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

Cefaclor is orally administered second-generation cephalosporins. Cefaclor is similar in many aspects to cephalexin, but differs by being more active in vitro against a number of Gram-negative bacteria (Bill and Washington, 1977).
The chemical structures of cefaclor is shown in Figure 21.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro activity of cefaclor and cefprozil is summarized in Table 21.1.

Gram-positive aerobic bacteria

All of these cephalosporins lack activity against methicillin-resistant Staphylococcus aureus (MRSA), enterococci (Preston, 1979), and Listeria monocytogenes.

Cefaclor is more active than cephalexin against most streptococci, but against S. aureus it is not as active. This is because the drug is somewhat less resistant to staphylococcal beta-lactamase than cephalexin (Bill and Washington, 1977; Tally et al., 1979).

Cefprozil is active against S. aureus, including beta-lactamaseproducing strains. S. epidermidis is typically susceptible to cefprozil, but S. haemolyticus and S. hominis are often resistant. Streptococcus pyogenes and groups B, C, F, and G streptococci are susceptible. S. pneumoniae is quite susceptible to cefprozil and penicillin-resistant strains tend to have a lower MIC of cefprozil than penicillin. S. viridans is typically susceptible, but strains with high-level penicillin resistance are also cefprozil resistant (MIC 32 mg/ml).

Gram-negative aerobic bacteria

All of these cephalosporins lack activity against Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, extendedspectrum beta-lactamase-producing Enterobacteriaceae, and AmpC hyper-producing Enterobacteriaceae (Neu and Fu, 1978; Preston, 1979).

Cefaclor is more active than cephalexin against many wild-type Gram-negative bacteria, such as meningococci, gonococci, E. coli, Klebsiella pneumoniae, and Proteus mirabilis (Sanders, 1977; Scheld et al., 1977; Gillett et al., 1979). Ampicillin-susceptible strains of H. influenzae, and most which are ampicillin resistant because of betalactamase production, are susceptible to cefaclor. Most strains which show intrinsic resistance to ampicillin (so-called BLNAR strains) are cefaclor resistant (Powell and Williams, 1988; Powell et al., 1991; Picard and Malouin, 1992). Moraxella catarrhalis is usually cefaclor susceptible.

Anaerobic bacteria

The Bacteroides fragilis group are usually resistant to these cephalosporins (Bach et al., 1978). Anaerobic Gram-positive cocci and some Gram-negative anaerobes (other than those of B. fragilis group) may be cefaclor susceptible.

Among Gram-positive anaerobes, the peptostreptococci and Clostridium spp. are susceptible to cefrozil. Clostridium difficile, with an MIC of 4–8 mg/ml, is also moderately cefprozil susceptible, but the clinical significance of this is not known (Chin and Neu, 1987; Eliopoulos et al., 1987; Kayser, 1987; Leitner et al., 1987; Mazzulli et al., 1990; Thornsberry, 1992; Barry et al., 1994). Among Gram-negative anaerobes, the Prevotella spp. such as P. melaninogenica and Fusobacterium spp. may be sensitive, but other Bacteroides spp., and in particular B. fragilis, are resistant (Chin and Neu, 1987; Eliopoulos et al., 1987; Leitner et al., 1987; Scribner et al., 1987; Arguedas et al., 1991; Thornsberry, 1992; Goldstein et al., 1995).

b. Emerging resistance and cross-resistance

Broader spectrum beta-lactamases such as extended-spectrum betalactamases, AmpC beta-lactamases, and metallo-beta-lactamases will lead to resistance to these cephalosporins.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Oral doses of 250–500 mg 6-hourly are suitable for adults (Korzeniowski et al., 1977). An adult dosage of 0.5 g 8-hourly is also satisfactory (Wernstedt et al., 1979). Cefaclor in a dose of 2 g can be used for singledose treatment of acute uncomplicated urinary tract infections in adults (Greenberg et al., 1981).

b. Newborn infants and children

In children the dosage is 40–50 mg/kg body weight per day, given in three or four divided doses (McCracken et al., 1978; Rodriguez et al., 1979). For the treatment of milder infections in children, a dosage of 40 mg/kg, given in two divided doses, is also satisfactory (Ede`n et al., 1983).

Altered dosages

Impaired renal function

Although cefaclor’s half-life in normal subjects is 40–60 minutes it increases to only 3 hours in anephric patients (Levison et al., 1979). As a result, dosage reduction is only necessary when the creatinine clearance is less than 40 ml/min (Bloch et al., 1977; Santoro et al., 1978). Patients with severe renal failure should receive 25% of the usual dose, and those with moderate renal failure 50% of the usual dose. Cefaclor is removed from the body by hemodialysis (Gartenberg et al., 1979). During this procedure its clearance is doubled and approximates to that which occurs in a patient with a creatinine clearance of about 20 ml/min; after hemodialysis, the usual cefaclor dose should be repeated (Spyker et al., 1982).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Food intake reduces the maximum concentration of cefaclor in the serum and prolongs the time to attain this concentration. However, the area under the concentration–time curve and urinary recovery of the drug are unaffected (Oguma et al., 1991). The drug is approximately 50% serum protein bound (Tally et al., 1979).

b. Drug distribution

Cefaclor is rapidly absorbed from the gastrointestinal tract. After a 200 mg oral dose, the mean peak serum level at 1 hour is 6 mg/ml, which falls to 0.33 mg/ml at 4 hours. Cefaclor’s half-life is 0.58 hours (Korzeniowski et al., 1977). The serum half-life of cefaclor in patients with severe renal failure is only about 3 hours, which suggests that it is also eliminated by nonrenal mechanisms (Glynne et al., 1978; Rotschafer et al., 1982).

Cefaclor diffuses readily into soft-tissue interstitial fluid (Waterman and Scharfenberger, 1978). Its concentration in sputum is usually low, and it is not excreted in saliva (Levison et al., 1979). Cefaclor attains therapeutically effective concentrations in middle ear fluid of patients with otitis media (Ede`n et al., 1983).

c. Clinically important pharmacokinetic and pharmacodynamic features 

Like other cephalosporins, these drugs exert a time-dependent bactericidal activity.

d. Excretion

Approximately 70% of an orally administered dose can be recovered from urine as the active drug during the first 6 hours. During this period, after a 250 mg oral dose, urine concentrations are in the range 50–1000 mg/ml. Urinary levels of cefaclor are adequate to inhibit susceptible pathogens, even in patients with moderately severe renal failure (Santoro et al., 1978). The serum half-life is only prolonged about 3-fold in patients with essentially no renal function. This indicates that cefaclor has a major nonrenal route of elimination. A considerable proportion of the drug is metabolized in the body (Levison et al., 1979; Rotschafer et al., 1982). In animals, cefaclor is also excreted via the bile, and biliary concentrations greatly exceed serum levels (Waterman and Scharfenberger, 1978).

TOXICITY

a. Cefaclor

Therapy with this drug has been associated with a low frequency of side-effects. Gastrointestinal symptoms, such as diarrhea and nausea, have occurred in about 2.6% of treated patients. Cefaclor has only a minor effect on the anaerobic intestinal microflora (Nord et al., 1987).

Hypersensitivity phenomena, such as allergic rashes, have been noted in 1.55% of patients (Kammer and Short, 1979). Eosinophilia, positive Coombs’ test without hemolysis, reversible leukopenia, and elevated transaminases have also been noted occasionally. Muray et al. (1980) reported eight children who developed a severe generalized rash and arthritis while taking oral cefaclor; six were taking the drug for the second time. Symptoms subsided within 4–5 days after cefaclor was stopped. Such serum sickness-like reactions appear to occur more commonly with cefaclor than with cephalexin (Platt et al., 1988).

These reactions occur with cefaclor because of the drugs biotransformation in the liver to immunogenic metabolites (Boguniewicz and Leung, 1995). Serious nephrotoxicity has not been observed with cefaclor (Kammer and Short, 1979).
Pneumococcal meningitis developed in a child treated for otitis media with cefaclor (Raucher et al., 1982). Thus, cefaclor, like some other cephalosporins, should be used with great caution for infections which may be complicated by bacterial meningitis.

CLINICAL USES OF THE DRUG

In general, the use of these oral cephalosporins is limited to treatment of relatively mild infections.

a. Cefaclor

This drug has been satisfactory for the treatment of urinary tract infections, including cases of complicated and/or recurrent infections. Pyelonephritis caused by ampicillin-resistant organisms, such as Klebsiella spp., also responds to cefaclor (Kammer and Short, 1979; Lindan, 1979). Uncomplicated urinary tract infections in nonpregnant women may respond to 2 g single-dose cefaclor therapy (Greenberg et al., 1981). A single daily dose of 250 mg cefaclor has been used as a prophylactic antibiotic for patients with recurrent urinary infections (Brumfitt and Hamilton-Miller, 1990).
Cefaclor has been curative for children and adults with acute streptococcal pharyngitis (Stillerman, 1986; Peter, 1992), otitis media, and maxillary sinusitis. In children with acute otitis media, it is about as effective as amoxicillin (Giebink et al., 1984; Mandel et al., 1993). It is effective in otitis media and sinusitis caused by beta-lactamaseproducing strains of H. influenzae and M. catarrhalis (Bluestone et al., 1979; McLinn, 1980; Ekedahl, 1983; Wald et al., 1984; Bluestone, 1992).

 Cefaclor is ineffective for eradicating H. influenzae from pharyngeal carriers (Horner et al., 1980). It is about equally as effective as amoxicillin for the treatment of infective exacerbations of chronic bronchitis (Mattson et al., 1979; Law et al., 1983). In a small group of patients, Maeson et al. (1990) found low-dosage cefaclor unsatisfactory for chronic bronchitis. Oberlin and Hyslop (1990) analyzed data from 18 clinical studies and concluded that cefaclor had been successful as treatment of upper and lower respiratory tract infections caused by M. catarrhalis.

References

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