Cefotaxime: Antimicrobial Activity, Susceptibility, Administration and Dosage, Pharmacokinetics etc.

Cefotaxime is referred to as a third-generation or extended-spectrum cephalosporin. It was developed in the 1970s and was approved by the US Food and Drug Administration (FDA) in 1981 (Lo and Friedman, 2002). The spectrum of activity of cefotaxime is substantially the same as that of ceftriaxone. Owing to differences in the frequency of dosing (ceftriaxone is typically administered once daily, whereas cefotaxime is usually given three times per day), the use of cefotaxime has been comparatively less than that of ceftriaxone. Both of these drugs have been regarded by many clinicians as ‘‘workhorse’’ therapy in both community-acquired and hospital-acquired infections. Cefotaxime retains excellent activity against many common community-acquired pathogens (for example, Streptococcus pneumoniae and Haemophilus influenzae) – however, its activity against the Enterobacteriaceae has diminished in recent years owing to the proliferation of beta-lactamases such as the extended-spectrum beta-lactamases (ESBLs). Cefotaxime does not have substantial activity against methicillinresistant Staphylococcus aureus (MRSA), enterococci, Pseudomonas aeruginosa, or most anaerobic organisms.

Cefotaxime is (6R,7R)-3-(acetyloxymethyl)-7-[[2-(2-amino-1,3- thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicy-clo [4.2.0]oct-2-ene-2-carboxylic acid; its formula is C16H17N5O7S2 and molecular weight is 455.4650; the chemical structure of cefotaxime is shown in Figure 26.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro activity of cefotaxime against wild-type organisms (those which lack acquired or mutational resistance mechanisms) is summarized in Table 26.1.

Gram-positive cocci

Cefotaxime is highly active against most aerobic Gram-positive organisms, with the exception of enterococci and related species. There is exquisite activity against streptococci (including S. pneumoniae and S. pyogenes) with MICs90 0.032 mg/ml or less (Table 26.1).

Cefotaxime is active against staphylococci (MICs90 2 mg/ml) with the exception of methicillin-resistant strains. Anaerobic Gram-positive cocci such as Peptococcus and Peptostreptococcus are typically susceptible to cefotaxime (Rolfe and Finegold, 1981; Lee et al., 1996; Aldridge and Johnson, 1997). The in vitro activity of cefotaxime against common Gram-positive pathogens is summarized in Table 26.2.

Gram-positive bacilli

Proprionibacterium acnes (Smith et al., 1986) are susceptible to cefotaxime. In a study of just four isolates of Actinomyces, all organisms had a cefotaxime MIC r4 mg/ml (Rolfe and Finegold, 1981).

Gram-negative cocci

Cefotaxime is exquisitely active against wild-type strains of Neisseria gonorrhoeae and N. meningitidis with MIC90s 0.016 mg/ml or less (Table 26.1). The antibiotic is also highly active against Moraxella catarrhalis (Zhanel et al., 2003).

Gram-negative bacilli

Cefotaxime is highly active against H. influenzae with MIC90s 0.032 mg/ ml or less (Table 26.1). Wild-type strains of the Enterobacteriaceae (i.e. those lacking ESBLs or having mutational hyperproduction of the AmpC beta-lactamase) are also typically susceptible to cefotaxime.

Other organisms

The leptospirae are susceptible to cefotaxime – in fact, the MICs and MBCs of cefotaxime against these organisms are lower than those of penicillin (Oie et al., 1983; Murray and Hospenthal, 2004). Chlamydia trachomatis and Chlamydophila pneumoniae are resistant to cefotaxime (Hammerschlag and Gleyzer, 1983; Bostock et al., 2004). In general, the rickettsiae are also resistant to cefotaxime. Borrelia burgdorferi is susceptible in vitro to cefotaxime (MIC90 = 0.12 mg/ml) (Mursic et al., 1987).

Activity of desacetylcefotaxime

Cefotaxime is metabolized to 3-desacetylcefotaxime. The antibacterial activity of desacetylcefotaxime is 4- to 8-fold less than that of cefotaxime (Jones et al., 1982; Neu, 1982a). Desacetylcefotaxime does not inhibit many strains of Morganella, most strains of P. aeruginosa, some strains of S. marcescens, some strains of Providencia, and many strains of B. fragilis at clinically achievable concentrations (Jones et al., 1982). Cefotaxime and desacetylcefotaxime act synergistically against many bacteria, so that the presence of the metabolite often increases rather than decreases the activity of cefotaxime (Wise et al., 1980a; Jones et al., 1982; Neu, 1982a).

b. Emerging resistance and cross-resistance

Gram-positive cocci

Isolates of S. pneumoniae which have diminished susceptibility to penicillin may have diminished susceptibility to cefotaxime (see Table 26.2). Virtually all isolates of S. pneumoniae which are penicillin susceptible (using a definition of r0.06 mg/ml as penicillin susceptible) are cefotaxime susceptible (cefotaxime MIC range 0.016–0.12 mg/ml) (Jones et al., 2002; Kosowska et al., 2005). Most studies have shown that fewer than 3% isolates which are penicillin-intermediate (using a definition of MIC 0.1–1 mg/ml as penicillin-intermediate) lack cefotaxime susceptibility (Jones et al., 2000; Jones et al., 2002; Kosowska et al., 2005). In a large evaluation of penicillin-resistant strains (defined as penicillin MIC Z2 mg/ml), 76.7% remained cefotaxime susceptible, 15.0% were cefotaxime intermediate and 8.3% were cefotaxime resistant (Jones et al., 2002).

Gram-negative cocci

Cefotaxime has largely retained susceptibility against N. meningitidis, even in the presence of reduced penicillin susceptibility (cefotaxime MIC90 0.007 mg/ml, range r0.0015–0.03 mg/ml) (Jorgensen et al., 2005). On the basis of pharmacodynamic studies, an appropriate breakpoint for cefotaxime against N. meningitidis in the cerebrospinal fluid (CSF) is r0.06 mg/ml (based on dosing of cefotaxime 2 g every 8 hours i.v. (Burgess et al., 2007). Eight patients infected with N. meningitidis with reduced susceptibility to cefotaxime (MIC 0.5 to W32 mg/ml) have been described in a single report from India (Manchanda and Bhalla, 2006). Four of the five patients treated with ceftriaxone had a partial–delayed response to ceftriaxone (Manchanda and Bhalla, 2006).

Gram-negative bacilli

More than 99% of H. influenzae strains, which are beta-lactamasepositive and resistant to amoxicillin–ampicillin, are susceptible to cefotaxime (Marco et al., 2001; Zhanel et al., 2003). However, betalactamase-negative ampicillin-resistant (BLNAR) H. influenzae do have increases in cefotaxime MIC (Marco et al., 2001; Zhanel et al., 2003; Hasegawa et al., 2006). In an assessment in Japan, betalactamase-negative ampicillin-susceptible strains had a cefotaxime MIC50 of 0.016 mg/ml and MIC90 of 0.03 mg/ml (range 0.004–0.06 mg/ml). However, BLNAR strains had a cefotaxime MIC50 of 0.5 mg/ml, MIC90 of 1 mg/ml, and an MIC range of 0.125–2 mg/ml.

MECHANISM OF DRUG ACTION

Similar to other beta-lactam antibiotics, cefotaxime inhibits bacterial wall synthesis by binding to PBPs. The antimicrobial spectrum of cefotaxime depends on the affinity pattern of cefotaxime for the PBPs for different bacterial species versus the stability of the antibiotic to the effects of beta-lactamases that are present. The permeability of the organism is also important and is influenced by the presence or absence of outer membrane proteins and activity of efflux pumps.
Cefotaxime binds to PBPs 1a, 1b, and 3 of E. coli at lower concentrations than many other cephalosporins. Binding to PBP 3 causes filamentation before cell death, whereas binding to PBP 1a and 1b may lead to rapid lysis and death of bacteria (Curtis et al., 1979; Neu, 1982b; Neu, 1982c). The desacetylcefotaxime metabolite of cefotaxime also has high affinity for PBPs 1a, 1b, and 3 in E. coli, although the cefotaxime parent drug demonstrated greater binding rates for the same PBPs (Schrinner et al., 1984). Bacteroides fragilis appears to have only three PBPs, and cefotaxime binds to all of them (Botta et al., 1983).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

The dose of cefotaxime used depends on the nature and severity of the infection, the likely MIC of causative organisms and the renal function of the patient. Recommended dosage regimens range from a single dose of 0.5 g for some gonococcal infections to a maximum of 12 g/day for some life-threatening infections. The most frequently used dosage regimen is 1–2 g every 8 hours, but there are also a substantial number of data on 1–2 g every 12 hours. Dosing every 4–6 hours is recommended for some infections (Cherubin et al., 1982; Corrado et al., 1982; Trang et al., 1985). There are limited data on the use of continuous infusion of cefotaxime (Hitt et al., 1997; Buijk et al., 2004), although it is a reasonable concept because the antibiotic displays time-dependent killing (see below under 5c. Clinically important pharmacokinetic and pharmacodynamic features).

Cefotaxime is usually administered intravenously (i.v.), although it may be given intramuscularly (i.m.). To reduce pain, it can be administered i.m. with lignocaine, which has no effect on its absorption (Esmieu et al., 1980). Individual doses may be given by rapid (3 to 5-minute) i.v. injections; a 1-g dose should be dissolved in 4 ml of sterile water for this purpose. Cefotaxime can be given also as a short 20 to 30-minute infusion (1–2 g dissolved in 40 ml, or as a prolonged infusion over 4 hours (2 g dissolved in 100 ml) (Esmieu et al., 1980; Luthy et al., 1981; Doluisio, 1982). In a study of continuous infusion, 4 g of cefotaxime was dissolved in 50 ml normal saline and infused with an electronic pump (Buijk et al., 2004).

b. Newborn infants and children

For children, the dosage is 100–150 mg/kg/day, administered in three or four divided doses (Esmieu et al., 1980; Kafetzis et al., 1981a; Kalager et al., 1982). For serious infections, such as bacterial meningitis, the daily dose can be increased. IDSA recommendations are for the use of the following intravenous cefotaxime regimens for bacterial meningitis: 50 mg/kg every 8–12 hours in neonates 7 days old or less, 50 mg/kg every 6–8 hours in neonates 8–28 days old and 75 mg/kg every 6–8 hours in infants and children (Tunkel et al., 2004). For children over 50 kg, the usual adult dosage should be used; the maximum daily dosage should not exceed 12 g.

In very low birth weight neonates with body weight less than 1500 g, a dose of cefotaxime 50 mg/kg every 24 hours may be used for infections outside the central nervous system because of the prolonged clearance of both cefotaxime and desacetylcefotaxime (Kearns et al., 1989). Other dosing regimens of cefotaxime in preterm infants have been published, as follows, using a dose of 25 mg/kg: every 12 hours for preterm infants less than 1 week of age, every 8 hours for preterm infants 1–4 weeks and term infants less than 1 week of age, and every 6 hours for term infants more than 1 week of age (Kafetzis et al., 1982).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cefotaxime is susceptible to metabolic degradation, with formation of a microbiologically active metabolite, desacetylcefotaxime (Coombes, 1982). As metabolism is part of the disposition of cefotaxime, pharmacokinetic studies without measurement of metabolites must be regarded as incomplete. Key pharmacokinetic values for cefotaxime 1-g doses are: Cmax 20–156 mg/ml, half-life 0.9–1.34 hours and volume of distribution approximately 10–20 l (Fu et al., 1979; Harding et al., 1981; Kemmerich et al., 1983; Nix and Schentag, 1995). Corresponding values for desacetylcefotaxime are Cmax 12.5–16.6 mg/ml, half-life 1.4–1.6 hours and volume of distribution approximately 17 l (Harding et al., 1981; Kemmerich et al., 1983).

Cefotaxime is not absorbed after oral administration, so it is typically administered intravenously. In some parts of the world it is also given intramuscularly. Intraperitoneal administration of cefotaxime in patients on peritoneal dialysis results in rapid and effective absorption into the vascular compartment (Albin et al., 1985). There are also reports of cefotaxime being injected subconjunctivally and intravitreally (Del Piero et al., 1985; Rubinstein et al., 1987; Hou and Hu, 1997).

b. Drug distribution

If a 1-g dose is given by a ‘‘bolus’’ i.v. injection over 3 minutes to adults, the mean serum concentration 5 minutes after the injection is 86.1 mg/ml. The serum level thereafter falls and adequate therapeutic concentrations only persist for 4–6 hours; the half-life after this dose is approximately 1.25 hours. After the i.v. injection of 1 g cefotaxime, a maximal mean desacetylcefotaxime level of 16.6 mg/ml is already present 5 min after the injection; the level of this metabolite slowly decreases with a mean half-life of about 1.5 hours. After 1–2 hours desacetylcefotaxime serum concentrations are equal to, or above, corresponding cefotaxime concentrations (Kemmerich et al., 1983). Standiford et al. (1982) showed that after i.v. infusion of 2 g cefotaxime over 30 minutes, mean serum cefotaxime levels 1, 2, and 4 hours after the infusion fell to 29, 10, and 3 mg/ml, respectively. By 6 hours cefotaxime was undetectable in the serum; its elimination half-life was 1.18 hours. In a similar study, the desacetylcefotaxime peak of 10.1 mg/ml was reached between 30–40 minutes after parent drug administration, at 4 hours it was equal to cefotaxime concentration and thereafter its level was slightly higher than that of cefotaxime (Vallee and LeBel, 1991).

c. Clinically important pharmacokinetic and pharmacodynamic features

Cephalosporins exhibit time-dependent bactericidal activity and produce prolonged postantibiotic effects (PAEs) only with staphylococci (Craig, 1998). Against E. coli, cefotaxime demonstrates a PAE of 24–52 minutes in CSF and just 5–12 minutes in Mueller–Hinton broth (Karlowsky et al., 1993). The duration of time that serum levels exceed the MIC is the important pharmacodynamic parameter correlating with efficacy for these drugs. Animal infection models (neutropenic mouse thigh infection or pneumonia) indicate that maximal efficacy for cephalosporins is attained when serum levels are above the MIC for 60–70% of the dosing interval for Enterobacteriaceae and streptococci and for 40–50% of the dosing interval for S. aureus (Craig, 1995).

The dose, frequency, and duration of infusion for cefotaxime influence the pharmacodynamics of the drug. For example, cefotaxime 1 g every 8 hours (each dose administered over 3 minutes) leads to a mean peak concentration of 86 mg/ml after 5 minutes and to a concentration of 1.8 mg/ml after 4 hours (Kemmerich et al., 1983). In a Monte-Carlo simulation in which the target percent of time above MIC (%TW MIC) was 50%, Burgess et al. (2007) showed that cefotaxime 2 g every 8 hours would have a greater than 95% probability of achieving this target for all MICs r0.5 mg/ml. Jones et al. (2005) have proposed that, as a result of pharmacodynamic considerations, a breakpoint cefotaxime MIC of 1 mg/ml should be regarded as indicative of a susceptible organism.

d. Excretion

Cefotaxime is excreted in urine in an active unchanged form by both glomerular filtration and tubular secretion. High levels of active cefotaxime are attained in urine; after a 1-g dose, urine levels in the first 2 hours are in the range 151–2178 mg/ml (Fu et al., 1979). Probenecid decreases renal clearance by almost 50% by partially blocking tubular secretion. When probenecid is administered concomitantly, cefotaxime serum levels are nearly doubled and are also prolonged (Luthy et al., 1981).

Some cefotaxime is metabolized in the liver, and the major metabolite is desacetylcefotaxime, which is antibacterially active. This is mainly excreted in urine where it attains high concentrations. In the first 24 hours about 60% of an administered dose is excreted in the urine as unchanged cefotaxime, and about 29% as desacetylcefotaxime (Kemmerich et al., 1983). A small amount of desacetylcefotaxime undergoes further transformation in the liver, before urinary excretion, producing in turn desacetylcefotaxime lactone and then two metabolites, designated M2 and M3, which do not possess antibacterial activity.

e. Drug interactions and drug-lab modifications

There is little evidence of any clinically significant interaction between cefotaxime and other drugs (Todd and Brogden, 1990). In a study performed in the early 1980s, ‘‘serum pools’’ were created from healthy adults and patients with a variety of medical conditions or receiving various other drugs (Baer et al., 1983). Addition of cefotaxime and its metabolite to the serum pool of patients who had received aminoglycosides such as gentamicin or tobramycin did not cause any apparent rise in creatinine but caused significant increases in phosphorus concentration (Baer et al., 1983). It is not known if this is the result of direct assay interference or a physicochemical interaction. The clinical importance of the increase in phosphorus is doubtful.

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