INTRODUCTION:

Cefuroxime axetil is the oral prodrug formulation of the injectable antibiotic cefuroxime sodium. It has essentially the same antibacterial activity as its parent moiety, making cefuroxime the only second-generation cephalosporin with both an intravenous and oral formulation. Cefuroxime is a second generation cephalosporin antibiotic with a broad spectrum activity and a poor absorption profile from gastrointestinal tract. It led to the synthesis of the 1-acetoxyethyl ester of cefuroxime (cefuroxime axetil)¹.

It is important that cephalosporin compounds for oral administration should be in a form which provides high bioavailability (90-100%) so that their absorption into the blood stream is maximized and the amount of antibiotic remaining in the gastrointestinal tract is minimized.

According to the Biopharmaceutical Classification System (BCS), cefuroxime axetil is a poorly water soluble drug having class II qualities with low solubility but high permeability². Solubility and permeability are the important parameters in formulation development and regulatory standards.

For BCS II, the rate limiting step or the slowest step is drug release from the dosage form and solubility in the gastrointestinal fluid and not the absorption; thus by increasing solubility, bioavailability also increases³. Solubility of a drug can be enhanced by various means such as solvent deposition, solid dispersion, eutectic mixture, micronization, use of surfactant, molecular encapsulation etc⁴.

STRUCTURE AND DERIVATION:

Cefuroxime axetil is the 1-acetoxyethyl ester of cefuroxime. The axetil salt renders the molecule more lipophilic, thus allowing enhanced oral absorption. Once cefuroxime axetil reaches the intestinal mucosa and portal blood flow it rapidly undergoes de-esterification to yield the active parent compound cefuroxime⁵.

Chemical structure of cefuroxime

MECHANISM OF ACTION:

Cefuroxime axetil is a second-generation cephalosporin that contains the classic 3-1actam ring structure. Bactericidal activity in vivo is resultant of its binding to essential target proteins, termed the penicillin-binding proteins, which are located in the bacterial cell wall. Inhibition of these proteins leads to bacterial cell wall elongation and leakage, thus the bacteria are unable to divide and mature⁶.

PHARMACOKINETICS:

Cefuroxime axetil is available as a tablet and a flavored suspension. Although the tablets have undergone three product reformulations in an attempt to standardize absorption, the bioavailability issues have been resolved with the currently marketed tablet. Cefuroxime axetil is converted to the active moiety, cefuroxime, in less than 3 min once absorbed.

Due to the rapid conversion it is not possible to detect cefuroxime axetil in the systemic circulation. Peak serum concentration achieved after a single 250mg dose in the fed state is 4.7mcg/ml and is reached after 2.1 h post-ingestion⁷. The administration of food with cefuroxime axetil substantially increases its absorption⁸.

The bioavailability was shown to increase from 36% to 52% when a 500mg dose was taken in a fasting state compared to being administered after food⁹. The mechanism for this increased bioavailability is not completely understood. It has been proposed that food-induced cholecystokinin release which causes the gall bladder to contract and release bile may be responsible for improving absorption¹⁰.

Cefuroxime axetil, as cefuroxime, is approximately 30% protein bound and has a volume of distribution¹¹. Distribution of this antibiotic into body fluids and tissues is variable, however, it does penetrate well (35-90%) into the tonsil tissue, sinus tissue, and bronchial mucosa¹².

Once de-esterified and released into systemic circulation, cefuroxime is not metabolized further, but is eliminated unchanged in the urine. In patients with normal renal function, the plasma elimination half-life after a dose of 500 mg of cefuroxime is 1.4. h. The elimination half-life increases as the renal function declines. In patients with creatinine clearances¹³. Based on these results, it is recommended that the dosing interval be extended in patients with renal dysfunction (see Table 1).

Table I. Dosage guidelines for renal dysfunction

Estimated creatinine clearance	Recommended dosage
30-49 ml/min/I.73 m²	Standard individual dose given every 12 h
10-29 ml/min/I.73 m²	Standard individual dose given every 24 h
< 10 ml/min/I.73 m²	Standard individual dose given every 48 h

TOLERABILITY:

Cefuroxime axetil is generally well tolerated. Gastrointestinal disturbances, including nausea, vomiting and diarrhoea, are the most frequently reported adverse events and occur in between 3 and 4% of recipients of the drug. 2.2% of 912 patients discontinued treatment with cefuroxime axetil because of drug-related adverse events (predominantly nausea, vomiting, diarrhoea or abdominal pain). Stevens-Johnson syndrome, toxic epidermal necrolysis, headaches, hypersensitivity reactions and pseudomembranous colitis have also been observed occasionally during cefuroxime axetil treatment.

SIDE EFFECTS AND INTERACTIONS:

Cefuroxime axetil is associated with a low incidence of adverse effects and is generally well tolerated. The most frequently reported adyerse effects are primarily gastrointestinal in nature, including

· Loose stools (3.7%)

· Nausea (2.6%)

· Vomiting (2.6%).

Other occasionally reported adverse events associated with cefuroxime axetil include antibiotic associated colitis and liver function abnormalities. Hypersensitivity reactions including Stevens Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis have been reported rarely during post-marketing surveillance¹⁴.

SPECTRUM OF ANTIMICROBIAL ACTIVITY:

Cefuroxime axetil has a wide spectrum of bactericidal activity both in vivo and in vitro against many gram-positive bacteria, some gram-negative bacteria, and few anaerobic bacteria. It even covers those strains that produce 13-1actamases¹⁵. It is highly effective against many of the common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxdla catarrhalis.

It is one of the few oral cephalosporins with some activity against isolates of S. pneumoniae that are intermediately resistant to penicillin¹⁶. It also has good activity against the pathogens that lead to skin and soft tissue infections, including methicillin-sensitive staphylococci and S. pyogenes. The most frequently encountered urinary tract infection pathogens, Escherichia coli, Proteus mirabilis, and Klebsidla pneumoniae, are also susceptible to cefuroxime axetil.

Cefuroxime axetil has coverage for both the penicillinase-positive and -negative strains of Neisseria gonorrhea, and thus is an alternative choice for uncomplicated gonorrhea. It has activity against Borrelia burgdorferi, the bacteria responsible for Lyme disease, and some anaerobic bacteria such as Peptococcus species. Most strains of Clostridium difficile and Bacteroides fragilis are resistant, and therefore render this antibiotic a poor choice for most obstetric and gynecological surgeries¹⁷.

Pseudomonas species, Campylobacter species, Adnetobacter calcoaceticus, most strains of Serratia species, Proteus vulgaris, and certain strains of terococci are resistant to therapy with cefuroxime axetil. 1 Resistance is being reported for some nosocomial isolates of Enterobacteriaceae, primarily K. pneumoniae and E. coli. This is due to bacterial production of novel plasmid-mediated 13-1actamases¹⁸.

CLINICAL APPLICATIONS:

Multiple clinical trials have investigated the therapeutic efficacy of cefuroxime axetil in upper and lower respiratory tract infections, uncomplicated urinary tract infections, skin and soft tissue infections, uncomplicated gonorrhea, and early stage Lyme disease. Although cefuroxime axetil has labeled indications for all of the previously mentioned infections, it is generally not the preferred antibiotic for initial treatment since equally efficacious and less expensive options are available. For general use in obstetrics and gynecological infections, cefuroxime axetil may be considered a useful alternative for treating uncomplicated gonorrhea and urinary tract infections (UTIs). It is considered safe to use in pregnancy (pregnancy category B)¹⁹.

ANTIBACTERIAL ACTIVITY:

The spectrum of activity of cefuroxime encompasses the Gram-positive pathogens Streptococcus pneumoniae (penicillin-sensitive and -intermediate strains, but not penicillin-resistant strains), S. pyogenes and methicillin- and oxacillin-sensitive staphylococci. Cefuroxime is not active against methicillin-resistant staphylococci, enterococci or Listeria monocytogenes.

Cefuroxime also has good activity against a wide range of Gram-negative bacteria, including both β -lactamase positive and negative strains of the common respiratory pathogens Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.

In addition, cefuroxime exhibits activity against Klebsiella pneumoniae, Proteus mirabilis and Escherichia coli although there is some evidence of resistance in K. pneumoniae and E. coli, mainly due to production of novel plasmid-mediated β -lactamases, in the hospital setting. Many Enterobacter species are resistant to cefuroxime, as are species of Pseudomonas and Acinetobacter.

UNCOMPLICATED GONORRHEA:

For treatment of uncomplicated gonorrhea, the Centers for Disease Control and Prevention (CDC) recommends ceftriaxone 125mg IM once plus a 7 day course of doxycycline for the presumptive concurrent infection with Chlamydia. This regimen has a greater than 95% cure rate for anal and genital infections while also achieving cure rates of- >90% for pharyngeal infections.

Another advantage for cefuroxime is it may also abort incubating syphilis, a concern when treatment is not accompanied by a 7 day course of doxycycline. Cefuroxime axetil orally as a single dose is considered an alternative regimen. However, a single dose of this shorteracting cephalosporin will not cover incubating syphilis nor C. trachomatis²⁰.

Clinical trials conducted using 1-1.5g single doses of cefuroxime axetil either alone or in combination with probenecid have produced cure rates of 96-100% in gonococcal genitorectal infections in both men and women²¹. However, these high cure rates were not achieved in patients with pharyngeal gonococcal infections, In comparative trials vs. amoxicillin plus probenecid, cefuroxime axetil was shown to be equally effective²². There have been no comparative trials between cefuroxime axetil and ceftriaxone^23,24.

UTIs:

The most commonly identified UTI pathogens include E. coli, K. pneumoniae, and P. mirabilis. Cefuroxime axetil has been shown to be effective against these urinary pathogens, but provides broader coverage than necessary for most uncomplicated UTIs. The antibiotic of choice for the treatment of acute uncomplicated UTIs is trimethoprim in combination with sulfamethoxazole (TMP/SMX) or amoxicillin. For patients with an allergy to these agents, cefuroxime axetil is an expensive alternative.

Several dosing regimens for treatment of UTIs have proved effective with cefuroxime axetil. In one clinical trial in non-pregnant women, single dose therapy with 1,000 mg resulted in a 88% clinical and bacteriological cure at week post-therapy²⁵, A slightly longer 3 day therapy trial with 125 mg twice daily had a similar efficacy, an 84.8% clinical cure²⁶. The more traditional 7 day therapy 125 mg twice daily resuited in a 97% bacteriological cure at 1 week post therapy²⁷.

CONCLUSIONS:

Cefuroxime axetil is a broad spectrum 13-1actam antibiotic. It has many approved indications, however, it is considered a second-line alternative. It is not the drug of choice for any infection, particularly those encountered in the field of obstetrics and gynecology. It is safe to use in pregnancy and has a low adverse effect profile, but due to its excessive acquisition cost and better therapeutic alternatives, it should be reserved for select cases.

CONFLICT OF INTEREST:

The author has no conflicts of interest regarding this article.

ACKNOWLEDGMENTS:

The author would like to thank Dr Dinesh Kaushik for their constant encouragement and kind support during the study.

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Received on 19.07.2023 Modified on 21.08.2023

Asian J. Pharm. Tech. 2023; 13(4):281-284.

DOI: 10.52711/2231-5713.2023.00050