as cross-reactivity is possible. There are no other absolute contraindications, but its use requires careful consideration and possible dosage modification in patients with significant renal impairment.

Special Considerations

The use of cefotaxime in specific patient populations requires adjustments to dosing or increased vigilance for adverse effects.

Pregnancy and Lactation

Pregnancy: Cefotaxime is classified as a Pregnancy Category B drug under the former FDA classification system, indicating that animal reproduction studies have not demonstrated a fetal risk, but adequate and well-controlled studies in pregnant women are lacking. It crosses the placenta and achieves measurable concentrations in amniotic fluid and fetal tissues. It is considered acceptable for use when clearly needed, such as for treating serious infections in the mother. The benefit of treating a life-threatening infection generally outweighs the theoretical risks.

Lactation: Cefotaxime is excreted into human breast milk in low concentrations. While these levels are unlikely to cause significant effects in a nursing infant, potential consequences could include modification of bowel flora, diarrhea, or rash. The American Academy of Pediatrics considers cephalosporins compatible with breastfeeding, but monitoring the infant for signs of gastrointestinal disturbance or candidiasis is prudent.

Pediatric and Geriatric Considerations

Pediatrics: Cefotaxime is approved for use in neonates, infants, and children. Dosage is typically based on body weight or body surface area. For neonates, especially preterm infants, dosing intervals are often extended (e.g., every 12 hours) due to immature renal function, which prolongs the drug’s half-life. It has been a cornerstone in the treatment of neonatal sepsis and meningitis.

Geriatrics: Elderly patients are more likely to have age-related reductions in renal function. Since cefotaxime is primarily renally excreted, dosage adjustments based on estimated creatinine clearance are often necessary to prevent drug accumulation and potential toxicity, such as seizures. Renal function should be assessed prior to and during therapy.

Renal and Hepatic Impairment

Renal Impairment: Dosage adjustment is required in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min). The dosing interval is typically extended, as the half-life of both cefotaxime and its active metabolite increases significantly. For example, with a creatinine clearance of 10-30 mL/min, the recommended interval may be every 12 hours; for clearance below 10 mL/min, every 24 hours. In patients on intermittent hemodialysis, a supplemental dose is usually given after each dialysis session, as the drug is readily dialyzable.

Hepatic Impairment: Since cefotaxime is metabolized in the liver to its active desacetyl form, hepatic impairment might alter its pharmacokinetics. However, the primary route of elimination for both parent and metabolite remains renal. Therefore, dosage adjustments are not routinely recommended for hepatic impairment alone. In cases of combined hepatic and renal dysfunction, careful monitoring and potential dose reduction may be warranted.

Summary/Key Points

Cefotaxime represents a critical agent in the antimicrobial armamentarium, with a well-defined pharmacological profile that supports its clinical use.

Bullet Point Summary

• Cefotaxime is a third-generation cephalosporin antibiotic with a broad spectrum of activity, particularly against Gram-negative Enterobacteriaceae, and stability against many beta-lactamases.
• Its bactericidal mechanism involves irreversible inhibition of penicillin-binding proteins (PBPs), disrupting bacterial cell wall synthesis and leading to cell lysis.
• Pharmacokinetically, it requires parenteral administration, distributes widely including into the CSF during inflammation, is partially metabolized to an active desacetyl metabolite, and is eliminated primarily by renal excretion.
• Major therapeutic applications include serious infections such as meningitis, sepsis, pneumonia, and intra-abdominal infections, often in combination with anti-anaerobic coverage.
• It is generally well-tolerated, with diarrhea and hypersensitivity reactions being the most common adverse effects. The risk of Clostridioides difficile-associated diarrhea must be considered.
• Significant drug interactions are few but include probenecid (increases serum levels) and potential additive nephrotoxicity with aminoglycosides.
• Dosage adjustments are essential in patients with renal impairment, and caution is advised in those with a history of severe beta-lactam allergy.

Clinical Pearls

• The pharmacodynamic driver for efficacy is time above the MIC (T > MIC). Dosing intervals should be chosen to optimize this parameter for the suspected pathogen.
• Despite its broad spectrum, cefotaxime is not active against ESBL-producing organisms, Pseudomonas aeruginosa, enterococci, or methicillin-resistant Staphylococcus aureus (MRSA). Empirical use should be guided by local resistance patterns.
• In suspected meningitis, high-dose regimens (e.g., 2 g every 4-6 hours in adults) are employed to ensure adequate CSF penetration.
• Renal function should be assessed prior to initiating therapy in all adults, especially the elderly, to guide appropriate dosing and prevent neurotoxicity from accumulation.
• While cross-reactivity with penicillins is a concern, a detailed allergy history is crucial. Many reported “penicillin allergies” are not IgE-mediated and do not preclude the use of cephalosporins when they are the optimal therapeutic choice.

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