Cefoxitin Sodium: Antibacterial Efficacy & Clinical Applications

Cefoxitin sodium is an intravenous (IV) antibiotic used to treat certain infections caused by bacteria. It works by killing the bacteria that cause the infection. Common side effects include diarrhea or pain, itching, swelling, or redness near the injection site. Serious side effects are much less common, but can include a type of diarrhea that is difficult to treat. Notify your healthcare provider right away if you develop watery or bloody diarrhea. Cefoxitin sodium injection is used to treat infections caused by bacteria including pneumonia and other lower respiratory tract (lung) infections; and urinary tract, abdominal (stomach area), female reproductive organs, blood, bone, joint, and skin infections. Cefoxitin injection may also be used before and during surgery, in order to prevent the patient from getting an infection. Cefoxitin injection is in a class of medications called cephamycin antibiotics. It works by killing bacteria effectively.

Cefoxitin sodium: Antibacterial Activity and Pharmacological Properties

Cefoxitin sodium is a β-lactam antibiotic derived from cephamycin C, a naturally occurring substance produced by Streptomyces lactamdurans. Its resistance to destruction by β-lactamases results in a broad spectrum of antibacterial activity which includes anaerobic as well as Gram-positive and Gram-negative aerobic bacteria, including many resistant to cephalothin and other cephalosporins. Given by intravenous or intramuscular injection, cefoxitin is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes as well as by anaerobic bacteria. It is generally well tolerated, thrombophlebitis, skin rash and some degree of discomfort after intramuscular injection, being the most commonly reported side effects. Cefoxitin sodium has not been shown to cause adverse effects on renal function. is a β-lactam antibiotic derived from cephamycin C, a naturally occurring substance produced by Streptomyces lactamdurans. Its resistance to destruction by β-lactamases results in a broad spectrum of antibacterial activity which includes anaerobic as well as Gram-positive and Gram-negative aerobic bacteria, including many resistant to cephalothin and other cephalosporins. Given by intravenous or intramuscular injection, Cefoxitin sodium is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes as well as by anaerobic bacteria. It is generally well tolerated, thrombophlebitis, skin rash and some degree of discomfort after intramuscular injection, being the most commonly reported side effects. [1]

The efficacy of cefoxitin in vivo has been demonstrated in experimental infection in animals challenged with Gram-negative and Gram-positive aerobic and facultative bacteria or with anaerobic bacteria. Cefoxitin sodium is generally bactericidal against susceptible Gram-positive and Gram-negative aerobic bacteria at concentrations equal to or only 1 or 2 dilutions higher than the minimum inhibitory concentration. Generally, the bactericidal activity of cefoxitin is not appreciably influenced by the size of the inoculum, but the bactericidal activity against Klebsiella and indolepositive Proteus sometimes decreases as the inoculum size is increased. As cefoxitin is active against both aerobic and anaerobic bacteria, particularly B. fragilis, it has been used to treat intra-abdominal and female genital tract infections which are often caused predominantly by anaerobes or anaerobic plus aerobic bacteria. Against such infections, Cefoxitin sodium has been clinically effective in over 85 % of patients including those who had failed to respond to treatment with other antimicrobial agents. In patients considered to have impaired immune response as a result of primary disease and/or concomitant immunosuppressive therapy for neoplastic disease, cefoxitin was effective and free of troublesome complications. Cefoxitin sodium has been found to be effective in bacteraemia and some cases of bacterial endocarditis, but in bacterial endocarditis it appears that the concomitant administration of probenecid may be beneficial.

Cefoxitin sodium versus carbapenems as definitive treatment

Since the 1990s, the emergence and diffusion of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) has been a global concern. In 2021, the rate of invasive ESBL-E isolates has reached 7.5% in French healthcare settings. ESBL-E infections treatment is becoming challenging due to high frequency of co-resistance mechanisms to other antibiotics classes, such as fluoroquinolones and aminoglycosides; therefore, therapeutic options are often very limited. One possible alternative to carbapenems could be cefoxitin, a cephamycin developed in the 1970s, resistant to ESBL hydrolysis and highly active against ESBL-E in vitro. Currently, Cefoxitin sodium is the standard treatment for perioperative surgical prophylaxis, and is proposed as second-line antibiotic therapy for acute ESBL-Escherichia coli (ESBL-EC) pyelonephritis in adults. Indeed, cefoxitin and other cephamycins have been shown to be effective in several small cases series of mild infections, such as urinary tract infections and bacteremia without signs of severity. In a multicenter retrospective study, Senard et al. showed no significant difference in clinical and microbiological success between Cefoxitin sodium and carbapenems as the definitive treatment of ESBL-EC urinary tract infections in men. [2]

The aim of our study was thus to compare the clinical efficacy of Cefoxitin sodium as definitive antibiotic therapy for ICU patients with ESBL-KP bacteremia, versus standard carbapenem therapy. Selection of cefoxitin- and carbapenem-resistant Enterobacterales in both groups was also analyzed. A total of 110 patients with bloodstream infections were enrolled. Sixty-three patients (57%) received definitive antibiotic therapy with cefoxitin, while forty-seven (43%) were treated with carbapenems. 30-day clinical success was not significantly different between patients treated with cefoxitin (57%) and carbapenems (53%, p = 0.823). PS-adjusted and PS-matched analysis confirmed these findings. Change of definitive antibiotic therapy was more frequent in the cefoxitin sodium group (17% vs. 0%, p = 0.002). No significant differences were observed for the other secondary endpoints. The acquisition of carbapenem-resistant Pseudomonas aeruginosa was significantly higher in patients receiving carbapenem therapy (5% vs. 23%, p = 0.007). Our results suggest that cefoxitin sodium as definitive antibiotic therapy could be a therapeutic option for some ESBL-KP bacteremia, sparing carbapenems and reducing the selection of carbapenem-resistant Pseudomonas aeruginosa strains.

Cefoxitin sodium Does Not Induce Production of Penicillin Binding Protein 2a

Recently the cefoxitin sodium disk has been proposed as an alternative method of detecting MRS. Cefoxitin is a cephamycin-type antibiotic, and it has been described as an inducer of methicillin resistance by production of the PBP2a. The paper published by Annie Felten et al. has been used as a reference suggesting the use of the cefoxitin disk as being helpful in oxacillin resistance detection. According to these authors, “surprisingly, cefoxitin induced the PBP2a production in vitro in MSSA isolates for which cefoxitin sodium MICs were high.” The methicillin-susceptible Staphylococcus aureus (MSSA) strain referred to by these authors is S. aureus N315, which was isolated in Japan in 1982, and at that time it was identified as methicillin susceptible and cefoxitin sodium resistant. This strain became resistant to methicillin after induction by cefoxitin. In 1992, it was known that this strain would not be classified as MSSA because it is a pre-methicillin-resistant S. aureus (MRSA) strain.[3]

As a result, when many researchers and clinical bacteriologists are looking for alternative methods for detection of low-level methicillin resistance, it is very important to explain that cefoxitin sodium does not induce PBP2a production in vitro in MSSA isolates unless this isolate is pre-MRSA, with a functional mecI gene. Based on published data, it may be postulated that low-level methicillin resistance in staphylococcus strains could be easily detected if the isolate was also resistant to cefoxitin sodium due to the participation of native PBP2. We did not exclude the possibility of the mechanism's association with participation of several native PBPs that permit the expression of methicillin resistance.

References

[1]Brogden, R N et al. “Cefoxitin: a review of its antibacterial activity, pharmacological properties and therapeutic use.” Drugs vol. 17,1 (1979): 1-37. doi:10.2165/00003495-197917010-00001

[2]Dequidt T, Bastian S, Nacher M, Breurec S, Carles M, Thiery G, Camous L, Tressieres B, Valette M, Pommier JD. Cefoxitin versus carbapenems as definitive treatment for extended-spectrum β-lactamase-producing Klebsiella pneumoniae bacteremia in intensive care unit: a propensity-matched retrospective analysis. Crit Care. 2023 Nov 1;27(1):418. doi: 10.1186/s13054-023-04712-2. PMID: 37915017; PMCID: PMC10619259.

[3]da Costa Darini AL, Palazzo IC. Cefoxitin does not induce production of penicillin binding protein 2a in methicillin-susceptible Staphylococcus aureus strains. J Clin Microbiol. 2004 Sep;42(9):4412; author reply 4412-3. doi: 10.1128/JCM.42.9.4412-4413.2004. PMID: 15365061; PMCID: PMC516335.

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