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

Cephalexin (also spelt cefalexin) is a semisynthetic first-generation cephalosporin antibiotic intended for oral administration. Cephalexin was the first oral cephalosporin introduced for clinical use in 1969. It is 7-(D-a-amino-a-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate. Cephalexin has the molecular formula C16H17N3O4S  H2O and the molecular weight is 365.41; cephalexin’s chemical structure is illustrated in Figure 19.1.

The nucleus of cephalexin is related to that of other cephalosporin antibiotics. Cephalexin has a D-phenylglycyl group as substituent at the 7-amino position and an unsubstituted methylgroup at the 3-position. The compound is a zwitterion; i.e. the molecule contains both a basic and an acidic group. The isoelectric point of cephalexin in water is approximately 4.5–5.

The crystalline form of cephalexin is a monohydrate. It is a white crystalline solid with a bitter taste. Solubility in water is low at room temperature; 1 or 2 mg/ml may be dissolved readily, but higher concentrations are obtained with increasing difficulty. Each capsule contains cephalexin monohydrate equivalent to 250 mg (720 mmol) or 500 mg (1439 mmol) of cephalexin. Figure 19.1 Chemical structure of cephalexin.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The antibacterial spectrum of cephalexin resembles that of other first-generation cephalosporins, such as cephalothin or cephazolin (Muggleton et al., 1968; see Chapter 18, Cephalothin and Cefazolin). Table 19.1 summarizes in vitro susceptibility.

Gram-positive aerobic bacteria

Cephalexin is active against common Gram-positive organisms causing uncomplicated skin and soft-tissue infection, although the advent of methicillin-resistant Staphylococcus aureus (MRSA) in the community has compromised its overall activity. Cephalexin has good activities against Streptococcus pyogenes (MIC of 0.12–1 mg/ml) (Jones and Sader, 2006) viridans streptococci (Alcaide et al., 1995) and S. agalactiae (Sader et al., 2004). Methicillin-susceptible S. aureus (MSSA) still maintains its susceptibility to cephalexin (MIC 1–16 mg/mL) (Jones and Sader, 2006); the 2009 Clinical Laboratory Standards Institute (CLSI) MIC breakpoint for MSSA is r8 mg/ml for susceptible, 16 mg/ ml for intermediate, and Z32 mg/ml for resistant. MRSA strains are resistant to cephalexin with MICs of W16 mg/ml (Jones and Sader, 2006; CLSI, 2009).

The activity based on the MIC50s and MIC90s for S. pneumoniae for cephalexin is the poorest among oral cephalosporins. S. pneumoniae generally has become resistant to cephalexin with a reported MIC50 of 64 and MIC90 of 128 mg/ml or higher in some centers (Hsueh et al., 2004); although some strains are still susceptible. The CLSI has not determined an MIC breakpoint of cephalexin for S. pneumoniae. (CLSI, 2009).

Gram-negative aerobic bacteria

Over the years, the activity of cephalexin against major Gram-negative bacilli, such as Escherichia coli and Klebsiella pneumoniae, has diminished. The 2009 CLSI MIC breakpoint for Enterobacteriaceae is r8 mg/ml for susceptible, 16 mg/ml for intermediate, and Z32 mg/ml for resistant. 

Anaerobic bacteria

Anaerobic Gram-positive cocci, such as the Peptococcus and Peptostreptococcus spp., are usually moderately sensitive. Most strains recovered from airway associated infections are inhibited by 8–16 mg/ml. Other strains are resistant, needing 64 mg/ml or higher for inhibition (Tally et al., 1975; Busch et al., 1976).

Anaerobic Gram-positive rods, such as Clostridium perfringens, C. tetani, and other Clostridium spp., are relatively resistant. Some strains may be inhibited by 8–16 mg/ml cephalexin, but others need 32–64 mg/ml, or even higher, for inhibition (Tally et al., 1975). Other bacteria Mycoplasma and mycobacteria are cephalexin-resistant. Cephalexin is inactive against B. burgdorferi in vitro and would not be predicted to be clinically effective in the treatment of Lyme disease (Nowakowski et al., 2000).

b. Emerging resistance and cross-resistance

S. aureus is a common pathogen in uncomplicated skin and soft-tissue infections, such as cutaneous abscesses, furuncles, and carbuncles. Long-standing recommended treatment for uncomplicated skin and soft-tissue infections is incision and drainage of purulent lesions and blactam antibiotics, such as cephalexin, as first-line antibiotic therapy.
However, community-acquired methicillin-resistant S. aureus (CAMRSA) has become an increasingly common pathogen (Moran et al., 2006). 

c. In vitro synergy and antagonism

Synergy and antagonism has been rarely studied with cephalexin and is of little clinical importance to its current usage.

MECHANISM OF DRUG ACTION

Cephalexin, similar to penicillin and other cephalosporins, is mainly bactericidal. It inhibits the third and final stage of the synthesis of bacterial cell walls by preferentially binding to specific penicillinbinding proteins (PBPs) that are located inside the bacterial cell wall.

PBPs are responsible for several steps in the synthesis of bacterial cell wall and are found in quantities of up to several thousand molecules per bacterial cell. Its ability to interfere with PBP-mediated lysis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (Curtis et al., 1979).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Cephalexin is administered orally. A parenteral form is not generally available but has been used for investigational purposes. The adult dosage for oral administration ranges from 1 to 4 g daily in divided doses. The usual adult dose is 250–500 mg every 6 hours. For milder infections, such as streptococcal pharyngitis, skin and skin-structure infections, and uncomplicated cystitis in patients over 15 years of age, cephalexin may be given at a dose of 500 mg 12-hourly (Kumar et al., 1988).

b. Newborn infants and children

The usual recommended daily dosage for pediatric patients is 25– 50 mg/kg in divided doses. For streptococcal pharyngitis in patients over one year of age and for skin and skin structure infections, the total daily dose may be divided and administered every 12 hours. It can be given up to 100 mg/kg/day in moderate to severe infection. There are currently no data regarding the safety of cephalexin use in premature neonates.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cephalexin is almost completely absorbed after oral administration (Meyers et al., 1969). Cephalexin absorption is unimpaired in patients with obstructive jaundice, achlorhydria, partial gastrectomy, and congestive cardiac failure. There is no impairment of absorption in patients with celiac disease, small bowel diverticulosis and cystic fibrosis, but absorption is slightly impaired in those with Crohn’s disease (Davies and Holt, 1975; Rubio, 1986).Cephalexin is about 15% serum protein bound (Kind et al., 1968).

b. Drug distribution

Following a 250 or 500 mg oral dose of cephalexin, average peak serum concentrations of 9 or 15–18 mg/l respectively, are achieved within 1 hour. Mean serum concentrations decline to 1.6 or 3.4 mg/l after 250- or 500-mg doses, respectively, at 3 hours post dose (Griffith and Black, 1970). Probenecid prolongs and enhances serum levels. The above serum levels are attained after oral administration of the usual cephalexin preparation, cephalexin monohydrate. Cephalexin hydrochloride has also been made available. This is more rapidly absorbed, and serum levels at 15 and 30 minutes after dosing are higher than those attained by the monohydrate. The peak serum level and the area under the curve is the same as those attained with the monohydrate. Clinically, both preparations have the same efficacy (Kumar et al., 1988). Both preparations are available in some markets.

c. Clinically important pharmacokinetic and pharmacodynamic features

Time above the MIC is the pharmacokinetic–pharmacodynamic parameter that correlates with the therapeutic efficacy of the various b-lactam antibiotics, including cephalexin. In vivo bacteriostatic effect was observed when serum levels were above the MIC for 30–40% of the dosing interval, whereas maximum killing was approached when levels were above the MIC for 60–70% of the time (Craig, 1998; Craig, 2003).

d. Excretion

Cephalexin is excreted in urine in an active, unchanged form by glomerular filtration and tubular secretion. Seventy percent to 100% of the dose is found in the urine 6–8 hours after each dose. Concentrations of cephalexin of 500–1000 mg/l in urine follow 250–500 mg oral doses of cephalexin, many times greater than the minimum inhibitory concentration for the usual urinary tract pathogens (Griffith, 1983). As noted earlier, cephalexin accumulates in patients with impaired renal function. In normal subjects, the mean serum half-life is 0.9 hours, but in patients with severe renal function impairment it increases to 20–30 hours (Kabins et al., 1970). Less than 1% of cephalexin is excreted in bile. After repeated doses, moderately high cephalexin levels (15–90 mg/l) are attained in gallbladder bile, provided that the gallbladder is functioning normally. Biliary levels are much lower in patients with nonfunctioning gallbladders, and in the presence of complete biliary obstruction no cephalexin is excreted in bile (Sales et al., 1972).

Cephalexin is not metabolized or inactivated in the body (Griffith and Black, 1971).

e. Drug interactions

Probenecid delays excretion by partially blocking renal tubular secretion (Braun et al., 1968; Griffith and Black, 1971). Some clinicians use this to increase drug concentrations in the body. Patients receiving acid suppressive therapy (histamine-2 receptor antagonists) tended to have a higher rate of failure with cephalexin therapy. The hypothesized interaction between histamine-2 receptor antagonists and cephalexin involves delayed absorption and an alteration in antimicrobial pharmacodynamics (Madaras-Kelly et al., 2004). Concomitant administration of cholestyramine reduces cephalexin absorption, and therefore these two drugs should not be administered simultaneously (Parsons et al., 1975; Parsons and Paddock, 1975).

TOXICITY

a. Gastrointestinal side-effects

As with all other oral cephalosporin, gastrointestinal disturbances is one of the most commonly reported side-effects. Diarrhea, vomiting, and abdominal cramps occur in some patients receiving oral cephalexin therapy. This class of reaction is reported to occur in less than 5% of patients. According to Bartlett et al. (1979), pseudomembranous colitis (due to C. difficile) is not a rare complication of oral cephalosporin therapy. They reported five patients who developed C. difficile colitis after receiving oral cephalexin as a single drug, and two others who had received cephalexin plus one of the parenteral cephalosporins.

b. Hypersensitivity reactions

Skin rashes and eosinophilia have been observed in cephalexin-treated patients. Serum sickness can also occur but seems relatively rare (Platt et al., 1988). Cephalexin caused toxic epidermal necrolysis in one patient (Dave et al., 1991). It has been assumed that cephalexin is not cross-allergenic with the penicillins, and some publications suggest that 91–94% of patients with a history of penicillin allergy do not react to cephalexin or cephalothin (Dash, 1975). Nevertheless, cephalexin should be avoided in patients with anaphylaxis or urticaria developing after administration of penicillin, cephalosporins or other beta-lactam antibiotics.

c. Nephrotoxicity

This has been rare with oral cephalexin (Kabins et al., 1970). The drug does not aggravate pre-existing renal disease (Kunin and Finkelberg, 1970). Hematuria and eosinophilia occurred in two patients with bacterial endocarditis who were treated with very high oral cephalexin doses (20 or 24 g per day plus probenecid); one patient also developed a transient elevation of serum creatinine. All abnormalities disappeared when cephalexin was ceased (Verma and Kieff, 1975).

d. Hematologic side-effects

A positive Coombs’ test has been reported with cephalexin therapy (Erikssen et al., 1970). The clinical significance of this is not clear – Coombs’ positive hemolytic anemia is rare. Forbes et al. (1972) described a 14-year-old patient with hemophilia who developed severe intravascular hemolysis 9 days after starting cephalexin in a dose of 2 g daily. Hemolysis ceased after cephalexin was stopped. Other less commonly reported side-effects are reversible neutropenia, eosinophilia, and thrombocytopenia (Mitropoulos et al., 2007).

e. Neurotoxicity

Cephalexin may occasionally cause central nervous system disturbances. Diplopia, headache, tinnitus, and ataxia occurred in one patient; these symptoms gradually disappeared within 2 weeks of cessation of the drug (Erikssen et al., 1970). Similar symptoms were observed in another patient by Kind et al. (1968). If very high serum levels of cephalexin are reached, convulsions and coma may result. Saker et al. (1973) described a patient with severe renal disease treated with cephalexin who developed a grand mal seizure which was followed by disorientation lasting for over 1 week. The drug was given in a dose of 2 g daily, and its serum level before the seizure was 120 mg/ml.

f. Hepatotoxicity

Modest elevation of serum transaminases concentration has been reported (Mitropoulos et al., 2007).

g. Use in pregnancy

Cephalexin has been administered as early as the second month of pregnancy without evidence of fetal damage (Goodspeed, 1975).

CLINICAL USES OF THE DRUG

The clinical effectiveness and favorable adverse effect profile of cephalexin has allowed the drug to have a continued place in therapy for over 40 years. However, the emergence of CA-MRSA infection has raised speculation as to the ongoing role of cephalexin as a first choice antibiotic.

a. Skin and soft-tissue infection

Cephalexin has long been used for skin and soft-tissue infection, given its activity against S. pyogenes and S. aureus. A number of studies have evaluated its effectiveness in the context of the worldwide increase in CA-MRSA. Ruhe and colleagues have shown that use of a microbiologically inactive antibiotic (such as cephalexin) was an independent predictor of treatment failure for CA-MRSA skin and soft-tissue infections (Ruhe and Menon, 2007; Ruhe et al., 2007).

b. Genito-urinary tract infection

Increasing resistance of E. coli to this agent has limited the use of cephalexin for the treatment of cystitis, although the high urinary concentrations which are achieved may allow it to retain effectiveness for uncomplicated infection (Warren et al., 1999). A 7-day regimen of cephalexin should be regarded as a second-line agent for acute cystitis. Cephalexin can also be used during pregnancy (Nicolle, 2002; Colgan et al., 2006). Its use is not recommended for the initial treatment of severe cystitis or acute pyelonephritis.

c. Respiratory tract infection

Cephalexin is active against S. pyogenes and provides effective therapy in streptococcal pharyngitis. It has poor activity against penicillinresistant pneumococci, H. influenzae and M. catarrhalis, and is not recommended for empirical treatment of sinusitis, otitis media, and lower respiratory tract infections such as pneumonia (Schentag and Tillotson, 1997; Appelbaum, 2002; Slavin et al., 2005; Mandell et al., 2007).

d. Bone and joint infection

Cephalexin can be used as sequential therapy in the treatment of hematogenous ostoemyelitis in children (Peltola et al., 1997). In one retrospective study involving 39 children with acute osteomyelitis, cephalexin was successfully used as a sequential oral antibiotic. It was given for a median of 28 days (range 14–42 days). At the six-month follow-up, no failures or complications were noted (Bachur and Pagon, 2007). For adult patients, there are no data on utility of sequential therapy with cephalexin.

e. Acute lymphadenitis

Generally, treatment is not usually necessary for acute bilateral lymphadenitis, which most frequently is related to a self-limited viral illness. On the other hand, acute unilateral cervical lymphadenitis is often caused by S. aureus or S. pyogenes. In a mild to moderately ill child, empirical treatment with cephalexin (25–100 mg/kg/day (p.o.) divided every 6 to 8 hours, maximum dose 4 g/day) is recommended (Al-Dajani and Wootton, 2007). Cephalexin is not recommended for initial therapy in severely ill children, especially in areas where CAMRSA is prevalent. The total length of therapy of cephalexin is usually 10–14 days.

f. Prophylaxis for infective endocarditis

Recent guidelines on the prevention of infective endocarditis by the American Heart Association published in 2007 (Wilson et al., 2007) have come out with major changes in the updated recommendations. Cephalexin plays a part in these recommendations.

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