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

Ceftriaxone (Ro 13-9904) is a 2-aminothiazolyl methoxyimino thirdgeneration cephalosporin derivative (Figure 27.1). Ceftriaxone offers good activity against many wild-type Gram-negative organisms with reasonable activity against Gram-positive organisms (Shannon et al., 1980; Neu et al., 1981). Notable exceptions include a lack of consistent activity against Pseudomonas aeruginosa and enterococci. Ceftriaxone is bound extensively to plasma proteins (83–96%), the degree of which is concentration dependent (Stoeckel, 1981; Neu, 1982), and has a long half-life (approximately 8 h) (Seddon et al., 1980; Stoeckel, 1981). Ceftriaxone is unique because of its prolonged serum half-life, which permits once- or twice-daily dosing (Garzone et al., 1983). Ceftriaxone is also characterized by satisfactory penetration into cerebrospinal fluid (Cadoz et al., 1981).

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro spectrum of activity of ceftriaxone is very similar to that of cefotaxime (Neu, 1982).

Gram-positive cocci

Ceftriaxone has retained its potent activity against the most commonly encountered Gram-positive human pathogens despite widespread and ongoing clinical use for more than 15 years (Table 27.1) (Karlowsky et al., 2002). Notable exceptions include methicillin-resistant staphylococcus Staphylococcus aureus (MRSA) and enterococci. Generally, S. aureus and coagulase-negative staphylococci are marginally less susceptible to ceftriaxone than to cefotaxime (Angehrn et al., 1980; Shannon et al., 1980). However, ceftriaxone is more active than ceftazidime against S. aureus (Keenholtz et al., 1983; Sader et al., 2005). Ceftriaxone is active against methicillin-susceptible S. aureus (MSSA). 

Ceftriaxone has similar activity to cefotaxime against Streptococcus pyogenes, group B streptococci, and Streptococcus pneumoniae. Although ceftriaxone is highly active against S. pneumoniae, the antibiotic susceptibility of this pathogen in recent times has been a source of confusion potentially for several reasons: (1) the clinical disease spectrum of the organism (different breakpoints for meningeal and nonmeningeal disease); (2) recent revision of the breakpoints recommended by the CLSI; and (3) the introduction of the polyvalent pneumococcal vaccines and its effect on microbiologic susceptibility patterns. Rates of resistance to all beta-lactam antibiotics increase proportionally to the rate of penicillin resistance (Pottumarthy et al., 2005a). Furthermore, ceftriaxone resistance in S. pneumoniae is almost always observed only in those strains which are also penicillin resistant (Fenoll et al., 2008).

Gram-positive bacilli

Listeria spp., of which L. monocytogenes is the primary human pathogen, are naturally resistant or intermediately resistant to third-generation cephalosporins (Troxler et al., 2000). The MIC breakpoints defined by Troxler et al. were those for staphylococci as breakpoints have not been specifically defined by the CLSI for Listeria spp. Corynebacterium may be resistant to ceftriaxone. A small study with 20 isolates of Corynebacterium spp. demonstrated an MIC range of Z0.25–32 mg/ml with MIC50 and MIC90 32 and W32 mg/ml, respectively (Sader et al., 2004).

Gram-positive anaerobes

Anaerobic Gram-positive cocci such as Peptococcus and Peptostreptococcus are typically susceptible to ceftriaxone (Pollock et al., 1983; Aldridge and Johnson, 1997; Roberts et al., 2006).

Although uniform susceptibility to penicillin and amoxicillin (MIC o1 mg/ml) was identified in all 87 clinical isolates of Actinomyces species tested, differences in susceptibility to ceftriaxone were exhibited by some species (Smith et al., 2005). In that study, all isolates of A. israelii had ceftriaxone MICs r0.125 mg/ml, while some A. europaeus isolates had ceftriaxone MICs Z8 mg/ml (Smith et al., 2005).

For Lactobacillus spp., ceftriaxone MIC ranges varied widely according to species, and ceftriaxone demonstrated activity lower than penicillin or ampicillin in 85 Lactobacillus bacteremia isolates (Salminen et al., 2006).

Gram-negative cocci

Ceftriaxone is typically regarded as exquisitely active against Neisseria meningitidis (Perez Trallero et al., 1989; Blondeau and Yaschuk, 1995; Enting et al., 1996; Tapsall et al., 2001). However, the first cases of nonsusceptibility to ceftriaxone (MIC W0.12 mg/ml) have recently been reported in eight chidlren from India (Manchanda and Bhalla, 2006). In that study, ceftriaxone MICs ranged from 0.25 to 8 mg/ml. Five of the isolates were also resistant to penicillin (MIC Z0.5 mg/ml). Five patients demonstrated a partial/delayed response to ceftriaxone therapy (i.e. afebrile 6–15 days after starting antibiotic treatment). The mechanism of reduced susceptibility to ceftriaxone has not been described.

Gram-negative bacilli

Haemophilus influenzae, including beta-lactamase-producing strains, shows full susceptibility to ceftriaxone. Large-scale studies conducted in the USA, Europe, Asia, and Australia have found H. influenzae to be 100% susceptible to ceftriaxone (Livermore et al., 2001; Jacobs et al., 2003; Bouchillon et al., 2005; Jones et al., 2007). An investigation with 8523 isolates showed full susceptibility to ceftriaxone with MIC90 0.008 mg/ml (Jacobs et al., 2003). Nonsusceptibility to ceftriaxone (MIC as high as 32 mg/ml) has been reported in H. influenzae in China, although mechanisms of resistance were not explored in that report (Wang et al., 2000). Tristram et al. (2008) has reported two clinical isolates of H. parainfluenzae which produced a TEM-15 extended-spectrum beta-lactamase (ESBL) and had cefotaxime MICs of 8–16 mg/ml. Ceftriaxone MICs were not reported in that article, but it appears highly likely that ceftriaxone MICs would also have been elevated.

Ceftriaxone has little activity against P. aeruginosa (Fass et al., 1996; Fluit et al., 2001; Rhomberg et al., 2004; Bouchillon et al., 2005; Jones et al., 2007). Furthermore, in vivo treatment of P. aeruginosa with ceftriaxone may result in emergence of ceftriaxone-resistant strains (Paull and Morgan, 1986). Ceftriaxone in combination with gentamicin, tobramycin, or amikacin shows in vitro synergy with some strains of P. aeruginosa, but antagonism or indifference with others (Angehrn, 1983; Watanakunakorn, 1983).

Overall, ceftriaxone has low activity against Acinetobacter spp. in vitro (Fass et al., 1996; Rhomberg et al., 2004; Bouchillon et al., 2005). Antimicrobial susceptibility profiles from intensive care units demonstrate variable susceptibility from country to country: lowest in Italy (8.8%) and highest in Germany (42.3%) (Jones et al., 2004a). Stenotrophomonas maltophilia is always resistant to ceftriaxone (Neu et al., 1981; Fass et al., 1996; Jones et al., 1998). Burkholderia cepacia, responsible for infective exacerbations in cystic fibrosis, is invariably resistant to ceftriaxone (Fass et al., 1996). Ceftriaxone has no activity against Achromobacter xylosoxidans (Fass et al., 1996; Jones et al., 1998).

Gram-negative anaerobes

The Bacteroides fragilis group is highly resistant to ceftriaxone, with susceptibility rates typically less than 15% (Wexler et al., 2005). As with cefotaxime, ceftriaxone is hydrolyzed by chromosomal betalactamases of B. fragilis (Rolfe and Finegold, 1981; Pollock et al., 1983).

A study with 542 blood isolates of the B. fragilis group in 1987–1999 found ceftriaxone to be the least potent cephalosporin against this bacteria (cefoxitinW ceftizoxime W cefotetan = cefotaxime = cefmetazole W ceftriaxone) (Aldridge et al., 2003). Prevotella spp. has variable susceptibility to ceftriaxone depending on the species (Pollock et al., 1983; Aldridge and Johnson, 1997; Wexler et al., 2005; Roberts et al., 2006). In contrast, more than 85% Fusobacterium and Porphyromonas strains are ceftriaxone susceptible (Wexler et al., 2005; Roberts et al., 2006).

Other organisms

Chlamydia trachomatis is resistant to ceftriaxone with both MIC and MBC W32 mg/ml (Hammerschlag and Gleyzer, 1983; Talbot and Romanowski, 1989). Ceftriaxone may have some activity against Coxiella burnetii, although the antibiotic is not used clinically for Q fever. In a small study with 13 C. burnetii isolates, ceftriaxone was bacteriostatic for four isolates and slowed the multiplication of the other nine at o4 mg/ml (Torres and Raoult, 1993). The leptospirae are more susceptible to ceftriaxone than to penicillin with MIC90s of 0.39 versus 6.25 mg/ml for penicillin G (Murray and Hospenthal, 2004). Mycoplasma spp., Mycobacterium spp., and fungi are resistant.

b. Emerging resistance and cross-resistance

Selection for resistance to beta-lactam agents, including ceftriaxone, arises via (1) modification or bypassing of the normal penicillin-binding protein (PBPs); (2) impermeability or efflux of the Gram-negative organism outer membrane; and (3) production of beta-lactamases (Livermore, 1998). PBP modification is the most important mechanisms of resistance in Gram-positive cocci, but beta-lactamases are preeminent in Gram-negative species (Livermore, 1998). Resistance to beta-lactams, including ceftriaxone, in MRSA is due to expression of PBP-2a, a low-affinity PBP which is encoded by the mecA gene (Chambers, 1999). In S. pneumoniae, high-level resistance to third-generation cephalosporins is due to alterations of PBPs 1a and 2x (Coffey et al., 1995). The low susceptibility of enterococci a-lactam antibiotics is associated with the synthesis of a particular PBP (e.g. PBP-5) that has a low affinity for beta-lactam agents (Fontana et al., 1992).

Ceftriaxone has retained activity against penicillinase-producing, penicillin-resistant, and quinolone-resistant N. gonorrhoeae (Jones et al., 2005a; Jones et al., 2005b). Ceftriaxone is unaffected by the TEM-1 beta-lactamase of penicillinase-producing N. gonorrhoeae. Beta-lactamases capable of hydrolyzing ceftriaxone have not been detected so far in N. gonorrhoeae.

MECHANISM OF DRUG ACTION

Ceftriaxone, similar to other cephalosporins, inhibits bacterial wall synthesis of actively dividing cells by binding to one or more PBPs. Formation of a defective cell wall results in osmotic instability of a bacterial cell. Bacterial species have a unique set of PBPs. The affinity pattern of ceftriaxone for the PBPs for different bacterial species affects the drug’s antimicrobial spectrum of activity. It has enhanced activity against Gram-negative bacteria for the same reasons as for cefotaxime. Ceftriaxone induces filamentation in E. coli and P. aeruginosa, suggesting that it binds primarily to the PBP 3 (Hall et al., 1981).

MODE OF DRUG ADMINISTRATION AND DOSAGE

Ceftriaxone is not absorbed after oral administration, and so it must be administered by either the intramuscular (i.m.) or intravenous (i.v.) route. It is more suitable for i.m. administration than other thirdgeneration cephalosporins because it has a prolonged serum half-life, which allows administration at 12-h or 24-h intervals (Eron et al., 1983; Legua et al., 2002). In the ambulatory setting, ceftriaxone has been successfully used to treat a range of serious bacterial infections in all age groups and in patients who were either immunocompetent or immunocompromised, and/or neutropenic (Nathwani, 2000). The antibiotic has also been widely used in hospitalized patients.

a. Adults

When given i.m., the drug can be mixed with lidocaine (lignocaine) to reduce pain (Patel et al., 1982; Aronoff et al., 1983; Russo et al., 1988; Legua et al., 2002). Lidocaine can reduce the pain of an i.m. injection of ceftriaxone when compared with sterile water as a diluent (Schichor et al., 1994). A 1-g vial of ceftriaxone was reconstituted with 3.6 ml of 1% lidocaine without epinephrine, resulting in a total volume of 4 ml in one study (Russo et al., 1988). Ceftriaxone solution should be injected well within the body of a relatively large muscle, and not more than 1 g should be injected at a single site (Lamb et al., 2002; Roche, 2007a); a maximum of 2 ml of solution can be given in each site (gluteus muscle or lateral thigh) (Russo et al., 1988). The efficacy of i.m. ceftriaxone 1 or 2 g daily as parenteral home therapy has been reported (Russo et al., 1988).

b. Neonates and children

The dosage is 50–100 mg/kg body weight daily, given in one or two divided doses (Steele and Bradsher, 1983; Peltola et al., 1989). Ceftriaxone 50–75 mg/kg/day not to exceed 2 g, (or as two equally divided doses) is recommended for skin and soft-tissue infections and other serious nonmeningeal infections (Roche, 2007a). Single daily doses of 50 mg/kg have been effective for the treatment of children with a variety of nonmeningitic bacterial infections (Congeni et al., 1985). For the treatment of bacterial meningitis, a variety of different guidelines and reviews recommend either once-daily or 12-hourly dosing (AAP Committee on Infectious Diseases, 1997; Kaplan, 2002; Tunkel et al., 2004; Chavez-Bueno and McCracken, 2005). A dosage of 50 mg/kg 12-hourly has been recommended for meningitis, which could be preceded by an initial loading dose of 75 mg/kg (Schaad and Stoeckel, 1982; del Rio et al., 1983; Steele and Bradsher, 1983).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Ceftriaxone is only poorly absorbed following oral administration (Pickup et al., 1981). Although there has been some work on oral formulations of ceftriaxone, this research has not advanced to clinical trials. Ceftriaxone is rapidly and completely absorbed following i.m. administration (Patel and Kaplan, 1984). The bioavailability for a 1 g i.m. dose of ceftriaxone is 100% (Zhou et al., 1985). The mean bioavailability of subcutaneous administration of ceftriaxone is 96% (Borner et al., 1985).

b. Drug distribution

Serum levels in relation to dosage

Serum concentration peaks at 30 min after i.v. infusion (Patel et al., 1981; Meyers et al., 1983; Scully et al., 1984) and 1–3 h after i.m. injection (Pickup et al., 1981; Meyers et al., 1983). If 1 g of ceftriaxone is given i.v. to adults as a 30-min infusion, the mean peak serum level, attained immediately after infusion, is 123.2 mg/ml; this falls to 94.8, 57.8, 20.2, and 4.6 mg/ml at 1.5, 4, 12, and 24 h after commencement of the infusion, respectively (Meyers et al., 1983). In children with meningitis who received ceftriaxone 50 or 75 mg/kg intravenously, mean peak plasma concentrations (Cmax) were 216 and 275 mg/ml, respectively (Roche, 2007a). After i.m. injection of a 1-g dose to adults, a mean peak serum level of 79.2 mg/ml is attained at 1.5 h; thereafter this level falls slowly, being 58.2, 35.5, and 7.8 mg/ml at 4, 12, and 24 h after the injection, respectively (Meyers et al., 1983).

Distribution of the drug in the body

In common with cefotaxime, ceftriaxone penetrates poorly into the cerebrospinal fluid (CSF) of animals with uninflamed meninges, but it reaches therapeutically effective concentrations in those with bacterial meningitis. In humans, there is only 1.5% penetration of the drug into the CSF in those with uninflamed meninges (Chandrasekar et al., 1984). 

c. Clinically important pharmacokinetic and pharmacodynamic features

Ceftriaxone shows time-dependent antibiotic killing and its bactericidal activity relates most to the time that serum drug concentrations remain above the MIC (T W MIC) for a given organism (Drusano and Goldstein, 1996; Craig, 1998). For effective bactericidal activity, cephalosporin concentrations should exceed the MIC value against common pathogens for at least 40–50% of the dosing interval (Drusano and Goldstein, 1996; Owens et al., 2001; Andes and Craig, 2005). Ceftriaxone, like other beta-lactams, generally demonstrates a postantibiotic effect (PAE) only against Gram-positive bacteria (Craig, 1998). A study evaluating S. pneumoniae isolates found PAEs of ceftriaxone ranging from 1 to 7.2 h after the isolates had been exposed to concentrations ten times the MIC value (Spangler et al., 1997). In another study, its mean PAEs against S. aureus, S. pneumoniae, H. influenzae, and E. coli strains were 0.9, 2.6, 0.8, and 2.1 h, respectively (Odenholt et al., 1998).

d. Excretion

Urine

Ceftriaxone is minimally metabolized in the body (Seddon et al., 1980). Between 33% and 67% of a dose is excreted in the urine as unchanged drug (Patel and Kaplan, 1984). High concentrations of the active drug are attained in urine. Compared with other cephalosporins, ceftriaxone is only slowly eliminated by the kidneys. High serum protein binding (about 95%) may partly explain its slow renal clearance (Wise and Andrews, 1983). Glomerular filtration is the primary method of elimination (Patel and Kaplan, 1984). Renal elimination is only about 7% of glomerular filtration rate and tubular secretion does not occur (Seddon et al., 1980). The drug is not reabsorbed by renal tubules (Arvidsson et al., 1982).

Bile

The remainder of a dose of ceftriaxone is secreted in the bile and ultimately is found in the feces as microbiologically inactive compounds (Patel and Kaplan, 1984). The degree of biliary excretion varies considerably between individuals. Following biliary excretion, the drug is probably gradually inactivated in the intestine by fecal enzymes (Welling et al., 1992). After i.v. administration of radioactivelabeled ceftriaxone to human volunteers, 44% of the dose was recovered as microbiologically inactive material in the feces (Patel et al., 1981; Patel and Kaplan, 1984). Although biliary excretion of ceftriaxone is significant, no significant pharmacokinetic differences in normal volunteers were detected compared with patients having undergone cholecystectomy (Hayton et al., 1986).

e. Drug interactions

Ceftriaxone should not be mixed with calcium-containing solutions or products and not administered in the same or different infusion lines or sites in any patient within 48 h of each other (FDA, 2007). The reconstitution of ceftriaxone sodium with diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, or calcium-containing infusions, such as total parenteral nutrition solution, can result in the formation of a ceftriaxone–calcium salt (Roche, 2007b). Fatal reactions with ceftriaxone–calcium precipitates in the lungs and kidneys have occurred in both term and premature neonates following concomitant use of ceftriaxone sodium and calcium-containing solutions or products, even via different administration lines and at different times (Roche, 2007b; Runel Belliard and Sibille, 2007). No such reactions have been seen in patient groups other than neonates, but the theoretical possibility exists that this may occur.

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