Cefixime: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Cefixime is an orally administered cephalosporin with a broader antimicrobial spectrum than those of earlier oral cephalosporins, such as cephalexin and cefaclor. It is referred to as a third-generation oral cephalosporin, but its spectrum of activity is not quite as wide as that of other oral third-generation cephalosporins (e.g. cefpodoxime) or parenteral third-generation cephalosporins (e.g. cefotaxime) (The Medical Letter, 1989). Its molecular weight is 453. Its chemical structure is shown in Figure 29.1.

Although cefixime was not available in the USA from July 2002 to April 2008, cefixime 400-mg tablets are again available in this country [Centers for Disease Control and Prevention (CDC) 2008]. In some parts of the world (e.g. India), cefixime is available in combination with clavulanic acid. These novel combinations will not be discussed in detail here. Historically, the major usage of cefixime has been in oral treatment of gonorrhoea.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

A summary of the in vitro activity of cefixime is shown in Table 29.1.

Gram-positive aerobic bacteria

Cefixime has good activity against group A and B beta-hemolytic streptococci. However, Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and Listeria monocytogenes are resistant (Barry et al., 1994). Penicillin-susceptible pneumococci are typically susceptible to cefixime, but this is not universal (Barry et al., 1994). Just as is the case with related oxyiminocephalosporins (e.g. cefuroxime), over 20% of pneumococcal isolates can be cefiximeresistant (Kitayama et al., 1999). Pneumococci must be tested in vitro against these cephalosporins to assure susceptibility. Penicillin-resistant Streptococcus pneumoniae is typically cefixime resistant.

Gram-negative aerobic bacteria

Neisseria gonorrhoeae and Haemophilus influenzae are susceptible to cefixime (both beta-lactamase-positive and -negative strains) (Fluit et al., 2005). However, the MICs of cefixime are considerably higher against ampicillin-resistant H. influenzae strains which do not produce beta-lactamase [so-called beta-lactamase-negative ampicillin-resistant (BLNAR) strains] compared with those of ampicillin-susceptible strains (both positive and negative for beta-lactamase) (Jacobs and Bajaksouzian, 1997) (Table 29.1). H. parainfluenzae is also susceptible (Mendelman et al., 1989; Mortensen and Himes, 1990; Nash et al., 1991; Sader et al., 1993). The majority of Moraxella catarrhalis isolates now produce one of two different beta-lactamases, referred to as BRO- 1 and BRO-2. The majority of strains now produce BRO-1 enzyme. Cefixime is more active against isolates which produce BRO-2 enzyme (MIC 0.063 mg/ml) than those that produce BRO-1 (MIC 0.25 mg/ml) (Nash et al., 1991; Fung et al., 1994). Both Bordetella pertussis and B. parapertussis are moderately resistant (Hoppe and Mu¨ller, 1990).

Anaerobic bacteria

Gram-positive anaerobes such as Peptostreptococcus and Clostridium spp. are typically resistant to cefixime (Stone et al., 1989; Lehtonen and Huovinen, 1993; Sader et al., 1993). The activity of cefixime against Gram-negative anaerobes such as the Bacteroides fragilis group is poor (Table 29.1) (Stone et al., 1989; Sader et al., 1993).

Other bacteria

Borrelia burgdorferi is somewhat susceptible to cefixime (MIC 0.8 mg/ ml). However, against this spirochete, ceftriaxone is more active (MIC 0.02 mg/ml) (Agger et al., 1992).

b. Emerging resistance and cross-resistance

In 1999–2000, gonococci with reduced susceptibility to cefixime appeared in Japan, and three such isolates were identified in Hawaii in 2001 (Wang et al., 2003). Most of these isolates had cefixime MICs of 0.5 mg/l or greater. In 2000–2001, 17% of gonococci in Japan had reduced susceptibility to cefixime (Ameyama et al., 2002). In addition, increasing MICs of gonococci for ceftriaxone, cefixime, and cefdinir have been noted in Denmark, Australia, Brunei, China, and Papua New Guinea since 2004 (Newman et al., 2007). These isolates reached the western coast of the USA by late 2007 (Pandori et al., 2009).

c. In vitro synergy and antagonism

Cefixime has been combined with clavulanate in some parts of the world. This produces synergistic activity against ESBL-producing organisms but dose not enhance activity against AmpC producers (Rawat et al., 2009). Addition of clavulanate will not enhance cefixime activity against gonococci with altered PBPs. In vitro results support synergy for the combination of cefixime plus azithromycin against gonococci (Sathia et al., 2007). Potential synergic activity of combination cefixime + amoxicillin against pneumococci has been evaluated in checkerboard testing in vitro. In one study, in vitro synergy was noted in 17/42 (40%) penicillin-resistant isolates. Synergy was also noted in vivo in murine systemic and respiratory tract infection models (Matsumoto, 1998). In a study utilizing penicillin-sensitive, - intermediate and -resistant isolates, partial–complete synergy was noted in 71% (partial in 16/17, complete in 1/17) and an additive effect in 29%. Results were similar for intermediate and resistant isolates. These results were obtained with amoxicillin concentrations of 1 mg/l or less (Jones and Johnson, 1998).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Cefixime is only administered orally. The usual adult dosage is 400 mg once daily or 200 mg twice daily (Kiani et al., 1988; Verghese et al., 1990; Raz et al., 1994; Anonymous, 2007). For the treatment of uncomplicated gonorrhoea (urethritis, cervicitis, proctitis, pharyngitis), single-dose oral cefixime (400 mg) is recommended (Portilla et al., 1992; CDC, 1993). To complete a treatment course for disseminated gonococcal infection commenced with systemic ceftriaxone, 400 mg twice daily of cefixime should be given to complete a total course of 1 week (Anonymous, 2007). For Lyme borreliosis, 200 mg should be given once daily for 100 days with concurrent probenecid (500 mg three times daily) (Anonymous, 2007).

b. Newborn infants and children

The usual pediatric dosage is 8 mg/kg/day, administered once or twice daily (Piippo et al., 1991; Rodriguez et al., 1993; Anonymous, 2007). For the treatment of uncomplicated gonococcal infection, if the subject is at least eight years old and weighs at least 45 kg, the usual adult dosage regimen should be used (Anonymous, 2007).

c. Altered dosages

Impaired renal function

When creatinine clearance (CLCr) falls below 60 ml/min, the following dosage regimen adjustment is recommended: CLCr 21–60 ml/min and in patients undergoing hemodialysis (HD), 75% of the usual dose should be given once daily; CLCr r20 ml/min and in patients undergoing continuous ambulatory peritoneal dialysis (CAPD), 50% of the usual dose should be given at double the usual dosing interval (Anonymous, 2007).

Both HD and CAPD drug clearance is negligible. Thus, no supplemental doses need be administered to compensate for dialysis therapy (Anonymous, 2007).

Impaired hepatic function

No dosing information is available in this group.

The elderly

Oral bioavailability is increased in some elderly individuals compared with younger subjects but this is considered to be not clinically significant. Although Cmax and AUC are elevated in healthy elderly subjects compared with young volunteers, this is probably due to the reduced renal function common in older subjects rather than an effect of aging per se. No dosage adjustment is necessary for aging by itself.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The mean bioavailability by 12 hours after dosing is 31% (Healy et al., 1989; Duverne et al., 1992; Fassbender et al., 1993). Drug absorption obeys Michaelis–Menten pharmacokinetics, with a nonlinear rate and extent of absorption, and dose-dependent bioavailability. Absorption ceases approximately 6 hours after dosing (Liu et al., 1997). Cefixime is approximately 70% plasma protein bound (Fassbender et al., 1993). The mean terminal disposition half-life is 2.4–4.2 hours in healthy volunteers (Mamzoridi et al., 1996; Liu et al., 1997; Nix et al., 1997). b. Drug distribution
After oral administration of a 400 mg dose to adults, a Cmax ranging from 2.8 to 4.5 mg/l is achieved 3–5 hours after dosing (Mamzoridi et al., 1996; Liu et al., 1997; Nix et al., 1997). The serum concentration falls to approximately 1 mg/l at 12 hours after dosing and approaches zero at 24 hours. Multiple-dose administration of 400 mg once daily does not lead to drug accumulation.

c. Clinically important pharmacokinetic and pharmacodynamic features

Like other cephalosporins, cefixime is a time-dependent killer. Ison et al. (2004) have undertaken a pharmacodynamic analysis of cephalosporins versus contemporary strains of gonococci. They found that a 400 mg oral cefixime dose exceeded the MIC90 of gonococcal strains for more than 22 hours. In other words, the time above MIC was more than 90% of the dosing interval.

d. Excretion

The biliary tract is responsible for a small proportion of cefixime total body clearance. In patients with T-tube drainage after cholecystectomy, about 5% of the dose was eliminated via this route. In these patients, after a single 200 mg oral dose, the mean Cmax in bile was 57 mg/l. Drug was still present in the bile at 20 hours after dosing (4.3 mg/l) (Westphal et al., 1993). Between 15% and 21% of the administered dose is excreted renally as parent compound (Fassbender et al., 1993; Mamzoridi et al., 1996).

e. Drug interactions

Magnesium- and aluminum-containing antacid administration together with cefixime, or 2 hours before or 2 hours after, do not signi- ficantly alter serum cefixime concentrations (Healy et al., 1989). Co-administration of nifedipine considerably enhances the absorption of cefixime in humans (from 31% at baseline to 53% with nifedipine) (Duverne et al., 1992). This is probably due to calcium channel blocker-enhanced intestinal absorption owing to enhanced active transport via a pH-dependent dipeptide transporter similar to that seen with other beta-lactams.

TOXICITY

In general, hypersensitivity reactions occur in r5% of recipients of cefixime. Reactions include urticaria, pruritus, rash (maculopapular, erythematous, morbilloform), fever, chills, eosinophilia, edema, erythema, angioedema, shock, Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis. Cross-sensitivity rates with penicillin allergy are not well established but appear to be in the range of 5% to 16% (may be as low as 3% to 7%). Cefixime should be avoided if the penicillin allergy is manifested as anaphylaxis or is anaphylactoid or immediate dermatologic (urticarial) in nature (Anonymous, 2007).

In animals exposed to doses of this agent many-fold higher than those utilized in humans, no fetotoxicity or impaired fertility has been seen. There have been no reports of fetotoxicity in humans(Anonymous, 2007).

Gastrointestinal symptoms, such as nausea, vomiting and, in particular, diarrhea, appear to be the main adverse effects of cefixime. In some patients, the diarrhea can be severe and can be secondary to C. difficile (Kiani et al., 1988; Nord et al., 1988; Verghese et al., 1990; Piippo et al., 1991; Gremse et al., 1994). In a volunteer trial, 400 mg of oral cefixime was given to six subjects once daily for 10 days. In five of six volunteers, C. difficile was detected. The strains of C. difficile differed from one volunteer to another (Chachaty et al., 1992). These findings were confirmed in a later study using 51 volunteers (Chachaty et al., 1993).

CLINICAL USES OF THE DRUG

a. Gonorrhoea

Single-dose cefixime 200–800 mg has been used successfully for the treatment of uncomplicated gonorrhoea (Dunnett and Moyer, 1992; Verdon et al., 1993; Hook et al., 1997; Aplasca De Los Reyes et al., 2001; Ramus et al., 2001; McMillan and Young, 2007). The 400 mg oral dose of cefixime does not provide as high, nor as sustained, a bactericidal level as that provided by the 125-mg dose of ceftriaxone (Workowski and Berman, 2006).

b. Acute bacterial exacerbations of chronic bronchitis

The results of cefixime treatment were good, but not superior, to those obtained with oral amoxicillin (Kiani et al., 1988). In one trial, 86 patients were randomized to receive 14 days of therapy with either 400 mg once-daily oral cefixime or 250 mg four times daily oral cephalexin. Clinical cure rates were 71% in the cefixime group and 50% in the cephalexin group (po0.05).

c. Community-acquired pneumonia

An open-label noncontrolled trial plus an open-label, randomized trial of roxithromycin versus cefixime support the efficacy of cefixime in adults with this clinical entity (Ludwig, 1998; Salvarezza et al., 1998). Cefixime has also been compared with amoxicillin–clavulanate as follow-up therapy after ceftriaxone for pneumonia in pediatric patients (Amir et al., 1996). However, cefixime lacks coverage of atypical organisms and many strains of S. pneumoniae and must be regarded as a second-line agent for community-acquired pneumonia.

d. Acute bacterial sinusitis

A single open-label noncontrolled trial found a 100% clinical cure/ improvement rate in 45 pediatric subjects (8 mg/kg once daily for 5–10 days) (Ludwig, 1988). Cefixime should be regarded as a second-line agent for this condition.

e. Pharyngitis and tonsillitis

An open-label randomized trial found similar clinical and bacteriologic response rates for cefixime (8 mg/kg once daily for 10 days), azithromycin (12 mg/kg once daily for 5 days), and amoxicillin– clavulanate (90 mg/kg/day for 10 days) in pediatric patients with streptococcal pharyngotonsillitis (Rush and Simon, 2003).

f. Otitis media

Cefixime in a dose of 8 mg/kg/day for 7–10 days was effective in an uncontrolled study of this disease in children (Ludwig, 1998). In two studies, its efficacy was about the same as that of cefaclor 40 mg/kg/day given in three divided doses (Piippo et al., 1991; Rodriguez et al., 1993) whereas in another two studies, it was about the same as that of amoxicillin–clavulanate (Gooch et al., 1997; Dabernat et al., 1998).

g. Urinary tract infections

Two open-label noncontrolled trials in uncomplicated and complicated UTIs in adults have shown efficacy of cefixime (Asvanich et al., 1998; Ludwig, 1998). In one randomized study, cefixime 400 mg once daily and oral ofloxacin 200 mg 12-hourly, both given for 3 days, were equally effective in the treatment of uncomplicated UTIs in women (Raz et al., 1994). Two studies in children support the efficacy of cefixime monotherapy compared with that of sequential therapy with i.m. ceftizoxime (for 2 days) or i.v. cefotaxime (for 3 days) followed by cefixime (Hoberman et al., 1999; Gok et al., 2001).

h. Gastrointestinal infections

In a clinical trial evaluating typhoid fever therapy in children, oral cefixime 5 mg/kg 12-hourly for 14 days appeared as effective as i.v. ceftriaxone (Bhutta et al., 1994). In contrast, oral ofloxacin for 5 days was clinically superior to cefixime for 7 days as typhoid fever therapy in children (Cao et al., 1999). In addition, a comparative trial in children found azithromycin and cefixime to be clinically indistinguishable from placebo in the treatment of uncomplicated salmonella enteritis (Chiu et al., 1999).

i. Augmentation of irinotecan

Oral cefixime co-therapy ameliorates the diarrhea seen with i.v. irinotecan and allows the oral use of this poorly bioavailable drug, producing systemic exposures similar to those seen with the i.v. formulation. Cefixime is thought to suppress beta-glucuronidase producing aerobes in the gut that deglucuronidate SN-38 glucuronide in the intestine to the active (and GI-toxic) metabolite SN-38.

j. Other uses

Oral cefixime has been used to lower the risk of febrile neutropenic sepsis in children with cancer and sickle cell disease (Williams et al., 1996; Paganini et al., 2000; Shenep et al., 2001).

Limited studies have assessed the efficacy of cefixime in the treatment of Lyme disease. Oksi et al. (1998) compared 30 patients who received oral cefixime 200 mg combined with probenecid 500 mg three times daily for 100 days to another group of 30 patients who received i.v. ceftriaxone 2 g daily for 14 days followed by oral amoxicillin 500 mg combined with probenecid 500 mg three times daily for 100 days. There was no statistically significant difference in the outcome of infection between the two groups. However, the total number of patients with relapses or no response at all and the number of positive PCR findings after therapy were greater in the cefixime group.

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