Cefoxitin: A Comprehensive Pharmacological and Clinical Review

1. Introduction to Cefoxitin

1.1. Overview, Classification, and Origin

Cefoxitin is a semi-synthetic, broad-spectrum antibiotic agent intended for parenteral administration, primarily utilized in the management of serious bacterial infections.[1] Within the landscape of antimicrobial agents, Cefoxitin holds a distinct position. It is classified as a cephamycin antibiotic, a subgroup of beta-lactam antibiotics, and is frequently categorized alongside second-generation cephalosporins.[1] This dual classification is not merely academic; it reflects its unique structural attributes and, consequently, its particular spectrum of activity and clinical utility. The "second-generation cephalosporin" grouping generally implies an enhanced spectrum against Gram-negative bacteria compared to first-generation agents, often with some activity against anaerobic bacteria. Cefoxitin aligns with this but its cephamycin nature, specifically the presence of a 7-alpha-methoxy group on its core structure, confers a notable degree of stability against a wide array of bacterial beta-lactamases.[2] This enzymatic stability is a cornerstone of its efficacy against certain challenging pathogens, including many anaerobic organisms, and distinguishes it from many other cephalosporins.

The genesis of Cefoxitin lies in natural product chemistry, as it is derived from cephamycin C.[1] Cephamycin C is itself a metabolite produced by the bacterium Streptomyces lactamdurans.[6] The term "semi-synthetic" signifies that the naturally occurring cephamycin C molecule undergoes chemical modification to yield Cefoxitin, a process aimed at optimizing its pharmacological properties, such as enhancing its stability against enzymatic degradation, broadening its spectrum of activity, or improving its pharmacokinetic profile.[2] For clinical use, Cefoxitin is typically available as Cefoxitin Sodium for injection, ensuring its solubility and suitability for parenteral administration.[6]

The distinction between its cephamycin classification and its grouping with second-generation cephalosporins is significant for clinical understanding. While the second-generation label provides a general idea of its spectrum relative to other cephalosporins, its identity as a cephamycin, characterized by the 7-alpha-methoxy group, is what truly defines its enhanced stability against beta-lactamases, particularly those produced by Gram-negative bacteria and anaerobes.[1] This stability is a key factor in its reliable activity against anaerobic bacteria, a feature that is more pronounced in cephamycins than in many true cephalosporins. This understanding is crucial for clinicians when selecting an antibiotic based on the suspected or confirmed pathogens and their likely resistance mechanisms.

2. Chemical and Physical Properties

A thorough understanding of Cefoxitin's chemical and physical characteristics is fundamental to its pharmaceutical development, formulation, and clinical application.

2.1. Nomenclature and Identifiers

Cefoxitin is identified by several names and codes across scientific and regulatory platforms:

• Generic Name: Cefoxitin.[1]
• Chemical Name (IUPAC): (6R,7S)-3-(carbamoyloxymethyl)-7-methoxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.[2] It is noteworthy that slight variations in chemical nomenclature exist depending on the pharmacopeial standards. For instance, the European Pharmacopoeia (EP) lists it as (6R,7S)-3-[(carbamoyloxy)methyl]-7-methoxy-8-oxo-7-[2-(thiophen-2-yl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, while the United States Pharmacopeia (USP) may refer to it as (6R,7S)-3-(Hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid carbamate (ester).[9] Despite these minor differences, they all describe the same active pharmaceutical ingredient.
• Synonyms: One common synonym is (6R,7S)-4-[(carbamoyloxy)methyl]-7-methoxy-8-oxo-7-[(thiophen-2-enyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.[1]
• CAS Number: For Cefoxitin (the free acid form), the CAS Registry Number is 35607-66-0.[3] The commonly used Cefoxitin Sodium salt is identified by CAS Number 33564-30-6.[9]
• DrugBank ID: DB01331.[1]
• FDA UNII (Unique Ingredient Identifier): 6OEV9DX57Y.[2]

2.2. Chemical Structure, Formula, and Molecular Weight

The molecular architecture of Cefoxitin is central to its antibiotic activity:

• Chemical Formula: The empirical formula for Cefoxitin base is C16​H17​N3​O7​S2​.[1] For Cefoxitin Sodium, the formula is C16​H16​N3​NaO7​S2​.[6]
• Molecular Weight:
• Average Molecular Weight (Cefoxitin base): Approximately 427.45 g/mol (reported as 427.452 g/mol or 427.4 g/mol).[1]
• Monoisotopic Molecular Weight (Cefoxitin base): 427.050791293 Da [1] or 427.05079224 Da.[2]
• Molecular Weight (Cefoxitin Sodium): 449.44 g/mol.[6]
• Structure: Cefoxitin's structure features the core beta-lactam ring fused to a dihydrothiazine ring, a scaffold characteristic of cephalosporin-class antibiotics. Attached to this core are specific side chains that modulate its activity and pharmacokinetic properties: a 2-thienylacetamido group at position 7 and a carbamoyloxymethyl group at position 3. A critical and defining feature is the presence of a methoxy group at the 7-alpha position of the beta-lactam nucleus; this moiety is the hallmark of cephamycin antibiotics and is largely responsible for Cefoxitin's enhanced stability against many bacterial beta-lactamases.[2]

2.3. Physical Characteristics

• Appearance: Cefoxitin typically presents as a white to almost white powder or crystalline solid.[3]
• Solubility: It is reported to be soluble in dimethylformamide (DMF) and insoluble in ether and chloroform.[3] The sodium salt form is used for aqueous injections.
• Melting Point: Cefoxitin exhibits a melting point of approximately 127 °C, at which it undergoes decomposition.[3]
• Stability and Storage:
• The sterile powder for injection is typically sealed under a nitrogen atmosphere to maintain stability.[6]
• Unreconstituted Cefoxitin powder should generally be stored at cool room temperature, not exceeding 25°C (77°F).[4] Some research-grade materials may specify frozen storage conditions (<0°C) and note heat sensitivity.[3]
• Upon reconstitution, for example with Dextrose Injection, the resulting solution has a pH of approximately 6.5. The diluent is often formulated to ensure the reconstituted product is iso-osmotic, with an osmolality around 290 mOsmol/kg.[6]
• The stability of reconstituted Cefoxitin solutions is time- and diluent-dependent. It is imperative to adhere to specific storage instructions provided with the product, which may include refrigeration for a limited period. Reconstituted solutions should not be frozen and must be discarded if they exhibit color changes or particulate matter.[4]

These chemical and physical properties are crucial for quality control, formulation development, and ensuring the safe and effective administration of Cefoxitin in clinical settings.

Table 1: Key Chemical and Physical Properties of Cefoxitin

Property	Value (Cefoxitin Base unless specified)	Reference(s)
Generic Name	Cefoxitin	1
Chemical Name (IUPAC)	(6R,7S)-3-(carbamoyloxymethyl)-7-methoxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	2
CAS Number (Base)	35607-66-0	3
CAS Number (Sodium Salt)	33564-30-6	9
DrugBank ID	DB01331	1
Chemical Formula (Base)	C16​H17​N3​O7​S2​	1
Chemical Formula (Sodium Salt)	C16​H16​N3​NaO7​S2​	6
Molecular Weight (Base)	Approx. 427.45 g/mol	1
Molecular Weight (Sodium Salt)	449.44 g/mol	6
Appearance	White to almost white powder or crystal	3
Key Solubilities	Soluble in Dimethylformamide; Insoluble in Ether, Chloroform	3
Melting Point	127 °C (decomposes)	3
Storage (Unmixed Powder)	Cool room temperature (not above 25°C/77°F); some research grades: Frozen (<0°C), heat sensitive	3
Storage (Reconstituted)	Dependent on diluent; may require refrigeration; do not freeze; discard if color changes or particles present. pH approx. 6.5; iso-osmotic (approx. 290 mOsmol/kg) when reconstituted with Dextrose Injection.	4

3. Pharmacology

The pharmacological profile of Cefoxitin encompasses its mechanism of antibacterial action, its effects on microorganisms (pharmacodynamics), and its absorption, distribution, metabolism, and excretion (ADME) characteristics within the human body (pharmacokinetics).

3.1. Mechanism of Action

Cefoxitin exerts its antibacterial effect through a bactericidal mechanism, common to beta-lactam antibiotics, by inhibiting the synthesis of the bacterial cell wall.[1] This critical process is achieved by Cefoxitin's ability to bind to and inactivate Penicillin-Binding Proteins (PBPs).[1] PBPs are enzymes anchored to the inner bacterial cell membrane and are indispensable for the final stages of peptidoglycan assembly. Peptidoglycan is the primary structural polymer of the bacterial cell wall, providing rigidity and protection against osmotic stress. PBPs also play roles in cell wall remodeling during bacterial growth and division.[10]

By targeting various PBPs—such as D-alanyl-D-alanine carboxypeptidases (e.g., DacC, DacA), D-alanyl-D-alanine endopeptidases, and peptidoglycan D,D-transpeptidases (e.g., FtsI), as well as serine-type D-Ala-D-Ala carboxypeptidases [1]—Cefoxitin effectively disrupts the transpeptidation reactions. These reactions are responsible for cross-linking the peptidoglycan strands, a step crucial for the integrity and strength of the cell wall. Inhibition of these enzymes leads to the formation of a defective, weakened cell wall. Consequently, the bacterial cell becomes susceptible to osmotic lysis, particularly in hypotonic environments, leading to cell death.[10]

A pivotal aspect of Cefoxitin's mechanism, and one that significantly influences its spectrum of activity, is the presence of a methoxy group at the 7-alpha position of its beta-lactam nucleus.[2] This structural feature is a hallmark of cephamycin antibiotics and confers a high degree of stability against hydrolysis by many beta-lactamase enzymes, including both penicillinases and cephalosporinases, which are commonly produced by Gram-negative bacteria and anaerobic organisms.[1] Beta-lactamases are a primary defense mechanism for bacteria against beta-lactam antibiotics, as they cleave the beta-lactam ring, rendering the antibiotic inactive. Cefoxitin's resistance to many of these enzymes allows it to maintain its structural integrity and reach its PBP targets in bacteria that might otherwise be resistant to other beta-lactam agents. This enzymatic stability is a critical determinant of Cefoxitin's efficacy and its broader spectrum of activity, particularly its notable effectiveness against many anaerobic bacteria and certain beta-lactamase-producing Gram-negative bacilli. This chemical modification significantly expands its clinical utility compared to beta-lactams lacking this protective feature, making it a valuable option for infections where enzymatic degradation by beta-lactamases is a concern.

3.2. Pharmacodynamics

The pharmacodynamic properties of Cefoxitin describe the relationship between drug concentrations and its antimicrobial effect. As a beta-lactam antibiotic, Cefoxitin's bactericidal activity is generally considered to be time-dependent. This means its efficacy is more closely correlated with the duration for which the drug concentration at the site of infection remains above the Minimum Inhibitory Concentration (MIC) of the target pathogen (T > MIC), rather than with the peak concentration achieved.

Cefoxitin demonstrates activity against a diverse array of microorganisms, encompassing Gram-positive and Gram-negative aerobic bacteria, as well as a significant number of anaerobic bacteria.[1] Its inherent stability against many beta-lactamases, conferred by the 7-alpha-methoxy group, is a major contributor to this broad spectrum.[1] Specific molecular targets within bacteria that Cefoxitin inhibits include Penicillin-binding protein 1A (PBP1A), Penicillin-binding protein 1B (PBP1B), and Peptidoglycan D,D-transpeptidase FtsI in Escherichia coli, and serine-type D-Ala-D-Ala carboxypeptidase in Streptococcus pneumoniae.[1] By inhibiting these essential enzymes, Cefoxitin effectively halts cell wall construction, leading to bacterial death.

3.3. Pharmacokinetics

The pharmacokinetic profile of Cefoxitin dictates its dosing regimens and suitability for treating infections in various body compartments.

3.3.1. Absorption

Cefoxitin is not absorbed orally and therefore requires parenteral administration, typically via the intravenous (IV) or intramuscular (IM) route.[1] Following a 1-gram IV dose, serum concentrations of Cefoxitin are reported to reach 110 mcg/mL within 5 minutes, declining to less than 1 mcg/mL by 4 hours.[11] When administered intramuscularly, peak serum concentrations are generally achieved within 20 to 30 minutes.[12]

3.3.2. Distribution

Once in the systemic circulation, Cefoxitin distributes widely into most body tissues and fluids.[12] It has been shown to penetrate into pleural fluid, joint fluid, bile, gallbladder, liver, kidneys, bone, and sputum in concentrations that can be antibacterial.[1] However, its penetration into the cerebrospinal fluid (CSF) is generally poor, even in the presence of meningeal inflammation.[12] This characteristic limits its utility for the treatment of central nervous system infections.

The Volume of Distribution (Vd) for Cefoxitin in neonates and infants less than 2 months of age (postnatal age: 10 to 53 days) has been reported as 0.5±0.21 L/kg.[12] While specific numerical Vd values for adults are not consistently provided in human studies within the available materials, animal data from unweaned calves reported a steady-state volume of distribution (Vss) of 0.3187±0.0950 L/kg.[17] This suggests distribution primarily into the extracellular fluid compartment.

Protein Binding: Cefoxitin is moderately bound to plasma proteins, with reported binding percentages ranging from 50% to 80% [13], or more specifically, 65% to 79% in human adults.[12] Animal data indicated protein binding in calves between 42.0% and 55.0%.[17] The degree of protein binding can influence the amount of free, active drug available to exert its antimicrobial effect.

3.3.3. Metabolism

Cefoxitin undergoes minimal metabolism in the body. It is estimated that only about 2% of an administered dose is metabolized.[13] This indicates that the vast majority of the drug is eliminated from the body in its active, unchanged form.

3.3.4. Excretion

The primary route of elimination for Cefoxitin is via the kidneys.[11] It is excreted largely unchanged in the urine through a combination of glomerular filtration and active renal tubular secretion.[13] Approximately 85% of an administered dose is recovered in the urine within a 6-hour period, leading to high urinary concentrations.[11] This characteristic makes Cefoxitin particularly effective for treating urinary tract infections caused by susceptible organisms. A small proportion of the drug is also excreted in breast milk.[13]

The elimination half-life (t1/2​) of Cefoxitin is relatively short in individuals with normal renal function:

• Adults: Typically 41 to 59 minutes [1], or stated as 0.7 to 1.1 hours.[13]
• Geriatric patients (64-88 years) with age-appropriate renal function: The half-life is slightly prolonged, ranging from 51 to 90 minutes. This is attributed to the natural decline in renal function associated with aging.[6]
• Infants ≥3 months and Children: 42.4±5.3 minutes.[12]
• Neonates and Infants <2 months (postnatal age: 10 to 53 days): 1.4 hours.[12]

The half-life of Cefoxitin is significantly prolonged in patients with renal impairment, extending to 6.3 to 21.5 hours in cases of severe renal dysfunction.[13] This necessitates dosage adjustments in such patients.

Co-administration of probenecid can competitively inhibit the renal tubular secretion of Cefoxitin, resulting in higher and more sustained serum concentrations.[1] This interaction has been exploited therapeutically in certain situations to enhance Cefoxitin's efficacy. Cefoxitin can be removed from the body by hemodialysis, but it is not effectively cleared by peritoneal dialysis.[13]

The profound dependence on renal function for Cefoxitin elimination is a critical pharmacokinetic consideration. Since approximately 85% of the drug is excreted unchanged by the kidneys within a short timeframe [11], any compromise in renal function directly impacts its clearance. The short half-life in individuals with normal renal function (41-59 minutes) contrasts sharply with the significantly prolonged half-life (up to 21.5 hours) in those with severe renal impairment.[1] This direct relationship mandates careful assessment of renal function (e.g., via creatinine clearance estimation) prior to and during Cefoxitin therapy. Specific dosage adjustments are outlined for varying degrees of renal impairment to prevent drug accumulation, which could lead to increased risk of toxicity, and to ensure that therapeutic concentrations are maintained.[6] The observation that geriatric patients often exhibit higher plasma concentrations and longer half-lives, even with what might be considered "normal for age" renal function, further highlights the kidney's central role and the need for cautious dosing in this population.[6] The interaction with probenecid, which blocks tubular secretion, also underscores the importance of this renal pathway.[11]

4. Microbiology

The antimicrobial efficacy of Cefoxitin is defined by its spectrum of activity against various bacterial species and the mechanisms by which bacteria may develop resistance to it.

4.1. Spectrum of Antimicrobial Activity

Cefoxitin exhibits a broad spectrum of in vitro antimicrobial activity, effective against a wide array of Gram-positive and Gram-negative aerobic bacteria, as well as many clinically significant anaerobic bacteria.[1] This broad coverage is a key attribute contributing to its use in empirical therapy for mixed infections.

• Gram-positive aerobic bacteria: Cefoxitin is active against Staphylococcus aureus (including strains that produce penicillinase, an enzyme that inactivates many penicillins), Staphylococcus epidermidis, Streptococcus pneumoniae (a common cause of pneumonia and other respiratory infections), Streptococcus pyogenes (Group A streptococci, responsible for infections like strep throat and skin infections), and Streptococcus agalactiae (Group B streptococci, a concern in neonatal infections and infections in pregnant women).[6]
• Gram-negative aerobic bacteria: The drug demonstrates activity against several important Gram-negative pathogens, including Escherichia coli (a common cause of urinary tract and intra-abdominal infections), Haemophilus influenzae (implicated in respiratory infections), Klebsiella species (often associated with pneumonia and UTIs), Morganella morganii, Neisseria gonorrhoeae (including penicillinase-producing strains, important for treating gonorrhea), Proteus mirabilis, Proteus vulgaris, and Providencia species.[6] Additionally, Eikenella corrodens (non-β-lactamase producing strains) shows in vitro susceptibility, although the clinical significance of this finding is not fully established.[6]
• Anaerobic bacteria: Cefoxitin has notable activity against a range of anaerobic organisms. This includes various Bacteroides species, such as the clinically important Bacteroides fragilis group (which includes B. fragilis, Bacteroides distasonis, Bacteroides ovatus, and Bacteroides thetaiotaomicron). It is also active against Clostridium species, Peptococcus niger, and Peptostreptococcus species.[6] In vitro susceptibility has also been observed for Prevotella bivia and Clostridium perfringens, though their clinical relevance in Cefoxitin therapy is not definitively established.[6]
• Organisms with notable resistance or inactivity: It is important to recognize the limitations of Cefoxitin's spectrum. It is generally inactive against most strains of Pseudomonas aeruginosa, a common opportunistic pathogen, and many strains of Enterobacter cloacae.[13] Furthermore, Cefoxitin lacks activity against atypical pathogens such as Chlamydia trachomatis.[6]

Cefoxitin's substantial anaerobic coverage, particularly its historical effectiveness against Bacteroides fragilis, is a defining characteristic that stems directly from its cephamycin structure and the resultant stability against beta-lactamases. The 7-alpha-methoxy group, unique to cephamycins, provides protection against many beta-lactamase enzymes frequently produced by anaerobic bacteria.[1] This robust anaerobic activity has traditionally made Cefoxitin a valuable agent for treating mixed aerobic-anaerobic infections, such as those occurring in intra-abdominal and gynecological sites.[6] While some contemporary data and guidelines suggest that emerging resistance in B. fragilis may necessitate the addition or substitution of agents like metronidazole for reliable empiric coverage in certain intra-abdominal infections [19], Cefoxitin's documented activity against a broad range of anaerobes has been fundamental to its clinical positioning. This differentiates it from many other cephalosporins that possess limited or no significant anaerobic coverage.

Table 2: Spectrum of Activity of Cefoxitin against Key Pathogens

Pathogen Category	Specific Organism	Typical Susceptibility to Cefoxitin (based on provided data)	Reference(s)
Gram-Positive Aerobes	Staphylococcus aureus (incl. penicillinase-producing)	Susceptible	6
	Staphylococcus epidermidis	Susceptible	6
	Streptococcus pneumoniae	Susceptible	6
	Streptococcus pyogenes (Group A)	Susceptible	6
	Streptococcus agalactiae (Group B)	Susceptible	6
Gram-Negative Aerobes	Escherichia coli	Susceptible	6
	Haemophilus influenzae	Susceptible	6
	Klebsiella spp.	Susceptible	6
	Neisseria gonorrhoeae (incl. penicillinase-producing)	Susceptible	6
	Proteus mirabilis	Susceptible	6
	Pseudomonas aeruginosa	Inactive/Resistant	13
	Enterobacter cloacae (many strains)	Often Resistant	14
Anaerobic Bacteria	Bacteroides fragilis group (e.g., B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron)	Susceptible (but see note below)	6
	Clostridium spp. (e.g., C. perfringens)	Susceptible	6
	Peptococcus niger	Susceptible	6
	Peptostreptococcus spp.	Susceptible	6
Other	Chlamydia trachomatis	Inactive	6

Note: Some sources indicate potentially increasing resistance in Bacteroides fragilis to Cefoxitin, and alternative agents may be preferred for empiric therapy in certain settings.[19]

4.2. Mechanisms of Bacterial Resistance

Despite Cefoxitin's inherent stability against many beta-lactamases, bacteria can develop or acquire resistance through several mechanisms, diminishing its efficacy [5]:

1. Hydrolysis by Beta-Lactamases: While the 7-alpha-methoxy group provides significant protection, certain potent or specific bacterial beta-lactamases can still hydrolyze Cefoxitin. These may include some Class A enzymes (e.g., CfxA found in Bacteroides vulgatus, NmcA in Enterobacter cloacae) or certain extended-spectrum beta-lactamases (ESBLs) that have activity against cephamycins, although this is generally less common than their activity against other cephalosporins.[5] These enzymes inactivate Cefoxitin by cleaving the amide bond within its core beta-lactam ring.
2. Alteration of Penicillin-Binding Proteins (PBPs): Bacteria can acquire resistance by modifying their PBPs, the primary targets of Cefoxitin. Mutations in the genes encoding these proteins can lead to PBPs with reduced affinity for Cefoxitin. If the antibiotic cannot bind effectively to its target, it fails to inhibit cell wall synthesis. A well-known example is the PBP2a protein, encoded by the mecA gene, which is responsible for methicillin resistance in Staphylococcus aureus (MRSA). PBP2a has a very low affinity for most beta-lactam antibiotics, typically including Cefoxitin for therapeutic purposes.[5]
3. Decreased Permeability: Gram-negative bacteria possess an outer membrane that acts as a selective barrier, which antibiotics must traverse to reach the PBPs located in the periplasmic space or on the inner membrane. Resistance can arise from a reduction in the expression of outer membrane porin proteins (OMPs), such as OmpC, OmpF in E. coli or their analogues (e.g., Omp1, OmpK37, Omp38, OmpK35 in other species), or from mutations within these porin channels.[5] Such changes can restrict the influx of Cefoxitin into the bacterial cell, thereby lowering its intracellular concentration below effective levels.
4. Antibiotic Target Replacement/Bypass: In some instances, bacteria may acquire alternative enzymes that can perform the essential cell wall synthesis functions of the PBPs targeted by Cefoxitin but are themselves not inhibited by the antibiotic.[5] This allows cell wall synthesis to continue despite the presence of the drug.

An interesting aspect related to resistance mechanisms is the use of Cefoxitin in laboratory diagnostics. The Cefoxitin disk diffusion test is a standard method for the routine detection of mecA-mediated methicillin resistance in Staphylococcus species.[3] Although Cefoxitin is generally not effective for treating MRSA infections due to the low affinity of PBP2a for beta-lactams [5], it serves as a reliable surrogate marker in susceptibility testing. This is because Cefoxitin can be a more potent inducer of mecA gene expression in some staphylococcal isolates compared to oxacillin or methicillin, leading to more consistent and accurate detection of this resistance mechanism in the laboratory. This presents a nuanced situation where an antibiotic not typically used for treating a specific resistant organism (MRSA) is a key diagnostic tool for identifying that very resistance. For clinicians, a "Cefoxitin resistant" result for S. aureus is interpreted as indicative of MRSA, guiding therapeutic decisions away from most beta-lactam antibiotics, even though Cefoxitin itself would not be the chosen treatment for such an infection.

5. Clinical Applications

Cefoxitin's broad spectrum of activity, particularly its coverage of anaerobic bacteria and its stability against many beta-lactamases, has established its role in the treatment of various serious infections and as a prophylactic agent in certain surgical procedures.

5.1. Approved Therapeutic Indications

Cefoxitin is indicated for the treatment of serious infections caused by susceptible strains of designated microorganisms across a range of body systems.[1] Its use should ideally be guided by susceptibility testing to ensure efficacy and to mitigate the development of drug resistance.[6]

• Lower respiratory tract infections: This includes conditions such as pneumonia and lung abscess. Causative pathogens amenable to Cefoxitin therapy include Streptococcus pneumoniae, other streptococci (excluding enterococci), Staphylococcus aureus (both penicillinase-producing and non-penicillinase-producing strains), Escherichia coli, Klebsiella species, Haemophilus influenzae, and Bacteroides species.[6]
• Urinary tract infections (UTIs): Cefoxitin is effective for UTIs caused by E. coli, Klebsiella spp., Proteus mirabilis, Morganella morganii, Proteus vulgaris, and Providencia spp. (including P. rettgeri).[6]
• Intra-abdominal infections: This category includes peritonitis and intra-abdominal abscesses. Susceptible pathogens include E. coli, Klebsiella spp., Bacteroides spp. (notably including B. fragilis), and Clostridium spp..[6] It is important to note that some contemporary guidelines and observations suggest that Cefoxitin's reliability against B. fragilis may be diminishing in certain regions or contexts, leading to recommendations for including agents like metronidazole for empirical coverage of anaerobic pathogens in severe intra-abdominal infections.[19]
• Gynecological infections: Cefoxitin is used for infections such as endometritis, pelvic cellulitis, and pelvic inflammatory disease (PID). Susceptible organisms include E. coli, Neisseria gonorrhoeae (including penicillinase-producing strains), Bacteroides spp. (including B. fragilis), Clostridium spp., Peptococcus niger, Peptostreptococcus spp., and Streptococcus agalactiae.[6] When treating PID, if Chlamydia trachomatis is a suspected pathogen, concomitant therapy with an agent active against chlamydia (e.g., doxycycline) is essential, as Cefoxitin lacks activity against this organism.[6]
• Septicemia (Blood infection): Indicated for bloodstream infections caused by S. pneumoniae, S. aureus (including penicillinase-producing strains), E. coli, Klebsiella spp., and Bacteroides spp. (including B. fragilis).[6]
• Bone and joint infections: Primarily for infections caused by S. aureus (including penicillinase-producing strains).[4]
• Skin and skin structure infections: Effective against infections caused by S. aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes and other streptococci (excluding enterococci), E. coli, P. mirabilis, Klebsiella spp., Bacteroides spp. (including B. fragilis), Clostridium spp., Peptococcus niger, and Peptostreptococcus spp..[6]
• Gonorrhea and Associated Infections (Off-label/Alternative Use): Cefoxitin, often administered with probenecid to prolong its serum concentrations, has been used as an alternative treatment for uncomplicated cervical, urethral, or rectal gonorrhea caused by susceptible strains of N. gonorrhoeae.[13] However, current CDC guidelines may recommend other agents, such as ceftriaxone, as preferred therapy for gonorrhea due to evolving resistance patterns and potentially superior efficacy for pharyngeal infections.[19]

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefoxitin, it should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.[6]

5.2. Prophylactic Use in Surgery

Cefoxitin plays a significant role in preventing postoperative infections in specific surgical settings. It is indicated for surgical prophylaxis in patients undergoing:

• Uncontaminated gastrointestinal surgery.[6]
• Vaginal hysterectomy.[6]
• Abdominal hysterectomy.[6]
• Cesarean section.[4]

Its use is also reported for preventing infections in various other types of surgical procedures where coverage against its spectrum, including anaerobes, is beneficial.[4] For most surgical procedures, prophylactic administration of Cefoxitin should usually be discontinued within 24 hours post-surgery, as prolonged administration typically does not confer additional benefit in reducing infection rates and may increase the risk of adverse reactions and antimicrobial resistance.[6]

5.3. Dosage and Administration

Cefoxitin is administered parenterally, with the intravenous (IV) route being the most common and preferred, especially for patients with bacteremia, severe or life-threatening infections, or those who are poor-risk due to debilitating conditions.[1] Intramuscular (IM) administration is an option for certain indications, such as uncomplicated gonorrhea (often given with oral probenecid), or when IV access is problematic, though it is generally not preferred for severe infections.[12]

Cefoxitin is supplied as a sterile powder that requires reconstitution with a compatible diluent (e.g., Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection) prior to administration.[4] Some products are available in premixed solutions or in dual-chamber containers that facilitate reconstitution.[6] The healthcare provider should ensure proper mixing and inspect the solution for particulate matter or discoloration before use.

5.3.1. Adult Patients

Dosage and duration of therapy depend on the susceptibility of the causative organisms, the severity of the infection, and the patient's clinical condition.[6]

Treatment Dosages: [6]

• Usual Adult Dosage Range: 1 gram to 2 grams IV every 6 to 8 hours.
• Uncomplicated Infections (e.g., uncomplicated pneumonia, urinary tract infection, cutaneous infection): 1 gram IV every 6 to 8 hours (total daily dose of 3 to 4 grams).
• Moderately Severe or Severe Infections: 1 gram IV every 4 hours OR 2 grams IV every 6 to 8 hours (total daily dose of 6 to 8 grams).
• Infections Commonly Requiring Higher Dosages (e.g., gas gangrene): 2 grams IV every 4 hours OR 3 grams IV every 6 hours (total daily dose of 12 grams).
• The maximum recommended daily dosage for adults should generally not exceed 12 grams.[12]
• For infections caused by Group A beta-hemolytic streptococci, therapy should be continued for at least 10 days to minimize the risk of developing rheumatic fever or glomerulonephritis.[6] Surgical drainage of abscesses should be performed when indicated.

Prophylactic Dosages: [6]

• Uncontaminated Gastrointestinal Surgery, Vaginal Hysterectomy, or Abdominal Hysterectomy: 2 grams administered IV approximately 30 to 60 minutes before the initial surgical incision. This is followed by 2 grams IV every 6 hours after the first dose, for no more than 24 hours.
• Cesarean Section Patients:
• Option 1: A single 2-gram dose administered IV as soon as the umbilical cord is clamped.
• Option 2: A 3-dose regimen consisting of 2 grams IV administered as soon as the umbilical cord is clamped, followed by 2 grams IV given 4 hours and 8 hours after the initial dose.

5.3.2. Pediatric Patients

Dosage in pediatric patients is typically based on body weight.

Treatment Dosages (Children ≥3 months of age): [6]

• General Recommendation: 80 to 160 mg/kg of body weight per day, administered IV in 4 to 6 equally divided doses. The higher end of this dosage range should be used for more severe or serious infections.
• The total daily dosage in pediatric patients should not exceed 12 grams.
• Pelvic Inflammatory Disease (Children ≥45 kg and Adolescents):
• Outpatient Management (Mild to Moderate): 2,000 mg IM as a single dose, given in conjunction with a single oral dose of probenecid, followed by a 14-day course of oral doxycycline and oral metronidazole.[12]
• Inpatient Management (Severe): 2,000 mg IV every 6 hours, in combination with doxycycline. Once clinical improvement is observed (typically within 24 to 48 hours), therapy may be transitioned to an oral regimen of doxycycline and metronidazole to complete a total of 14 days of therapy.[12]
• Intra-abdominal Infection (Infants, Children, and Adolescents): 80 to 160 mg/kg/day IV, divided every 4 to 8 hours. The maximum dose per administration is 2,000 mg. It is noted that some guidelines (e.g., SIS/IDSA) may not recommend Cefoxitin for empiric treatment of intra-abdominal infections due to concerns about increasing resistance of anaerobic bacteria like the Bacteroides fragilis group; other options may be preferred in such cases.[12]
• Mycobacterial (Nontuberculous) Infection (e.g., Mycobacterium abscessus), pulmonary infection (Infants, Children, and Adolescents): Limited data suggest a dose of 150 mg/kg/day IV, divided every 6 to 8 hours, with a maximum daily dose of 12 g/day. Parenteral therapy duration is typically 4 to 12 weeks, followed by oral and/or inhaled therapy, with a total antibiotic treatment duration of ≥12 months after culture conversion.[12]
• Important Note: Safety and efficacy of Cefoxitin have not been established in children younger than 3 months of age.[6] Therefore, no specific dosage recommendation is made for this age group at this time.[6]

Prophylactic Dosages (Children ≥3 months of age): [6]

• 30 to 40 mg/kg per dose administered IV, given 30 to 60 minutes prior to the surgical procedure. This dose may be repeated in 2 hours if the procedure is prolonged or if there is excessive blood loss. The maximum dose per administration is 2,000 mg.

Table 3: Recommended Dosage Regimens for Cefoxitin in Adults and Pediatric Patients (Selected Indications)

Indication	Patient Population	Dosage	Route	Frequency	Key Comments	Reference(s)
Uncomplicated Infections (e.g., pneumonia, UTI)	Adults	1 gram	IV	Every 6-8 hours	Total 3-4 g/day	6
Moderately Severe/Severe Infections	Adults	1 gram OR 2 grams	IV	Every 4 hours OR Every 6-8 hours	Total 6-8 g/day	6
Infections Needing Higher Dosage (e.g., gas gangrene)	Adults	2 grams OR 3 grams	IV	Every 4 hours OR Every 6 hours	Total 12 g/day	6
Surgical Prophylaxis (GI, Hysterectomy)	Adults	2 grams (pre-op), then 2 grams	IV	30-60 min pre-incision, then Every 6 hours	Max 24 hours duration	6
Surgical Prophylaxis (Cesarean Section)	Adults	2 grams (single dose) OR 2 grams (initial), then 2 grams x 2 doses	IV	At cord clamp OR At cord clamp, then 4 and 8 hours later		6
General Treatment	Pediatric (≥3 months)	80-160 mg/kg/day (divided)	IV	Every 4-6 hours	Max 12 g/day. Higher end of range for severe infections.	6
Surgical Prophylaxis	Pediatric (≥3 months)	30-40 mg/kg	IV	30-60 min pre-surgery	Max 2 g/dose. May repeat in 2h if prolonged surgery.	6
Pelvic Inflammatory Disease (Severe)	Adolescents/Children $\geq 45$kg	2,000 mg (with doxycycline)	IV	Every 6 hours	Transition to oral therapy after clinical improvement.	12

5.4. Dosage Adjustments

Appropriate dosage adjustments are crucial for Cefoxitin therapy, particularly in patients with impaired renal function and in the elderly, due to its primary route of elimination.

5.4.1. Renal Impairment

Cefoxitin is substantially excreted by the kidneys. Therefore, in patients with impaired renal function, dosages must be adjusted to prevent accumulation of the drug and potential toxicity.

Adult Patients: [6]

• An initial loading dose of 1 gram to 2 grams IV may be administered to all patients, regardless of their renal function status, to rapidly achieve therapeutic concentrations.
• Subsequent maintenance dosages are based on the patient's creatinine clearance (CrCl), which is an estimate of glomerular filtration rate:
• Mild Impairment (CrCl 50-30 mL/min): 1 to 2 grams every 8 to 12 hours.
• Moderate Impairment (CrCl 29-10 mL/min): 1 to 2 grams every 12 to 24 hours.
• Severe Impairment (CrCl 9-5 mL/min): 0.5 to 1 gram every 12 to 24 hours.
• Essentially No Function (CrCl <5 mL/min): 0.5 to 1 gram every 24 to 48 hours.
• Patients on Hemodialysis: For patients undergoing hemodialysis, a loading dose of 1 to 2 grams should be administered after each hemodialysis session. The maintenance dose should then follow the guidelines for CrCl <5 mL/min (or as specifically recommended based on dialysis schedule and residual renal function). Cefoxitin is removed by hemodialysis.[13]
• If only serum creatinine concentration is available, creatinine clearance can be estimated using standard formulas (e.g., the Cockcroft-Gault equation), provided that the serum creatinine value represents a steady state of renal function.[6] For females, the calculated value is typically multiplied by 0.85.

Pediatric Patients: [6]

• In pediatric patients with renal impairment, the dosage and frequency of administration should be modified in a manner consistent with the recommendations for adults, taking into account the degree of renal dysfunction.

The necessity for meticulous dosage adjustments in individuals with renal impairment and in geriatric patients is a paramount safety and efficacy consideration. This directly reflects Cefoxitin's primary reliance on the kidneys for elimination.[6] Impaired renal function leads to slower drug removal, prolonging its half-life and increasing plasma concentrations, thereby elevating the risk of adverse effects.[6] The provision of specific, tiered dosage reduction guidelines based on creatinine clearance for adults, which are then adapted for pediatric use, underscores this critical relationship.[6] Failure to appropriately adjust doses in these populations can result in drug accumulation and an increased likelihood of adverse events, including potential central nervous system toxicity at high concentrations [24], diminishing the therapeutic index. Conversely, excessive caution leading to underdosing without proper renal function assessment could compromise therapeutic efficacy.

Table 4: Cefoxitin Dosage Adjustments in Adult Patients with Renal Impairment

Creatinine Clearance (CrCl) (mL/min)	Degree of Impairment	Recommended Cefoxitin Dose	Dosing Interval	Reference(s)
50 - 30	Mild	1 - 2 grams	Every 8 - 12 hours	6
29 - 10	Moderate	1 - 2 grams	Every 12 - 24 hours	6
9 - 5	Severe	0.5 - 1 gram	Every 12 - 24 hours	6
< 5	Essentially No Function	0.5 - 1 gram	Every 24 - 48 hours	6

Note: An initial loading dose of 1-2 grams may be given. For patients on hemodialysis, a loading dose of 1-2 grams should be given after each hemodialysis session, and maintenance doses should follow the CrCl <5 mL/min guidelines or specific nephrology consultation.

5.4.2. Geriatric Patients

Cefoxitin is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.[6] Since elderly patients are more likely to have a physiological decline in renal function, even if not clinically apparent, care should be exercised in dose selection. Monitoring of renal function may be particularly useful in this population.[6] Published studies have indicated that geriatric patients (aged 64 to 88 years) with renal function considered normal for their age still exhibited a longer half-life for Cefoxitin (51 to 90 minutes) and consequently higher plasma concentrations compared to younger adults. These pharmacokinetic changes were attributed to the decreased renal function associated with the aging process.[6] This observation underscores that age itself is a risk factor for altered drug handling, even if serum creatinine levels appear within the normal laboratory range. Standard adult doses, if not carefully considered and potentially adjusted, could lead to drug accumulation and an increased risk of adverse effects in elderly individuals. Therefore, while specific CrCl-based adjustments are the primary guide, a heightened level of caution, possibly involving more conservative initial dosing or closer monitoring, is warranted when administering Cefoxitin to geriatric patients.

5.4.3. Hepatic Impairment

The available information does not provide specific dosage adjustment guidelines for Cefoxitin in patients with hepatic impairment.[6] This is likely because Cefoxitin undergoes minimal hepatic metabolism and is primarily eliminated by the kidneys. However, it is advisable to conduct periodic assessments of organ system functions, including hepatic function, during prolonged therapy with any potent antibacterial agent like Cefoxitin.[6]

6. Safety Profile

The safe use of Cefoxitin requires an understanding of its contraindications, potential warnings and precautions, and common and serious adverse drug reactions.

6.1. Contraindications

Cefoxitin is contraindicated in individuals with:

• A history of documented hypersensitivity to Cefoxitin itself, any component of its formulation, or other cephalosporin antibiotics.[4] This includes serious allergic reactions such as anaphylaxis.
• Known allergy to corn or corn products, specifically for Cefoxitin formulations that contain corn-derived dextrose as a diluent or excipient.[4]
• While some sources list neonates younger than 3 months as a contraindication [24], official FDA labeling and other materials more commonly state that safety and efficacy have not been established in this age group, and thus no recommendation for use is made, rather than a strict contraindication for all potential uses.[6]

6.2. Warnings and Precautions

Several important warnings and precautions should be considered when prescribing or administering Cefoxitin:

• Hypersensitivity Reactions: Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibiotics, including cephalosporins like Cefoxitin.[4] Before initiating therapy, a thorough inquiry should be made regarding previous hypersensitivity reactions to Cefoxitin, other cephalosporins, penicillins, or any other allergens. Patients with a history of penicillin allergy should be treated with particular caution due to the potential for immunologic cross-reactivity between penicillins and cephalosporins.[4] If an allergic reaction to Cefoxitin occurs, the drug must be discontinued immediately, and appropriate emergency treatment (e.g., epinephrine, antihistamines, corticosteroids, airway management) should be instituted as clinically indicated.[4]
• Clostridioides difficile-Associated Diarrhea (CDAD): CDAD has been reported with the use of nearly all antibacterial agents, including Cefoxitin. The severity of CDAD can range from mild diarrhea to life-threatening pseudomembranous colitis.[4] Antibiotic treatment alters the normal colonic flora, leading to an overgrowth of C. difficile, which produces toxins A and B that contribute to CDAD. If CDAD is suspected or confirmed (e.g., by stool toxin assay or colonoscopy), ongoing antibiotic use that is not directed against C. difficile may need to be discontinued. Management of CDAD includes appropriate fluid and electrolyte replacement, protein supplementation, specific antibiotic treatment for C. difficile (e.g., oral vancomycin or fidaxomicin), and surgical evaluation if clinically warranted. It is important to note that CDAD can occur during antibiotic therapy or even weeks to months after cessation of treatment.[4] Patients experiencing diarrhea while on or after Cefoxitin should consult their healthcare provider; anti-diarrheal medications (anti-motility agents) should generally be avoided if CDAD is suspected, as they may worsen the condition.[4]
• Hematologic Effects: Cefoxitin therapy has been associated with various hematologic adverse effects. These can include easy bruising, unusual bleeding (e.g., epistaxis, gingival bleeding), pale skin, cold hands and feet, and profound tiredness, which may be indicative of conditions such as anemia, thrombocytopenia, neutropenia, or agranulocytosis.[4] During prolonged Cefoxitin therapy, periodic assessment of organ system functions, including hematopoietic function (e.g., complete blood counts), is advisable.[6]
• Renal Toxicity/Nephrotoxicity: Cefoxitin has the potential to cause kidney damage (nephrotoxicity), particularly when used at high doses, in patients with pre-existing renal impairment, or when co-administered with other nephrotoxic drugs such as aminoglycosides, potent diuretics (e.g., furosemide), or certain nonsteroidal anti-inflammatory drugs (NSAIDs).[1] Careful monitoring of renal function (e.g., serum creatinine, BUN, urine output) is recommended, especially in elderly patients and those with known or suspected renal dysfunction. Dosage adjustments are mandatory in patients with renal impairment (see Section 5.4.1). Reports of oliguria (little or no urination) or anuria, as well as jaundice (which could signify cholestatic liver injury or be part of a systemic illness affecting renal function), warrant immediate medical attention.[4]
• Neurotoxicity/Seizures: High concentrations of beta-lactam antibiotics, including Cefoxitin, particularly in the setting of renal insufficiency where drug accumulation can occur, may lead to central nervous system (CNS) toxicity. Manifestations can include encephalopathy, confusion, twitching, myoclonus, and seizures.[4] Cefoxitin should be used with caution in patients with a history of seizure disorders.[18] Dosage adjustments for renal impairment are critical to minimize this risk.
• Development of Drug-Resistant Bacteria: To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefoxitin and other antibacterial drugs, Cefoxitin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria susceptible to its action. Prescribing Cefoxitin in the absence of such evidence or for non-bacterial conditions (e.g., viral infections) is unlikely to benefit the patient and increases the risk of selecting for and promoting drug-resistant organisms.[6]
• Superinfections: As with other broad-spectrum antibiotics, prolonged use or repeated courses of Cefoxitin therapy may disrupt the normal microbial flora of the body, leading to the overgrowth of non-susceptible organisms. This can result in superinfections, such as fungal infections (e.g., oral or vaginal candidiasis) or infections with other resistant bacteria.[24] If superinfection occurs, appropriate therapeutic measures should be taken.
• Patients with History of Colitis: Cefoxitin should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis (e.g., ulcerative colitis, antibiotic-associated colitis), as antibiotics can exacerbate these conditions.[4]
• Malnourished Patients and Specific Co-morbid Conditions: Caution is advised when using Cefoxitin in malnourished patients, or in individuals with conditions such as diabetes mellitus, congestive heart failure, cancer, or those undergoing major surgery or experiencing a medical emergency, as these patients may be at higher risk for adverse outcomes or may have altered drug disposition.[4]

6.3. Adverse Drug Reactions

Cefoxitin therapy can be associated with a range of adverse drug reactions (ADRs), varying in frequency and severity.

Common Adverse Reactions: These are generally mild to moderate and may not require discontinuation of therapy, but should be monitored. [4]

• Local Injection Site Reactions: Pain, tenderness, swelling, bruising, redness, induration, or phlebitis/thrombophlebitis at the site of intravenous or intramuscular injection are common.
• Gastrointestinal Disturbances: Diarrhea is a frequently reported side effect. Nausea, vomiting, and abdominal pain or discomfort can also occur.
• Hypersensitivity Reactions (Mild): Skin rash (maculopapular, erythematous), pruritus (itching), and urticaria (hives) are relatively common.
• Fever: Drug-induced fever can occur.
• Genitourinary: Vaginal itching or irritation, or candidal vaginitis due to alteration of normal flora.
• General: Headache and changes in appetite have also been reported, though less emphasized.[8]

Serious Adverse Reactions: These are less common but can be severe and may require immediate medical attention and discontinuation of Cefoxitin. [4]

• Severe Hypersensitivity Reactions: Anaphylaxis (a life-threatening allergic reaction involving respiratory distress, hypotension, angioedema), angioedema (swelling of the face, lips, tongue, throat), bronchospasm.
• Severe Dermatologic Reactions: Serious and potentially life-threatening skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, characterized by fever, sore throat, burning eyes, widespread skin pain, and blistering or peeling of the skin and mucous membranes.
• Gastrointestinal: Severe, watery, or bloody diarrhea, often accompanied by abdominal cramps and fever, which may be indicative of Clostridioides difficile-associated diarrhea (CDAD) or pseudomembranous colitis.
• Renal and Urinary Disorders: Acute renal failure, interstitial nephritis, decreased urine output (oliguria/anuria), elevated serum creatinine and BUN, hematuria (blood in urine), proteinuria (protein in urine).
• Hepatic Disorders: Jaundice (yellowing of the skin or eyes), elevated liver enzymes (AST/SGOT, ALT/SGPT, alkaline phosphatase, LDH), cholestasis, hepatitis.
• Hematologic Disorders: Anemia (including hemolytic anemia), leukopenia, neutropenia, agranulocytosis, thrombocytopenia, eosinophilia, positive Coombs' test, prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT), easy bruising, or unusual bleeding.
• Neurologic Disorders: Seizures (especially with high doses or in patients with renal impairment), confusion, dizziness, light-headedness, encephalopathy.
• Cardiovascular Disorders: Hypotension, tachycardia, chest pain (less commonly reported but mentioned in some sources [18]).
• Other: Serum sickness-like reactions, return of fever, sore throat, chills, or other signs of a new or worsening infection (superinfection).

This list is not exhaustive, and other side effects may occur. Patients are advised to report any unusual or severe symptoms to their healthcare provider. Adverse events can also be reported to regulatory authorities such as the FDA's MedWatch program.[4]

The overall safety profile of Cefoxitin is generally comparable to that of other beta-lactam antibiotics. However, particular attention should be paid to its gastrointestinal tolerability, especially the risk of diarrhea and the more serious CDAD, given its broad-spectrum activity which can significantly disrupt colonic flora.[4] Vigilance for hypersensitivity reactions, ranging from mild rashes to severe anaphylaxis, is crucial, considering the potential for cross-reactivity in penicillin-allergic individuals. Given its primary renal excretion, monitoring renal function and adjusting doses accordingly, especially in the elderly or those with pre-existing kidney disease or on concomitant nephrotoxic drugs, is a key aspect of safe Cefoxitin use.[4] While serious hematologic and dermatologic reactions are less frequent, their potential severity warrants awareness. A careful assessment of the benefit-risk profile is essential for each patient, considering their clinical status, comorbidities, and concomitant medications.

Table 5: Summary of Common and Serious Adverse Drug Reactions Associated with Cefoxitin

System Organ Class	Common Adverse Reactions	Serious Adverse Reactions	Reference(s)
General Disorders and Administration Site Conditions	Injection site reactions (pain, swelling, redness, phlebitis), Fever	Anaphylaxis, Angioedema	4
Gastrointestinal Disorders	Diarrhea, Nausea, Vomiting, Abdominal pain	Clostridioides difficile-associated diarrhea (CDAD)/Pseudomembranous colitis (severe/bloody diarrhea, cramps, fever)	4
Skin and Subcutaneous Tissue Disorders	Rash (maculopapular, erythematous), Pruritus, Urticaria	Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), Erythema multiforme, Exfoliative dermatitis	4
Immune System Disorders		Hypersensitivity reactions (beyond skin), Serum sickness-like reactions	4
Renal and Urinary Disorders		Acute renal failure, Interstitial nephritis, Oliguria/Anuria, Elevated BUN/Creatinine	4
Hepatobiliary Disorders		Jaundice, Hepatitis, Elevated liver enzymes (AST, ALT, Alk Phos)	4
Blood and Lymphatic System Disorders		Anemia (incl. hemolytic), Leukopenia, Neutropenia, Agranulocytosis, Thrombocytopenia, Eosinophilia, Positive Coombs' test, Bleeding, Bruising	4
Nervous System Disorders	Headache (less common)	Seizures, Encephalopathy, Dizziness, Light-headedness	4
Infections and Infestations	Vaginal itching/irritation (candidiasis)	Superinfection (fungal or bacterial)	24
Cardiovascular Disorders		Hypotension, Tachycardia, Chest pain	4

7. Drug Interactions

Cefoxitin can interact with various other medications, potentially leading to altered efficacy or increased risk of adverse effects. These interactions often stem from its pharmacokinetic properties (especially renal excretion) or its pharmacodynamic effects (e.g., nephrotoxicity, effects on hemostasis).

7.1. Interactions with Other Antimicrobials

• Aminoglycosides: Co-administration of Cefoxitin with aminoglycoside antibiotics (e.g., gentamicin, amikacin, tobramycin, neomycin, kanamycin, netilmicin, streptomycin) may result in an increased risk of nephrotoxicity.[1] Both classes of drugs have intrinsic nephrotoxic potential, and their combined use can be additive or synergistic. Furthermore, Cefoxitin has been reported to potentially decrease the renal excretion rate of some aminoglycosides, which could lead to higher serum concentrations and an amplified risk of both nephrotoxicity and ototoxicity associated with aminoglycosides.[1] Careful monitoring of renal function is essential if this combination is deemed necessary.
• Other Cephalosporins and Beta-Lactams: The concurrent use of Cefoxitin with other cephalosporins (e.g., cefaclor, cefazolin, cefepime, ceftriaxone) may also elevate the risk or severity of nephrotoxicity.[1] For other beta-lactam antibiotics such as penicillins (amoxicillin, ampicillin, piperacillin) and carbapenems (meropenem, ertapenem) or monobactams (aztreonam), Cefoxitin may decrease their excretion rate, potentially causing their serum levels to rise.[1]
• Other Nephrotoxic Antimicrobials: The risk of nephrotoxicity can be increased when Cefoxitin is combined with other antimicrobials known for their renal toxicity, such as polymyxins (colistin, colistimethate), bacitracin, amphotericin B, and vancomycin.[1] Cefoxitin might also reduce the excretion of vancomycin and colistin, further enhancing their potential for toxicity.[1]
• Bacteriostatic Antibiotics: Theoretically, bacteriostatic antibiotics (e.g., tetracyclines, macrolides like erythromycin, chloramphenicol) could interfere with the bactericidal action of beta-lactam antibiotics like Cefoxitin, as beta-lactams are most effective against actively dividing bacteria. Concurrent use should generally be avoided if possible, particularly in severe infections where rapid bactericidal activity is desired.[13] However, one source indicates that Cefoxitin might decrease the excretion of tetracycline [1], which complicates this general principle.

7.2. Interactions with Anticoagulants

• Vitamin K Antagonists (e.g., Warfarin, Acenocoumarol): Cephalosporins, including Cefoxitin, have been reported to increase the risk or severity of bleeding when combined with oral anticoagulants like warfarin.[1] This may be due to several mechanisms, including interference with vitamin K synthesis by altering gut flora (though Cefoxitin itself does not possess the N-methylthiotetrazole (NMTT) side chain commonly associated with this effect), direct effects on platelet function, or displacement of anticoagulants from plasma protein binding sites. Cefoxitin has also been noted to potentially decrease the excretion rate of warfarin, which could lead to higher warfarin levels and an exaggerated anticoagulant effect.[1] Careful monitoring of prothrombin time (PT) or International Normalized Ratio (INR) is crucial when these drugs are used concomitantly.
• Other Anticoagulants and Antiplatelet Agents: Some data suggest that the therapeutic efficacy of various anticoagulants (e.g., heparin, low molecular weight heparins like enoxaparin, direct thrombin inhibitors like argatroban, Factor Xa inhibitors like apixaban) and antiplatelet agents (e.g., dipyridamole) might be decreased when used with Cefoxitin.[1] This is somewhat counterintuitive, as antibiotics are often associated with potentiating anticoagulation. This claim requires careful interpretation and may depend on the specific anticoagulant. Conversely, Cefoxitin may decrease the excretion rate of certain newer oral anticoagulants like edoxaban, rivaroxaban, and dabigatran etexilate, potentially increasing their exposure and bleeding risk.[1] Given these complex and sometimes conflicting interactions, close monitoring for signs of bleeding or thrombosis is warranted.

7.3. Effects on Laboratory Diagnostic Tests

Cefoxitin can interfere with certain laboratory tests, potentially leading to inaccurate results:

• Urine Glucose Tests: Cefoxitin may cause false-positive results for glucose in the urine when tests based on cupric sulfate reduction methods are used (e.g., Benedict's reagent, Clinitest). Enzymatic glucose oxidase tests (e.g., Clinistix, Diastix, TesTape) are not affected by Cefoxitin and should be used instead for monitoring urine glucose in patients receiving this antibiotic.[13]
• Serum and Urine Creatinine Tests: Cefoxitin can cause factitious elevations in serum or urine creatinine levels when the Jaffe reaction method (using alkaline picrate) is employed for measurement. This interference can lead to an overestimation of creatinine and, consequently, an underestimation of creatinine clearance if not recognized.[13] Alternative methods for creatinine measurement may be necessary, or this potential interference should be considered when interpreting results.
• Other Medical Tests: It is also generally advised that Cefoxitin can affect the results of certain other unspecified medical tests. Therefore, it is important for patients to inform any physician or laboratory personnel involved in their care that they are receiving Cefoxitin.[4]

7.4. Other Clinically Significant Interactions

• Probenecid: Probenecid significantly interacts with Cefoxitin by competitively inhibiting its active tubular secretion in the kidneys. This results in higher and more prolonged serum concentrations of Cefoxitin, effectively increasing its exposure.[1] This interaction is sometimes intentionally exploited in clinical practice to boost Cefoxitin levels and prolong its therapeutic effect, for example, in the treatment of gonorrhea.[13]
• General Nephrotoxic Agents: The risk of kidney damage is increased when Cefoxitin is co-administered with other drugs known to be nephrotoxic. This includes:
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, naproxen, acetylsalicylic acid, and indomethacin.[1]
• Loop diuretics like furosemide and ethacrynic acid. While ethacrynic acid clearly increases nephrotoxicity risk, furosemide has a more complex interaction, as it may also decrease Cefoxitin's excretion rate, potentially leading to higher Cefoxitin levels.[1]
• Other nephrotoxic drugs such as cyclosporine, tacrolimus, cidofovir, foscarnet, pentamidine, methotrexate, and cisplatin.[1]
• Hormonal Contraceptives: Broad-spectrum antibiotics, including potentially Cefoxitin, may reduce the efficacy of oral hormonal contraceptives (birth control pills, patches, rings, injections). This is thought to occur primarily by altering the gut microflora, which can interfere with the enterohepatic circulation of estrogens, or less commonly, by inducing hepatic enzymes (though enzyme induction is not a prominent feature of Cefoxitin). Patients using hormonal contraceptives should be advised to use an additional or alternative (barrier) method of contraception during Cefoxitin therapy and for a specified period afterward to prevent unintended pregnancy.[23]
• Acetaminophen: Cefoxitin may decrease the renal excretion rate of acetaminophen, potentially leading to higher serum concentrations and an increased risk of acetaminophen-related toxicity, particularly hepatotoxicity at high doses.[1]
• Disulfiram: An increased risk or severity of adverse effects has been reported when Cefoxitin is combined with disulfiram.[1] While Cefoxitin does not possess the NMTT side chain typically associated with disulfiram-like reactions (flushing, tachycardia, nausea, vomiting with alcohol ingestion), this interaction is listed in drug databases and warrants caution.
• Live Bacterial Vaccines: The efficacy of live bacterial vaccines (e.g., BCG vaccine, oral typhoid vaccine, oral cholera vaccine) may be diminished if administered concurrently with or shortly after a course of antibacterial agents like Cefoxitin, as the antibiotic can kill the attenuated bacteria in the vaccine. It is generally recommended to administer live bacterial vaccines at an appropriate interval before or after antibiotic therapy.[1]

The majority of Cefoxitin's clinically significant drug interactions are rooted in its primary pharmacokinetic pathway—renal excretion—and its inherent potential for nephrotoxicity. This creates a scenario where Cefoxitin can affect the levels of other renally cleared drugs, be affected by drugs that modulate renal function, and contribute to additive or synergistic kidney damage when combined with other nephrotoxins. Many of the listed interactions involve Cefoxitin decreasing the excretion rate of co-administered drugs, suggesting competition for renal elimination mechanisms, such as active tubular secretion, or potentially an impact on glomerular filtration.[1] Conversely, drugs like probenecid actively increase Cefoxitin levels by inhibiting its renal tubular secretion.[1] The substantial number of interactions highlighting an increased risk of nephrotoxicity when Cefoxitin is combined with other known nephrotoxic agents underscores the importance of careful patient assessment, particularly of renal function and concomitant medications, before and during Cefoxitin therapy to mitigate these risks.

Table 6: Clinically Significant Drug Interactions with Cefoxitin

Interacting Drug/Class	Potential Effect	Putative Mechanism / Note	Clinical Recommendation/Management	Reference(s)
Probenecid	Increased and prolonged Cefoxitin serum concentrations	Inhibition of renal tubular secretion of Cefoxitin	May be used therapeutically; monitor for Cefoxitin toxicity if not intentional.	1
Aminoglycosides (e.g., gentamicin, amikacin)	Increased risk of nephrotoxicity; potentially increased aminoglycoside levels	Additive nephrotoxicity; Cefoxitin may decrease aminoglycoside excretion	Avoid if possible; if used, monitor renal function closely and aminoglycoside levels.	1
Loop Diuretics (e.g., furosemide, ethacrynic acid)	Increased risk of nephrotoxicity (esp. ethacrynic acid); Furosemide may decrease Cefoxitin excretion	Additive nephrotoxicity; competition for renal excretion	Monitor renal function closely.	1
NSAIDs (e.g., ibuprofen, acetylsalicylic acid)	Increased risk of nephrotoxicity	Additive nephrotoxicity	Use with caution, monitor renal function.	1
Warfarin and other Vitamin K Antagonists	Increased risk of bleeding; potentially increased warfarin levels	Interference with Vitamin K metabolism or platelet function; Cefoxitin may decrease warfarin excretion	Monitor INR/PT closely and adjust anticoagulant dose as needed.	1
Hormonal Contraceptives	Potentially decreased contraceptive efficacy	Alteration of gut flora, interference with enterohepatic circulation of estrogens	Advise use of additional/alternative contraception during and after Cefoxitin therapy.	23
Live Bacterial Vaccines (e.g., Typhoid, BCG)	Decreased vaccine efficacy	Antibiotic may inactivate live bacteria in vaccine	Administer vaccine at appropriate interval from antibiotic therapy.	1
Urine Glucose Tests (Cupric Sulfate Reduction)	False-positive results	Chemical interference	Use glucose oxidase-based tests instead.	13
Serum/Urine Creatinine Tests (Jaffe Reaction)	False-positive elevations	Chemical interference	Be aware of potential interference when interpreting results; consider alternative methods.	13

8. Use in Specific Populations

The use of Cefoxitin in certain patient populations requires special consideration due to potential differences in pharmacokinetics, susceptibility to adverse effects, or lack of sufficient safety and efficacy data.

8.1. Pregnancy and Lactation

Pregnancy:

Cefoxitin is known to cross the placental barrier, meaning it can reach the fetal circulation.13 Animal reproduction studies performed with Cefoxitin have generally not revealed direct evidence of fetotoxicity, fetal harm, or teratogenicity at doses up to 7.5 times the maximum recommended human dose. However, an increased incidence of abortion was observed in animal studies at dose levels that also produced maternal toxicity.28

Crucially, there are no adequate and well-controlled studies of Cefoxitin use in pregnant women.[28] While the malformative risk associated with Cefoxitin use during pregnancy is generally considered unlikely [28], the lack of robust human data necessitates a cautious approach.

Regarding regulatory classification, the US Food and Drug Administration (FDA) has transitioned away from the letter-category system for pregnancy (A, B, C, D, X). Cefoxitin is now listed as "Not Assigned" under the new Pregnancy and Lactation Labeling Rule (PLLR).[28] Historically, it was likely considered a Category B drug. The Australian Therapeutic Goods Administration (TGA) classifies Cefoxitin under Pregnancy Category B1.[28] Category B1 indicates that studies in animals have not shown evidence of an increased occurrence of fetal damage, and the drug has been taken by only a limited number of pregnant women and women of childbearing age without an observed increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus.[28]

Given these considerations, Cefoxitin should be used during pregnancy only if it is clearly needed, and the potential benefit to the mother justifies the potential, albeit largely unquantified, risk to the fetus.[28] Pregnant patients or those planning to become pregnant should inform their doctor before starting Cefoxitin therapy.[4]

Lactation:

Cefoxitin is excreted into human breast milk, although generally in small amounts.13 Caution is recommended when Cefoxitin is administered to a nursing woman.28 The American Academy of Pediatrics (AAP) has previously considered Cefoxitin to be compatible with breastfeeding.28 However, there have been reports of maternal doses of cephalosporins (a class to which Cefoxitin belongs) resulting in adverse effects in breastfed infants, such as diarrhea and thrush (oral candidiasis) due to disruption of the infant's gut flora.28 Some experts suggest that nursing mothers receiving Cefoxitin might consider alternative feeding arrangements for their infants, particularly if the infant is premature or medically fragile.28 Breastfeeding patients should discuss the potential risks and benefits with their doctor.4

8.2. Pediatric Use

Cefoxitin is used in pediatric patients aged 3 months and older, with specific dosage recommendations based on body weight and indication (as detailed in Section 5.3.2).[6]

However, the safety and efficacy of Cefoxitin have not been established in neonates and infants younger than 3 months of age.[6] Consequently, no specific dosage recommendation is made for this very young age group.[6] Some sources even list use in neonates (<3 months) as a contraindication.[24]

Pharmacokinetic studies have shown differences in Cefoxitin disposition in neonates and young infants compared to older children and adults. For example, the elimination half-life is longer in neonates (approximately 1.4 hours in those <2 months of age) than in older children (approximately 42.4 minutes in those ≥3 months).[12] These differences underscore the need for caution and age-specific data if use in younger infants were to be considered.

For pediatric patients with renal impairment, dosage and administration frequency should be modified in a manner consistent with the recommendations provided for adults, based on the degree of renal dysfunction.[6]

8.3. Geriatric Use

The use of Cefoxitin in elderly patients (typically defined as aged 65 years and older) warrants careful consideration, primarily due to age-related physiological changes, especially in renal function. Cefoxitin is substantially excreted by the kidneys, and since renal function often declines with age, elderly patients are more likely to have reduced clearance of Cefoxitin. This can lead to higher plasma concentrations and a prolonged elimination half-life of the drug compared to younger adults, even if their serum creatinine levels appear within the normal range.[6]

Studies have specifically shown that geriatric patients (aged 64-88 years) with what was considered normal renal function for their age still exhibited a longer half-life (51 to 90 minutes versus 41 to 59 minutes in younger adults) and higher plasma concentrations of Cefoxitin.[6] This was attributed to the "decreased renal function associated with the aging process".[6] This pharmacokinetic alteration implies that standard adult doses, if not carefully evaluated and potentially adjusted, could lead to drug accumulation and an increased risk of adverse effects in the elderly.

Therefore, care should be taken in dose selection for geriatric patients. While specific age-based dose reductions are not mandated, it is prudent to consider the patient's overall clinical status and, importantly, their renal function. Monitoring of renal function (e.g., estimation of creatinine clearance) may be particularly useful in this population to guide appropriate dosage adjustments (as detailed in Section 5.4.1).[6] This cautious approach is essential because age itself acts as a risk factor for altered drug handling and increased susceptibility to drug-related toxicities.

9. Regulatory and Pharmaceutical Information

9.1. FDA Approval Status and Key Labeled Uses

Cefoxitin is an antibiotic approved by the U.S. Food and Drug Administration (FDA) for use in the United States.[2] It is pharmacologically classified by the FDA as a Cephalosporin Antibacterial.[2] Cefoxitin is available by prescription only (Rx status).[4]

According to FDA labeling documents, key approved therapeutic indications for Cefoxitin include the treatment of serious infections caused by susceptible strains of designated microorganisms in the following conditions [6]:

• Lower respiratory tract infections (including pneumonia and lung abscess)
• Urinary tract infections
• Intra-abdominal infections (including peritonitis and intra-abdominal abscess)
• Gynecological infections (including endometritis, pelvic cellulitis, and pelvic inflammatory disease)
• Septicemia
• Bone and joint infections
• Skin and skin structure infections

Additionally, Cefoxitin is FDA-approved for the prophylaxis of infection in patients undergoing specific surgical procedures, namely uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, or cesarean section.[6]

9.2. European Regulatory Status

The provided research materials do not contain explicit confirmation of a current, centralized marketing authorization for Cefoxitin itself specifically through the European Medicines Agency (EMA). While several documents discuss EMA processes and approvals for other antibiotics, such as Cefiderocol (a different siderophore cephalosporin) [29], or general regulatory actions concerning antibiotic indications [32], direct information on Cefoxitin's centralized EMA status is absent.

It is common for older antibiotics like Cefoxitin, which have been in use for many years, to have been authorized through national procedures in individual European Union member states rather than, or prior to the establishment of, the centralized EMA pathway.[33] If a medicine is not found in the EMA's database of centrally authorized products, it is often indicative of such national authorizations.[33] Therefore, while Cefoxitin is likely used in various European countries, its regulatory approval and specific labeled indications within Europe would typically be managed by the national competent authorities of each member state. The absence of information on a centralized EMA approval for Cefoxitin in the provided documents, contrasted with detailed information on newer agents, suggests that its regulatory standing in Europe is likely based on these individual national authorizations.

9.3. Brand Names, Manufacturers, and Formulations

• Brand Names: The most widely recognized brand name for Cefoxitin has historically been Mefoxin®.[4] However, it is noted that the brand name Mefoxin is discontinued in the U.S., though generic versions of Cefoxitin are likely available.[7] Other potential brand names from specific manufacturers may exist, such as CefoxCare™, mentioned by AdvaCare Pharma.[8]
• Manufacturers: Merck & Co., Inc. was the original manufacturer of Mefoxin®.[28] Currently, various pharmaceutical companies manufacture and supply Cefoxitin Sodium for injection. AdvaCare Pharma is described as a global supplier and manufacturer with GMP-certified facilities in China, India, and the USA.[8] Companies like SynZeal and TCI America also supply Cefoxitin, often for research and development purposes.[3]
• Formulations: Cefoxitin is typically supplied as Cefoxitin Sodium, USP, a sterile powder for reconstitution prior to parenteral administration.[6] Common formulations include:
• Injectable powder for injection, available in various vial sizes (e.g., 1 gram, 2 grams, or a 10-gram pharmacy bulk package).[4]
• Intravenous powder for injection (e.g., 1 gram, 2 grams).[4]
• Specialized packaging such as "Cefoxitin for Injection and Dextrose Injection," which is a sterile, nonpyrogenic, single-use packaged combination. This formulation contains Cefoxitin Sodium and Dextrose Injection (as diluent) in separate chambers (e.g., the DUPLEX® dual chamber container). After reconstitution, this provides a ready-to-use solution, for example, containing 1 gram or 2 grams of Cefoxitin in 50 mL.[6]

10. Comprehensive Summary and Key Considerations for Clinical Practice

Cefoxitin is a semi-synthetic cephamycin antibiotic, often grouped with second-generation cephalosporins, distinguished by its broad spectrum of activity that includes Gram-positive, Gram-negative, and, significantly, many anaerobic bacteria. Its efficacy is rooted in the inhibition of bacterial cell wall synthesis via binding to Penicillin-Binding Proteins. A key structural feature, the 7-alpha-methoxy group, confers considerable stability against a wide range of bacterial beta-lactamases, underpinning its activity against organisms that may be resistant to other beta-lactams.

Clinically, Cefoxitin is indicated for the treatment of serious infections across various body systems, including lower respiratory tract, urinary tract, intra-abdominal, gynecological, skin and soft tissue, bone and joint infections, and septicemia. Its robust anaerobic coverage makes it particularly valuable for mixed infections. Furthermore, Cefoxitin holds an important role in surgical prophylaxis for specific procedures like gastrointestinal surgery, hysterectomy, and cesarean section, aiming to reduce the incidence of postoperative infections.

Pharmacokinetically, Cefoxitin requires parenteral administration (IV or IM) and is characterized by wide tissue distribution, though with poor CSF penetration. It undergoes minimal metabolism and is primarily excreted unchanged by the kidneys. This renal excretion is rapid in individuals with normal renal function, resulting in a short elimination half-life (approximately 41-59 minutes), which often necessitates frequent dosing.

Several key considerations are paramount for the safe and effective clinical use of Cefoxitin:

1. Spectrum and Resistance: While broad, Cefoxitin's spectrum has limitations (e.g., inactivity against Pseudomonas aeruginosa, Enterobacter cloacae, and Chlamydia trachomatis). Clinicians must match its spectrum to the suspected or confirmed pathogens. Awareness of local resistance patterns is crucial, particularly concerning potential emerging resistance in organisms like Bacteroides fragilis. Susceptibility testing should guide therapy whenever possible.
2. Renal Function and Dosing: Due to its primary renal elimination, dosage adjustments are mandatory for patients with any degree of renal insufficiency to prevent drug accumulation and potential toxicity. Geriatric patients, who often have physiologically reduced renal function even with normal serum creatinine, require cautious dosing and may benefit from renal function monitoring.
3. Hypersensitivity: As with all beta-lactam antibiotics, there is a risk of hypersensitivity reactions, ranging from mild rash to severe anaphylaxis. A thorough patient history regarding allergies to penicillins or cephalosporins is essential before initiating therapy. Cross-reactivity with penicillins can occur.
4. Clostridioides difficile-Associated Diarrhea (CDAD): Cefoxitin, like other broad-spectrum antibiotics, can disrupt normal colonic flora, leading to CDAD. Clinicians should be vigilant for diarrhea developing during or after therapy, which could signify CDAD, a condition that can range from mild to life-threatening.
5. Nephrotoxicity: Cefoxitin itself has a low nephrotoxic potential, but this risk can be amplified when co-administered with other nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, NSAIDs). Renal function should be monitored, especially in high-risk patients or those on concomitant nephrotoxins.
6. Drug Interactions: Clinically significant interactions can occur, most notably with probenecid (which increases Cefoxitin levels), anticoagulants (potential for altered bleeding risk), and drugs affecting renal function or laboratory tests (e.g., false-positive urine glucose with copper reduction methods, false elevation of creatinine with Jaffe method). A careful review of concomitant medications is necessary.
7. Use in Specific Populations: In pregnancy, Cefoxitin should be used only if clearly needed, weighing benefits against potential risks due to limited human data. It is excreted in breast milk, and caution is advised during lactation. Safety and efficacy are not established in infants under 3 months.
8. Antimicrobial Stewardship: To preserve Cefoxitin's efficacy and minimize the development of antimicrobial resistance, its use should adhere to principles of antimicrobial stewardship, including appropriate indication, dosage, duration, and de-escalation based on culture and susceptibility results.

In conclusion, Cefoxitin remains a valuable therapeutic agent for specific, often serious, bacterial infections, particularly where its anaerobic coverage and beta-lactamase stability are advantageous. Its utility in surgical prophylaxis is also well-established. However, its optimal use requires a comprehensive understanding of its pharmacological profile, careful patient selection, appropriate dosing with particular attention to renal function, and vigilance for potential adverse effects and drug interactions.

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