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

Cefuroxime is a second-generation cephalosporin antibiotic, developed by Glaxo in the 1970s. It has been used worldwide for more than three decades against a variety of bacterial infections. There are two modes of cefuroxime administration available, cefuroxime sodium and cefuroxime axetil. Cefuroxime sodium is suitable for parenteral administration. The empirical formula is C16H15N4NaO8S and molecular weight is 446.4.

Figure 22.1 Chemical structure of cefuroxime sodium.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro activity of cefuroxime is summarized in Table 22.1.

Gram-positive aerobic bacteria

Cefuroxime is active against most streptococci but is inactive against enterococci (Eykyn et al., 1976; O’Callaghan et al., 1976; Mehtar et al., 1980; Hardy et al., 2000). It is typically active against penicillinsusceptible strains of Streptococcus pneumoniae. In recent studies, MIC90 values of cefuroxime for S. pneumoniae strains susceptible to penicillin ranged from 0.016 to 0.25 mg/l (Table 22.1) (Hardy et al., 2000; Kosowska et al., 2005). Recent worldwide studies indicate that MIC90 values for cefuroxime against all (penicillin-susceptible and penicillin-resistant strains) S. pneumoniae isolates range from 2 to 8 mg/ l (Hoban et al., 2001; Aspa et al., 2004; Dohar et al., 2004; Morrissey et al., 2005). Against isolates of S. pneumoniae that are intermediately susceptible and resistant to penicillin, MIC90 values of the drug range from 4 to 16 mg/l (Spangler et al., 1993; Hardy et al., 2000; Kosowska et al., 2005).

Cefuroxime exhibits good antibacterial activity against S. pyogenes (MIC90 values 0.015 to o0.12 mg/l) (Thornsberry et al., 2001; Dohar et al., 2004). In a study evaluating 786 isolates (86% group A and 8.4% group C b-hemolytic streptococci) collected in Spain, the antibacterial activity of cefuroxime was similar to that of other cephalosporins, including cefotaxime and cefixime (Scott et al., 2001). Other betahemolytic streptococcus and the viridans streptococci are sensitive (Thornsberry et al., 2001).

Gram-negative aerobic bacteria

Cefuroxime is stable to beta-lactamases such as TEM-1 and SHV-1 (Greenwood, 1977; Scott et al., 2001). Cefuroxime is quite active against Neisseria meningitidis (Brown and Fallon, 1980). It is active against N. gonorrhoeae (O’Callaghan et al., 1976; Hall et al., 1979; Piot et al., 1979; Yoshikawa et al., 1980; Yasin et al., 1997; Lesmana et al., 2001). However, the pharmacodynamics of cefuroxime does not support its use in treatment of gonorrhoea (see below under 7. Clinical uses of the drug).

Cefuroxime shows good activity against most strains of Haemophilus influenzae (including those that produce b-lactamase), with MIC90 values ranging from 1 to 4 mg/l (Sykes et al., 1977; Geddes et al., 1978; Richter et al., 1999; Zhanel et al., 2000; Hoban et al., 2001; Perez-Vzquez et al., 2003; Dohar et al., 2004; Morrissey et al., 2005). Moraxella spp. are usually susceptible.

Anaerobic bacteria

The Peptostreptococcus and Clostridium spp. may be susceptible (O’Callaghan et al., 1976; Goldstein and Citron, 1988). Some Gram-negative anaerobic bacilli, such as Propionibacterium (MIC90 of 2 mg/l), Fusobacterium necrophorum (MIC90 of 4 mg/l), Peptostreptococcus and Clostridium perfringens (MIC90 of 8 mg/l) may be inhibited by cefuroxime, but bacteria of the Bacteroides fragilis group usually need high concentrations for inhibition and are completely resistant (O’Callaghan et al., 1976; Jones et al., 1977; Spangler et al., 1994).

Other bacteria

Nocardia asteroides is only moderately sensitive (MIC 1–16 mg/ml) (Gutmann et al., 1983), and cefuroxime is typically not useful for treatment of nocardiosis. Treponema pallidum is susceptible in vitro and cefuroxime is effective in experimental infections in animals (Acred et al., 1980), but human experience is lacking. Borrelia burgdorferi is cefuroxime susceptible (Johnson et al., 1990; Agger et al., 1992). Chlamydia trachomatis is resistant (Bowie, 1982).

b. Emerging resistance and cross-resistance

Cefuroxime is hydrolyzed and rendered inactive by ESBLs, AmpC betalactamases, and most metallo-beta-lactamases. Pneumococcal isolates that are non-susceptible to penicillin frequently display some reduced susceptibility (i.e. cross-resistance) to cefuroxime (Aspa et al., 2004).

c. In vitro synergy and antagonism

There is little evidence of clinically useful synergy between cefuroxime and other antimicrobial agents.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

The i.m. or i.v. dose of cefuroxime can be varied widely, depending on the nature and severity of infection. Adult dosage in the range of 0.5– 2.0 g 8-hourly can be used (Norrby et al., 1977). For severe infections, such as bacterial meningitis, an adult dosage of 3 g i.v. 8-hourly has been used (Report, 1982); however, the advent of the third-generation cephalosporins makes cefuroxime use for meningitis effectively obsolete. For i.v. administration, each dose can be injected or infused over periods of 3–30 minutes (Foord, 1976; Goodwin et al., 1977).

b. Newborn infants and children

A typical dose for children is 60–75 mg/kg body weight, administered 8-hourly (Report from a Swedish Study Group, 1982).

c. Altered dosages Impaired renal function

Cefuroxime is excreted almost entirely by the kidneys and patients with renal failure require a modified dosage. The normal cefuroxime serum half-life of 1.4–1.8 hours is prolonged to approximately 20 hours in anuric patients (Bundtzen et al., 1981).

Cefuroxime sodium

An approximate dosage for use in patients with varying degrees of renal insufficiency has been published by Van Dalen et al. (1979). Patients with a creatinine clearance of more than 60 ml/min should be given a normal dose of 1 g 8-hourly. For those with creatinine clearance values of 45–60, 30–45, 15–30, 4–15, and less than 4 ml/ min, a 1-g dose should be given every 12, 18–24, 36–48, 60–72, or 72–96 hours, respectively. If a patient with a creatinine clearance less than 4 ml/min is being treated by regular hemodialysis, a dose of 1 g cefuroxime i.v. after each dialysis is sufficient. Hemodialysis is an effective means of eliminating cefuroxime from the body.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cefuroxime axetil is formulated as an ester prodrug to facilitate its oral absorption. Cefuroxime axetil is well absorbed from the gastrointestinal tract and is rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime and the ester group. The latter is metabolized to acetic acid and acetaldehyde, which have no inherent activity.

Compared with i.v. administered cefuroxime, the bioavailability of orally administered cefuroxime axetil is about 35% in fasting volunteers. If the ester is given within 15 minutes of a meal, bioavailability is about 45%, indicating that it should be administered shortly after food. Similar results were noted by Harding et al. (1984), who noted that in healthy volunteers serum levels and urinary recoveries were significantly greater for cefuroxime than for ampicillin, but when the drug was taken after fasting the values were similar for the two drugs (Harding et al., 1984). In children, bioavailability may be 25–88% higher when cefuroxime axetil and milk are administered simultaneously than when the same dose is given in the fasting state.

b. Drug distribution

If a 0.5-g dose of cefuroxime is infused i.v. over 30 minutes into adults, the mean peak serum level immediately after the infusion is 37.8 mg/ml; this level falls to 5.1 mg/ml at 3 hours, and the drug is still detectable in serum for 5–6 hours. If the same dose is given by rapid i.v. injection (over 3 minutes), the peak serum level is much higher (82.7 mg/ml), but at 3 hours and thereafter the levels are slightly lower than after the 30-minute infusion (Foord, 1976; Goodwin et al., 1977).
After a 0.5-g i.m. dose to adults, a mean peak serum level of 25.3 mg/ml is reached in 30 minutes. Following a 1-g i.m. dose, the peak is higher (39.1 mg/ml), but not doubled, and it is reached in 45–60 minutes. Serum levels after both doses are prolonged, and measurable concentrations of cefuroxime are still present 8 hours after the injection.
The t1/2 after i.m. or i.v. administration is 1.4–1.8 hours and is prolonged to approximately 20 hours in anuric patients (Bundtzen et al., 1981; Scott et al., 2001).

Distribution of the drug in the body

Cefuroxime penetrates well into pleural fluid (Hoffstedt et al., 1980) and into middle ear effusions of patients with chronic purulent otitis media (Martini and Xerri, 1982). Drug concentrations in bronchial secretions are relatively low, mean levels being 0.67 and 1.78 mg/ml after 750-mg and 1.5-g doses, respectively; but these levels exceed the MICs of susceptible pathogens (Peirce et al., 1980; Havard et al., 1981). After an oral dose of cefuroxime axetil (500 mg), the concentration of cefuroxime in bronchial mucosa ranged from 1.8 to 2.18 mg/g (Winter and Dhillon, 1991; Baldwin et al., 1992). Cefuroxime reaches therapeutically effective concentrations in muscle and fat tissue taken from proximal parts of ischemic amputated limbs (Bullen et al., 1981). In adults, after a 750 mg dose of i.v. cefuroxime, tissue levels in normal bone averaged 8 mg/g (Leigh et al., 1989). After oral administration of cefuroxime axetil, the concentrations in normal human bone were 20–30% of serum concentrations (Renneberg et al., 1993).

c. Clinically important pharmacokinetic and pharmacodynamic features 

As with other beta-lactam antibiotics, cefuroxime bactericidal activity relates most to the time that serum drug concentrations remain above the MIC of a given organism (i.e. time-dependent antibiotic killing). Pharmacodynamic studies suggest that cephalosporin concentrations should exceed the MIC for Z50% of the dosing interval to ensure bacterial eradication and clinical cure in respiratory tract infections (Andes 2001). In an evaluation of cefuroxime axetil (500 mg twice daily) plasma concentrations above the MIC90 for W90% of the dosing interval were observed for S. pneumoniae and H. influenzae. Against M. catarrhalis, the plasma concentration of cefuroxime axetil was above the MIC90 for only o25% of the time (Scott et al., 2001). Breakpoints derived from a combination of pharmacodynamic and microbiologic considerations are different for parenteral cefuroxime sodium compared with orally administered cefuroxime axetil (as would be expected given the differences in pharmacokinetics described above). The most recent Clinical Laboratory Standards Institute/MIC breakpoints of S. pneumoniae for cefuroxime axetil are o1.0 ug/ml (susceptible), 2.0 ug/ml (intermediate), and Z4.0 ug/ml (resistant); and o0.5 ug/ml (susceptible), 1 ug/ml (intermediate), and Z2.0 ug/ml (resistant) for parenteral cefuroxime (NCCLS, 2009).

Cefuroxime may exhibit a postantibiotic effect (PAE) against S. pneumoniae strains, ranging from 0.8 to 2.9 hours after the pathogens had been exposed to concentrations ten times the MIC value. In another in vitro study, after exposure of pathogens to four times the MIC value, cefuroxime exhibited a mean PAE of E1.5 hours against penicillin-susceptible S. pneumoniae, E2.5 hours against a penicillin-resistant S. pneumoniae strain, and o1 hour against S. pyogenes, S. aureus, and both b-lactamase-positive and blactamase-negative strains of H. influenzae and M. catarrhalis. These data are consistent with the fact that cephalosporins generally only demonstrate a PAE against Gram-positive bacteria (Scott et al., 2001).

d. Excretion

Cefuroxime is not inactivated in the body; virtually all of a parenterally administered dose is excreted via the kidney, in an active unchanged form, by glomerular filtration and tubular secretion. Over 95% of i.v. administered cefuroxime can be recovered from the urine during the first 24 hours. Thus, high concentrations of the drug are attained in urine; after a 0.5-g i.m. dose, urinary concentrations are 300–3000 mg/ ml during the first 6 hours (Foord, 1976; Goodwin et al., 1977). Some 38.65% of an administered dose of oral cefuroxime axetil can be recovered from the urine (Lang et al., 1990).
Very little cefuroxime is excreted via the bile. Biliary levels are lower than simultaneous serum levels even if the biliary tract is not obstructed. Severn and Powis (1979) found that after an i.v. dose of 750 mg of cefuroxime, the mean biliary level in diseased gallbladders was 4.8 mg/ml, and the mean level was only 9 mg/ml in the common bile duct bile, in patients without biliary tract obstruction.

e. Drug interactions

Drugs that reduce gastric acidity may result in a lower bioavailability of cefuroxime axetil than that of at fasting state and tend to cancel the effect of postprandial absorption. Concomitant administration of probenecid increases the serum concentrations of cefuroxime, the total area under the curve and its serum half-life. Overall, concomitant administration of probenecid decreases cefuroxime clearance by about 40% (Foord, 1976).

In common with other antibiotics, cefuroxime axetil may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen–progesterone contraceptives.

TOXICITY

Cefuroxime is relatively free from side-effects, but collateral damage in the form of subsequent C. difficile-related colitis or colonization with ESBL-producing organisms warrants some emphasis (Bartlett, 2008; Dial et al., 2008). Cefuroxime axetil has an effect on fecal flora of healthy volunteers; there was a reduction of anaerobes and more marked elimination of Enterobacteriaceae (Leigh et al., 1990). Nephrotoxicity is uncommon. Provided the dose is suitably reduced, the drug can be used in patients with pre-existing renal damage without further compromising renal function (Trollfors, 1980; Trollfors et al., 1980). In one study, 18 of 60 treated patients developed slight reversible rises in transaminases, and two a positive direct Coombs’ test without hemolysis (Norrby et al., 1977). It may interfere with platelet function, but only when excessively high serum levels are attained (Bang and Kammer, 1983). A psychotic reaction to i.v. cefuroxime has been reported in one patient (Vincken, 1984).

CLINICAL USES OF THE DRUG

The clinical role of cefuroxime appears to be steadily decreasing given the availability of similar, but more clinically effective agents such as ceftriaxone and cefixime.

a. Pneumonia and other respiratory tract infections

Given its activity against S. pneumoniae, H. influenza, and M. catarrhalis, cefuroxime has been used extensively for the treatment of various respiratory tract infections. Given the importance of pneumococcal pneumonia, studies evaluating serious pneumococcal infections are of great importance. Yu et al. (2003) evaluated the outcome of patients with pneumococcal bloodstream infection. Patients who were infected with pneumococci that were not susceptible to cefuroxime (median MIC by Etest, 3 mg/ml; median MIC by broth dilution assay, 8 mg/ml) but who were treated with cefuroxime, experienced a significantly higher mortality rate [4 (36.4%) of 11 died] than patients in whom cefuroxime was used and the organism was susceptible to the organism [4 (5.8%) of 53 patients died; p = 0.02] (Yu et al., 2003). In this study, most patients who were treated with cefuroxime received the standard dose at 750 mg every 8 hours.

b. Uncomplicated urinary tract infection

Oral cefuroxime has been regarded as less effective than trimethoprin– sulphamethoxazole and fluoroquinolones for most organisms causing urinary tract infection (UTI). However, the drug does concentrate in the urine and is active against all but ESBL or AmpC producing E. coli. Cefuroxime can be used as an alternative agent, especially during pregnancy. In complicated UTI or pyelonephritis, it can be used as switch-to-oral therapy after initial clinical improvement, based on organism susceptibility (Nicolle, 2002).

c. Skin and skin structure infection

Generally, unlike cephalexin which has good activity against S. aureus, cefuroxime has little role in the treatment of skin and soft-tissue infection (Stevens et al., 2005). Oral penicillin for 10 days has been recommended as treatment of choice for perianal streptococcal dermatitis in children. In a small prospective unblinded study, treatment with cefuroxime achieved a more rapid clinical improvement compared with oral penicillin (Meury et al., 2008).

d. intra-abdominal infection

Cefuroxime, in combination with metronidazole, has been shown to have an equal success rate of mild to moderate community-acquired intra-abdominal compared with piperacillin-tazobactam monotherapy (Ohlin et al., 1999) or imipenem monotherapy (Angeras et al., 1996).

e. Meningitis

Even though cefuroxime may penetrate the CSF in patients with meningeal inflammation, it is not recommended for the treatment of meningitis. Its efficacy is inferior to ceftriaxone and treatment with cefuroxime in children has been associated with increased hearing impairment (Schaad et al., 1990).

f. Gonorrhoea

Cefuroxime use for the treatment of gonorrhoea is inferior to ceftriaxone or cefixime and has been associated with clinical failure for gonococcal strains with MICs of 0.5–1 mg/ml. The pharmacodynamics of cefuroxime does not support its use for this infection (Ison et al., 2004). However, Gottlieb and Mills (1986) described some efficacy with oral cefuroxime axetil (1 g) plus probenecid – cure was observed in 29 of 30 urethral and 6 of 6 rectal gonococcal infections in men (Gottlieb and Mills, 1986).

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