Cefotaxime: Clinical Uses and Toxicity

Similar to ceftriaxone, cefotaxime is effective in a wide variety of clinical indications. a. Spontaneous bacterial peritonitis The causative organisms of SBP are usually those of the normal intestinal flora, and hence E. coli, K. pneumoniae, and streptococci are the most common causative organisms. Spontaneous bacterial peritonitis is only rarely caused by anaerobes or by more than one type of bacteria, so their presence in ascitic fluid should raise suspicion of secondary peritonitis. Third-generation cephalosporins such as cefotaxime are the antibiotics of choice for SBP because of their broad antibacterial spectrum and extremely good safety profile (Felisart et al., 1985; Ariza et al., 1991; Runyon et al., 1991b; Rimola et al., 1995a; Rimola et al., 1995b; Navasa et al., 1996; Ricart et al., 2000; Tuncer et al., 2003; Runyon, 2004; Chen et al., 2005).

Clinical Uses

Cefotaxime has been extensively studied in patients with SBP (see Table 26.5). At least six randomized trials have evaluated cefotaxime compared with other antibiotics for treatment of SBP (Felisart et al., 1985; Ariza et al., 1991; Navasa et al., 1996; Ricart et al., 2000; Tuncer et al., 2003; Chen et al., 2005). In all of these trials, cefotaxime was at least as effective as comparators (Table 26.5).

b. Peritonitis complicating peritoneal dialysis

Gram-negative organisms, especially Enterobacteriaceae, account for 20–30% of all peritoneal dialysis (PD)-related peritonitis (Szeto et al., 2006). Although not featured in the 2005 guidelines of the International Society for Peritoneal Dialysis, cefotaxime has been used intraperitoneally for treatment of PD peritonitis in children and adults (Bald et al., 1990; Bouchet et al., 1991).

c. Cholangitis and other biliary tract infections

Biliary tract infections are polymicrobial in 30–80% (Westphal and Brogard, 1999). The most common bacteria isolated are of colonic origin (van den Hazel et al., 1994), although anaerobes are rarely the sole infecting organisms. Recovery of anaerobes appears to be more common in patients with a history of biliary surgery, especially those with a bile duct–bowel anastomosis, in patients with a chronic biliary tract infection, and in the elderly (van den Hazel et al., 1994; Westphal and Brogard, 1999). In the initial stage of treatment of biliary tract infections (for example, acute cholangitis related to biliary tract obstruction) selection of antibiotics with good biliary penetration may not be clinically relevant because biliary excretion of any antibiotic is minimal in patients with obstructed biliary tract (van den Hazel et al., 1994).
Cephalosporins are widely used for the treatment of biliary tract infections (Bornman et al., 2003; Tanaka et al., 2007), but are poorly evaluated.

d. Neonatal necrotizing enterocolitis

Although no definitive infectious etiology is known to cause neonatal necrotizing enterocolitis, antimicrobial therapy against Gram-positive and Gram-negative organisms is essential. Anaerobic coverage should be considered, especially if pneumoperitoneum is suspected or confirmed (Kafetzis et al., 2003; Lin and Stoll, 2006). Various antibiotic regimens can be used; one frequently used regimen includes vancomycin, cefotaxime, and clindamycin or metronidazole. In one nonrandomized evaluation, neonates receiving cefotaxime and vancomycin had a better outcome than historical controls receiving ampicillin+gentamicin (Scheifele et al., 1987). Major complications were observed in 33% (10/30) receiving cefotaxime and vancomycin vs 68.4% (26/38) receiving ampicillin and gentamicin (p = 0.004). Significantly higher mortality was observed in those receiving ampicillin and gentamicin (Scheifele et al., 1987).

e. Other intra-abdominal infections

Cefotaxime is a potentially appropriate antibiotic for therapy of complicated intra-abdominal infections, in which the usual causative organisms are the Enterobacteriacae and anaerobic organisms, particularly B. fragilis. As cefotaxime lacks anti-anaerobic activity, it should be used in combination with an antibiotic with anti-anaerobic activity (e.g. metronidazole) in this setting. Cefotaxime is used for the management of both community acquired and healthcare-associated postoperative nosocomial infections. Guidelines of the Surgical Infection Society and the Infectious Diseases Society of America include cefotaxime plus metronidazole as an appropriate regimen for high-severity community-acquired intra-abdominal infections (Mazuski et al., 2002; Solomkin et al., 2003).

f. Shigellosis

Antimicrobial therapy for shigellosis shortens the duration of fever and diarrhea and reduces the excretion of infectious organisms in stool (Ashkenazi, 2004; Thielman and Guerrant, 2004). Most Shigella isolates are now often resistant to ampicillin, trimethoprim–sulfamethoxazole, and tetracyclines (Ashkenazi, 2004; Sur et al., 2004).

Fluoroquinolones, third-generation cephalosporins, or azithromycin are recommended for the treatment of shigellosis (Guerrant et al., 2001; Manatsathit et al., 2002; Ashkenazi, 2004; Thielman and Guerrant, 2004). Fluoroquinolones or azithromycin have advantages in that they can be administered orally. Use of third-generation cephalosporins (exclusively ceftriaxone) has been investigated (EidlitzMarcus et al., 1993). However, resistance to third-generation cephalosporins, mediated by extended-spectrum beta-lactamases, has been reported with Shigella (Acikgoz et al., 2003).

g. Typhoid fever

Historically, typhoid fever was treated with chloramphenicol, ampicillin, or trimethoprim–sulfamethoxazole, but antimicrobial resistance is now widespread (Parry et al., 2002). Since 1989, resistance to all three of these antibiotics has been noted worldwide, but particularly in strains in India, Pakistan, China, and the Persian Gulf (Mirza et al., 1996). Currently, 50–80% of isolates from China and the Indian subcontinent are multidrug resistant (Gupta, 1994), and 93% of isolates in an outbreak in Tajikistan were multidrug resistant (Mermin et al., 1999). Consequently, fluoroquinolones and third-generation cephalosporins have been increasingly used, but resistance to fluoroquinolones has, in turn, emerged and been associated with treatment failures (Murdoch et al., 1998; Mermin et al., 1999; Aarestrup et al., 2003) .

h. Nontyphoidal salmonellosis

Gastroenteritis, caused by Salmonella spp. is usually a self-limiting infection and does not require antibiotic treatment. However, in some immunocompromised patients (such as the newborn, the elderly, those with AIDS, or neoplasms), there is a greater risk of developing a severe extraintestinal complications, and, in these cases, antibiotic treatment is recommended. Because resistance to trimethoprim–sulfamethoxazole and ampicillin is common, use of a third-generation cephalosporin or fluoroquinolone is reasonable if susceptibilities are unknown (Hohmann, 2001). Notably, however, resistance of non-typhoidal salmonella to third-generation cephalosporins is increasing, mediated by either ESBLs or AmpC type beta-lactamases (Miriagou et al., 2004).

In limited studies, cefotaxime appeared effective in the treatment of bloodstream infections and other invasive disease caused by nontyphoidal salmonella (Soe and Overturf, 1987; Lepage et al., 1990).

i. Diarrhea caused by Vibrio species

Vibrio cholerae is likely to be susceptible to cefotaxime (Sciortino et al., 1996), although a recent study from India showed that just 73.8% of isolates were susceptible to the antibiotic (Mathur et al., 2003). In most cases of clinically significant cholera, tetracycline or doxycycline are the antibiotics of choice for adult patients (Sack et al., 2004). However, in areas in which tetracycline resistance is widespread, fluroquinolones or macrolides may be useful. Children may be treated with macrolides. Cefotaxime is not typically used for cholera. However, nonserogroup O:1 V. cholerae bacteremia and cerebritis has been successfully treated with cefotaxime, with subsequent ciprofloxacin therapy (Suankratay et al., 2001).

j. Infections caused by Yersinia enterocolitica, Y. pseudotuberculosis, and Y. pestis

Ninety-nine percent of isolates of Y. enterocolitica or Y. pseudotuberculosis are susceptible to cefotaxime (Lemaitre et al., 1991; Preston et al., 1994; Stock and Wiedemann, 1999; Rastawicki et al., 2000), but clinical experience with use of the drug for yersiniosis is very sparse. Typically, patients with gastroenteritis do not derive benefit from antibiotic therapy. However, patients with invasive disease do respond to antibiotic therapy. Gayraud et al. (1993) have described more than 50 cases of Y. enterocolitica bloodstream infection, the majority of which were treated with third-generation cephalosporins, including cefotaxime in 18 patients, usually in combination with fluoroquinolones or aminoglycosides. Failure has been observed with cefotaxime despite in vitro susceptibility (Noble, 1989), and it has been suggested that ceftriaxone is the preferred third-generation cephalosporin for this infection because of its high intracellular concentrations and activity in animal models (Kuhn et al., 1986; Scavizzi et al., 1987; Lemaitre et al., 1991; Gayraud et al., 1993).

k. Bacterial meningitis

The third-generation cephalosporins (especially cefotaxime and ceftriaxone) have revolutionized treatment of bacterial meningitis. Cefotaxime or ceftriaxone are recommended for empiric therapy of bacterial meningitis in children older than one month and in adults (Tunkel et al., 2004). Cefotaxime is specifically recommended as empiric therapy for neonatal meningitis in combination with ampicillin. Ceftriaxone use is generally not recommended for neonates because cases of fatal reactions have been observed when ceftriaxone– calcium precipitates developed in the lungs and kidneys in both term and premature neonates (Runel Belliard and Sibille, 2007). Additionally, bilirubin is ‘‘displaced’’ from albumin by ceftriaxone, thereby increasing the risk of neonatal jaundice (Gulian et al., 1987; Wadsworth and Suh, 1988; Martin et al., 1993). Neither cefotaxime or ceftriaxone is regarded as appropriate empiric therapy for bacterial meningitis occurring after penetrating head trauma, postneurosurgery, or in patients with CSF shunt infections (Tunkel et al., 2004).

l. Brain abscess

Cefotaxime is also an ideal drug for the therapy of bacterial brain abscess (Sjolin et al., 1991; Sjolin et al., 1993), although in most circumstances it should be combined with metronidazole to provide coverage against Gram-negative anaerobes. Cefotaxime itself is effective against Streptococcus milleri, methicillin-susceptible S. aureus and non-ESBL-producing E. coli (Sjolin et al., 1991; Saez-Llorens, 2003; Jansson et al., 2004). High-dose cefotaxime (3 g every 8 hours) used in combination with metronidazole has been reported to be effective for the treatment of brain abscess (Sjolin et al., 1993; Gomez et al., 1995; Jansson et al., 2004).

m. Community-acquired pneumonia

Cefotaxime is active against the usual respiratory pathogens that cause community-acquired pneumonia, such as S. pneumoniae, H. influenzae, and M. catarrhalis, although it lacks coverage against ‘‘atypical’’ organisms such as M. pneumoniae, C. pneumoniae, and Legionella spp. Cefotaxime or ceftriaxone is frequently used in combination with a macrolide as empiric treatment of communityacquired pneumonia. Such a combination is recommended in the most recent Infectious Diseases Society of America/American Thoracic Society guidelines (Mandell et al., 2007) for community-acquired pneumonia requiring inpatient hospitalization, although other national guidelines recommend penicillin. Cefotaxime (or ceftriaxone) is an effective parenteral agent for treatment of pneumococcal pneumonia without meningitis, for strains with reduced susceptibility to penicillin but with MICs of cefotaxime or ceftriaxone of o2 mg/ml (Friedland, 1995; Pallares et al., 1995; Choi and Lee, 1998; Feikin et al., 2000; Heffelfinger et al., 2000; CLSI, 2007). It is notable, however, that unlike for meninigitis, penicillin G continues to provide excellent clinical efficacy for community-acquired pneumonia caused by penicillin-intermediate and penicillin-resistant strains of S. pneumoniae. The use of cefotaxime for community-acquired pneumonia is supported by data from numerous randomized trials (see Table 26.8).

n. Nosocomial pneumonia

Nosocomial pneumonia may be caused by a wide variety of bacterial pathogens and can be polymicrobial. Common pathogens include aerobic gram-negative bacilli (e.g. E. coli, K. pneumoniae, Enterobacter spp, P. aeruginosa, Acinetobacter spp.) and Gram-positive cocci such as MRSA (ATS/IDSA, 2005). As previously noted, neither cefotaxime nor ceftriaxone provide appropriate therapy against many of these pathogens. Thus, ceftriaxone is regarded as an appropriate choice for hospital-acquired pneumonia in patients without risk factors for these multidrug-resistant organisms (ATS/IDSA, 2005). It would seem reasonable to extrapolate to include cefotaxime in this recommendation (Chastre, 2003).

o. Infective endocarditis

Cefotaxime has potential clinical utility in the treatment of some cases of infective endocarditis, especially those due to the HACEK (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) group of organisms (H. parainfluenzae, H. aphrophilus, H. paraphrophilus, H. influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and K. denitrificans) (Kaplan et al., 1989; Feder et al., 2003; Baddour et al., 2005). These organisms account for 5–10% of native-valve community-acquired endocarditis in patients who are not intravenous drug users (Geraci and Wilson, 1982). Members of the HACEK group may be beta-lactamase producing, rendering the organisms ampicillin resistant, although ESBLs are almost nonexistent (Pitout et al., 2002). Ceftriaxone is usually preferred to cefotaxime for outpatient therapy because it can be administered once daily.

p. Urinary tract infections

Cefotaxime is useful for hospitalized children and adults with community-acquired UTIs (Committee on Quality Improvement Subcommittee on Urinary Tract Infection, 1999; Warren et al., 1999; Naber et al., 2001). Escherichia coli is isolated from about 90% of episodes of acute nonobstructive community-acquired pyelonephritis (Nicolle, 2008). Several nonrandomized and randomized clinical trials of cefotaxime-containing regimens for the treatment of UTIs show cefotaxime has similar clinical efficacy to earlier antibiotics (see Table 26.10). However, the increase in community-acquired ESBL-producing E. coli (especially of CTX-M type) observed in some parts of the world, however, may limit the future usefulness of cefotaxime in this setting (Rodriguez-Bano and Paterson, 2006).

q. Gonorrhoea

Although penicillin was the mainstay of gonorrhoea treatment for years, the emergence of penicillin-resistant N. gonorrhoeae in 1976 and its subsequent widespread dissemination has made penicillin a generally unacceptable treatment alternative for gonorrhoea (Workowski and Berman, 2006; Newman et al., 2007). Increasing resistance to fluoroquinolones has also been a significant concern (CDC, 2002; CDC, 2004; Martin et al., 2006). In general, third-generation cephalosporins retain excellent activity against these resistant strains of N. gonorrhoeae (Ieven et al., 2003; Stathi et al., 2006; Wang et al., 2006). There are a small numbers of reports of decreased susceptibility to cephalosporins, but in general these reports are rare (CDC, 2005). Most in vitro data are with ceftriaxone, for which decreased susceptibility is defined as an MIC Z0.5 mg/ml (CLSI, 2007); in contrast, diminished susceptibility to cefotaxime is defined as an MIC W0.5 mg/ml (CLSI, 2007). Decreased susceptibility of N. gonorrhoeae to ceftriaxone has been reported in India, China, Japan, the USA, and Europe (Bala et al., 2003; Zheng et al., 2003; Ito et al., 2004; CDC, 2005; Martin et al., 2006; Tanaka et al., 2006).

r. Pelvic inflammatory diseases

Cefotaxime has been used for the treatment of endomyometritis after cesarean section, pelvic cellulitis after hysterectomy, and acute pelvic inflammatory disease (see Table 26.12). Pelvic inflammatory disease is usually associated with sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis. Organisms that comprise the vaginal flora (e.g. anaerobes, G. vaginalis, H. influenzae, enteric Gram-negative bacilli, and S. agalactiae) are also implicated (Workowski and Berman, 2006). Cefotaxime is not the drug of choice for pelvic inflammatory disease, but can be an alternative regimen in combination with doxycycline plus metronidazole for the treatment of pelvic inflammatory disease (Workowski and Berman, 2006). 

s. Skin and soft-tissue infections

Clinical cure rates of various skin and soft-tissue infections with cefotaxime are 70–90%, based on the results of randomized and nonrandomized clinical trials (see Table 26.13) (McCloskey et al., 1982; Strom et al., 1982; Diaz-Mitoma et al., 1985; Perez-Ruvalcaba et al., 1987; Ramirez-Ronda et al., 1987; Gentry et al., 1989a; Gentry et al., 1989b). In one study, clinical efficacy of parenteral cefotaxime was less than that of oral ciprofloxacin in the treatment of difficult infections of the skin and skin structure (Gentry et al., 1989a), but this difference was not evident in other reports (Perez-Ruvalcaba et al., 1987; Ramirez-Ronda et al., 1987). The relevance of these studies is questionable given the changing resistance profile of many organisms to fluoroquinolones over the last 20 years.

t. Soft-tissue infections caused by Vibrio vulnificus

In vitro, cefotaxime MIC50 and MIC90 for V. vulnificus is r0.03 mg/ml in Taiwanese reports (Hsueh et al., 1995). Reports from other geographic regions have confirmed high levels of susceptibility of V. vulnificus and V. parahaemolyticus to cefotaxime (Ottaviani et al., 2001; Zanetti et al., 2001; Han et al., 2007), although V. parahaemolyticus displayed significantly higher MICs for cefotaxime than V. vulnificus (Han et al., 2007). In vitro synergy is observed with cefotaxime plus minocycline (Chuang et al., 1997), and, in murine models, cefotaxime plus minocycline appeared superior to either drug alone (Chuang et al., 1998). Synergistic antimicrobial effects of cefotaxime and minocycline on proinflammatory cytokine levels were observed in a murine model of V. vulnificus infection. Reduction in cytokine levels was greatest in mice treated with cefotaxime–minocycline combination vs minocycline or cefotaxime alone (Chiang et al., 2007). In a time–kill study, cefotaxime plus ciprofloxacin was superior to that of cefotaxime plus minocycline (Kim et al., 2005).

u. Bone and joint infections

There are a small number of clinical trials of cefotaxime for use in bone and joint infections, although most are nonrandomized (see Table 26.14). These studies demonstrate a 75–100% clinical success rate when cefotaxime is used (LeFrock and Carr, 1982; Mader et al., 1982a; Mader et al., 1982b; LeFrock et al., 1985; Loffler et al., 1988; Gomis et al., 1990). The success rates reflect cefotaxime’s in vitro activity against the major pathogens that cause bone and joint infections. S. aureus is the most common pathogen in most types of osteomyelitis, although many other microorganisms are isolated according to the type of disease and epidemiologic factors (Lew and Waldvogel, 2004; Sia and Berbari, 2006). Up to 15% of cases are due to Gram-negative bacteria, which are mostly seen in immunocompromised patients (Weston et al., 1999).

Cefotaxime has activity against methicillin-susceptible S. aureus and the vast majority of enteric Gram-negative bacilli isolated from bone-related infections (Jones et al., 2004), although cefotaxime is not the drug of choice for staphylococcal infections. It is noteworthy, however, that ESBL-producing organisms have sometimes been implicated in acute septic arthritis (Schelenz et al., 2007).

v. Lyme disease

The most widely studied cephalosporin for therapy of Lyme disease is ceftriaxone (Wormser et al., 2006; see Chapter 27, Ceftriaxone). However, cefotaxime has been evaluated in randomized trials for late stage Lyme disease (see Table 26.15), and has been shown to be similar or superior to penicillin in one such study (Hassler et al., 1990). CSF cefotaxime concentrations reached the MIC90 for B. burgdorferi in all patients studied in one evaluation, whereas none of the patients treated with penicillin G had CSF concentrations above the MIC90 (Pfister et al., 1989). Cefotaxime does not cause the biliary complications that have been associated in some cases of ceftriaxone therapy (Ettestad et al., 1995).

w. Leptospirosis

In vitro studies have indicated that cefotaxime is at least as effective as penicillin G against Leptospira strains (Oie et al., 1983; Hospenthal and Murray, 2003), and cefotaxime’s activity against Leptospira has been confirmed by animal studies (Alexander and Rule, 1986). Anecdotal early reports confirmed the clinical efficacy of cefotaxime (Thangkhiew, 1987) such that cefotaxime is recommended by some for the treatment of severe leptospirosis (Griffith et al., 2006). A recent, large, open, randomized trial comparing penicillin, doxycycline, and cefotaxime (1 g every 6 hours) for patients with severe leptospirosis confirmed the effectiveness of cefotaxime (Suputtamongkol et al., 2004). A total of 264 patients had leptospirosis confirmed by serologic testing or culture, of whom 88 were given cefotaxime. None of these patients died.

x. Fever in neutropenic hemo-oncology patients

Antipseudomonal agents are typically recommended for the empiric therapy of febrile neutropenic patients (Hughes et al., 2002; Masaoka, 2004; Jun et al., 2005). However, there are some guidelines which consider the combination of cefotaxime with an aminoglycoside or with an antipseudmonal penicillin as acceptable therapy, even in intermediate or high-risk patients (Link et al., 2003). Cefotaxime has been evaluated in a small number of studies of febrile neutropenia, but always as part of combination therapy (see Table 26.16). In one of these studies, the combination of cefotaxime plus netilmicin was inferior to ceftazidime plus netilmicin in the subgroup of patients who had undergone hematologic transplantation (Hoffken et al., 1999).

y. Surgical prophylaxis

A number of randomized trials have been performed which evaluate cefotaxime as perioperative surgical prophylaxis (see Table 26.17). In none of these studies was cefotaxime inferior to comparator antibiotics. However, there is no evidence that second- or thirdgeneration cephalosporins are superior to first-generation cephalosporins in reducing postoperative infection rates (DiPiro et al., 1984; Gorbach, 1989; Geroulanos et al., 2001). Only one study describes lower rates of postoperative infection among patients given a single preoperative dose of cefotaxime compared with multiple doses of cefazolin or cefoxitin (Campillo and Rubio, 1992). 

TOXICITY

Similar to most other cephalosporins, the majority of adverse effects attributable to cefotaxime are mild and transient. 6a. Hypersensitivity reactions and other cutaneous reactions Although reports are exceedingly rare, it could be expected that angioedema and bronchospasm, possibly culminating in anaphylactic shock, may rarely occur (Sangaret et al., 1984). Hypersensitivity in the form of rash and pruritus, necessitating discontinuation of cefotaxime administration, occurs in about 2% of patients (Todd and Brogden, 1990). A case of Stevens–Johnson syndrome possibly associated with cefotaxime use has been reported causing blisters on the skin and mucous membranes, fever, and prostration (Liberopoulos et al., 2003). Erythema multiforme is extremely rare but has been reported (Green et al., 1986). Drug fever has been reported in 0.4% of patients (Todd and Brogden, 1990). A single case of photo-induced telangiectasia has been reported in association with cefotaxime use (Borgia et al., 2000). 

b. Cardiac toxicity

Cardiac arrhythmias have occurred when cefotaxime has been administered through a central venous line over 30 s or less (Kurowski et al., 1993). In this assessment, administration of the drug over 3–5 minutes via the same route was not associated with this adverse effect.

c. Hematologic effects

Isolated cases of severe anemia, neutropenia, and thrombocytopenia have been reported. A 21-month old infant developed a severe, intravascular, immune complex mediated hemolytic anemia (nadir hemoglobin 5.3 g/dl) while receiving cefifixime. Anemia recurred three months later, after a single intramuscular dose of cefotaxime. The anemia fully resolved after discontinuation of the cefotaxime. It was thought that the hemolysis attributed to cefotaxime was due to nonimmunologic adsorption of cephalosporin to the red blood cells of the patient (Li Volti et al., 1999). Other cases of immune hemolytic anemia have been reported (Salama et al., 1987; Shulman et al., 1990; Arndt et al., 1999). Neutropenia appears rare, with one case occurring in 772 evaluable patients in one study (Smith, 1982).

d. Gastrointestinal side-effects 

Overall, gastrointestinal side-effects of cefotaxime therapy have occurred in 1.4% of patients treated in premarketing studies (Sanofifi- Aventis, 2007). The most common symptoms are nausea, vomiting, and diarrhea. In the two large studies mentioned above, diarrhea was observed in 0.44–0.97% of patients, vomiting in 0.7%, abdominal pain in 0.1%, and mucosal candidasis in 0.28% (Young et al., 1980; Jacobs et al., 1992). Like many other antibiotics, previous cefotaxime use may be associated with subsequent C. diffificile infection. Several recent reports have documented deaths attributed to C. diffificile infection (Loo et al., 2005; McDonald et al., 2005; Muto et al., 2005).

e. Hepatotoxicity

Cefotaxime use has been associated with transient increases in liver function tests (Sanofifi-Aventis, 2007). Increases in transaminases, alkaline phosphatase, and bilirubin occurred in 1.4%, 7.9%, and 2.2% of patients treated with cefotaxime, respectively (Smith, 1982). This is similar to what is observed with other cephalosporins (Smith, 1982).

f. Effects on laboratory tests 

Treatment with cephalosporins, including cefotaxime, may occasionally result in positive direct Coombs’ tests (Sanofifi-Aventis, 2007). Cephalosporanic nucleus of cefotaxime may interfere with oxidationreduction reactions used in tests for determining the presence of urine glucose, thus producing a false-positive glucose result (Todd and Brogden, 1990). 

g. Neurologic and ophtlamic effects 

Hallucinations, vertigo, or disorientation occurred in 0.3% of 2157 treated patients, but no instances of epileptic seizures or myoclonus were noted in this report (Smith, 1982). Cefotaxime-associated headache has been reported (Sanofifi-Aventis, 2007). Intravenous administration of cefotaxime has not been associated with ocular toxicity. Intraocular administration of cefotaxime produced no signifificant changes in corneal endothelium in a study of patients undergoing cataract surgery (Kramann et al., 2001).

h. Nephrotoxicity 

Interstitial nephritis and increases in urea or creatinine have been noted occasionally in patients treated with cefotaxime (Sanofifi- Aventis, 2007). Two cases of acute interstitial nephritis have been reported. In a report of a 28-year-old man who had been given cefotaxime 500 mg i.m. daily for 5 days, creatinine increased to 1460 mmol/l (16.6 mg/dl). A renal biopsy showed that the tubulointerstitium was infifiltrated by chronic inflflammatory cells, including occasional eosinophils. The patient required dialysis for 10 days before the renal function returned to normal (al Shohaib et al., 1996). A second case of acute interstitial nephritis related to cefotaxime treatment was associated with antineutrophil cytoplasmic antibody (ANCA)-mediated renal vasculitis. Recovery of renal function and disappearance of ANCA occurred when cefotaxime was discontinued (Feriozzi et al., 2000). 

i. Fungal superinfection 

A 30-year-old woman died from Candida parapsilosis superinfection during a 27-month course of cefotaxime for an unsubstantiated diagnosis of chronic Lyme disease (Patel et al., 2000). This case highlights the hazards of prolonged antibiotic therapy and its effects on microbial flflora.

j. Injection site reactions

Local reactions following i.m. or i.v. injection occur in 4.3% of patients receiving cefotaxime (Sanofifi-Aventis, 2007). In two large studies (comprising more than 2000 patients each), phlebitis was reported in 0.3–0.4% of patients receiving cefotaxime (Young et al., 1980; Jacobs et al., 1992). Phlebitis occurred with both bolus injections and i.v. infusions. 

k. Risks 

in pregnancy Cefotaxime is a Food and Drug Administration Pregnancy Category B drug (Sanofifi-Aventis, 2007) and an Australian Drug Evaluation Committee Category B1 agent (Australian Drug Evaluation Committee, 1999). Like other cephalosporins, cefotaxime is generally considered safe for use in pregnancy (Weinstein, 1979; Schwarz, 1981). Cefotaxime has been reported to produce detectable concentrations in cord blood, amniotic flfluid, and fetal blood (Cho et al., 1982). The product information of the drug states that no evidence of fetal harm occurred in mice or rats (Sanofifi-Aventis, 2007). No teratogenic effects related to cefotaxime use have been reported, and there are no reports of adverse outcomes after inadvertent exposure during pregnancy (Berkowitz et al., 1981; Sanofifi-Aventis, 2007).

l. Breastfeeding

Previous studies show that the amount of cefotaxime excreted into breast milk after maternal administration is low (Kafetzis et al., 1981b; Takase, 1981). Cefotaxime is suggested to be safe for administration during breastfeeding (Matsuda, 1984; American Academy of Pediatrics Committee on Drugs, 2001).

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