Cefoperazone/sulbactam: Clinical Uses and Toxicity

Given that cefoperazone–sulbactam is the predominant formulation used at the present time, discussion regarding clinical uses will concentrate on this drug combination.

a. Intra-abdominal infection

Intra-abdominal infections caused by endogenous gastrointestinal microflora are usually polymicrobial and involve aerobic and anaerobic bacteria. The successful treatment of these infections requires surgical intervention together with antimicrobial therapy aimed at both the aerobic and anaerobic intestinal flora. Among the more common isolates from infections caused by intra-abdominal disease are Enterobacteriaceae and B. fragilis. Cefoperazone–sulbactam has the required activity, except against ESBL-producing isolates.

Clinical studies of cefoperazone–sulbactam in patients with intraabdominal infections have been encouraging. In a randomized trial involving 152 patients with intra-abdominal infections, of which 76 patients were treated with cefoperazone–sulbactam, Jauregui et al. (1990) found that cure rates for patients receiving cefoperazone–sulbactam were significantly higher than those of patients receiving clindamycin– gentamicin (86.8% in sulbactam–cefoperazone group vs 61.8% in the clindamycin–gentamicin group; (po0006). However, in another similar study, Greenberg et al. (1994) found no statistically significant difference in cure rates among the two groups. Thirty-three of 47 patients (70%) who received cefoperazone–sulbactam therapy were cured, compared with 15 patients (52%) who received clindamycin–gentamicin. Chandra et al. (2008) also found encouraging results for this indication (Chandra et al., 2008).

b. Febrile neutropenia

In an open evaluation by Bodey et al. (1993), cefoperazone–sulbactam (1 g sulbactam/2 g cefoperazone given at 8-hourly intervals) proved to be an effective regimen for initial therapy of fever in cancer patients, achieving an overall response rate of 76%. A prospective randomized trial comparing this combination with imipenem–cilastatin found a similar response rate (73% in cefoperazone–sulbactam group vs 74% in imipenem–cilastatin group). Interestingly, the cefoperazone–sulbactam group also reported a significantly lower rate of superimposed infection by C. difficile colitis (Bodey et al., 1996).

However, owing to its lack of activity against methicillin-resistant staphylococci, cefoperazone–sulbactam should be combined with a glycopeptide in those institutions where infections caused by these strains are frequently encountered (Bodey et al., 1996). In a prospective randomized controlled trial, cefoperazone– sulbactam at a higher dose of 4/2 g but longer duration (every 12 hours) were compared with imipenem at 500 mg every 6 hours as empirical monotherapy for febrile, granulocytopenic patients. Of 101 patients receiving cefoperazone–sulbactam, the overall favorable clinical response rates for cefoperazone–sulbactam was 88% (91 of 103 patients) which is similar to imipenem (84 of 104 patients, or 81%). 

Apart from a higher incidence of diarrhea with cefoperazone– sulbactam, the drug was well tolerated (Winston et al., 1998). Cefoperazone–sulbactam was also as effective as piperacillin combined with amikacin for early empirical therapy in neutopenic patients in a small evaluation 29 (96.7%) of 30 patients successfully treated vs 15 (93.8%) of 16, respectively (El Haddad, 1995). The rate of defervescence without modification of treatment was significantly higher in the cefoperazone–sulbactam group (p=0.03). In addition, probably because of its broader coverage of anti-Gram negative and anti-anaerobes; this combination regimen has resulted in fewer treatment modifications (20% in the cefoperazone–sulbactam group and 50% in piperacillin–amikacin group; po0.04).

c. Melioidosis

The dosage of antibiotics used for the treatment of melioidosis is typically high, especially during the intensive phase of therapy. However, cefoperazone–sulbactam at a ‘‘low’’ dose of 25 mg/kg/day of cefoperazone given three times a day (plus co-trimoxazole) was as effective as a high dose of ceftazidime plus co-trimoxazole in the treatment of severe melioidosis. In a randomized controlled trial involving 100 patients with severe melioidosis in Thailand, Chetchotisakd et al. (2001) observed that the outcomes were similar in terms of the mortality rate [18% (9 of 50) of cefoperazone–sulbactam recipients died, and 14% (7 of 50) of ceftazidime recipients died; 0.9% (95% CI,  3.6% to 5.4%; p=0.696)], bacterial eradication (i.e. median eradication was 2 days in both groups; p=0.791), and mean and median duration of time to defervescence. Of note, patients treated with cefoperazone–sulbactam tended to experience septic shock less often than those in the ceftazidime group. The authors of this study attributed this to the synergistic effects of both cefoperazone and sulbactam. The conclusions of this study have been criticized by Apisarnthanarak and Little (2002), who pointed out that the study was underpowered and, therefore, that it is risky to recommend cefoperazone–sulbactam as an alternative to ceftazidime on the basis of this study alone.

d. Hospital-acquired pneumonia

A randomized trial by Li et al. (1997) examined patients with moderate to severe hospital-acquired infection – 46% had respiratory infection (predominantly pneumonias), 34% had urinary tract infections, and 20% had skin and/or soft-tissue infections or other bacterial infections. The overall efficacy rates (defined as cures or markedly improved) were 95% for the cefoperazone–sulbactam group versus 90% for the cefotaxime group. Bacterial eradication rates were 85% and 81%, respectively. These differences were not statistically significant. In a small subgroup analysis of pneumonia patients by Choi et al. (2006), cefoperazone–sulbactam treatment resulted in 60% (9/15) complete and partial response, compared with 80% (8/10) in the imipenem treatment arm (p=0.402).

e. Acinetobacter infections

Acinetobacter baumannii infections are typically encountered in hospitalized patients – the choice of appropriate antimicrobial therapy is limited by the fact that resistance rates to many antimicrobial agents can be very high (Cisneros et al 1996; Halstead et al., 2007).

Data on the efficacy of cefoperazone–sulbactam therapy for the treatment of A. baumannii infection are limited, although some extrapolation can also be made from results with ampicillin–sulbactam, as it is the sulbactam moiety not the beta-lactam which has the anti-Acinetobacter activity (see Chapter 12, Sulbactam). Choi et al. (2006) examined the effectiveness of cefoperazone–sulbactam compared with imipenem–cilastatin for patients with A. baumannii bacteremia. Of 35 patients treated with cefoperazone–sulbactam (and in whom the organism was susceptible to the drug combination), the overall 7-day mortality rate was lower in the cefoperazone– sulbactam group than in the imipenem–cilastatin group, but this was not statistically significant (17.1% for cefoperazone–sulbactam group vs 33.3% for imipenem–cilastatin group, p=0.251). Thirty-day mortality rate was also lower in the cefoperazone–sulbactam group than in the imipenem–cilastatin group, but again this was not significant (20% for cefoperazone–sulbactam group vs 50% for imipenem–cilastatin group, p=0.065). The percentage of complete and partial responses was not statistically different (77% for the cefoperazone–sulbactam group vs 75% for the imipenem–cilastatin group). In the subgroup of pneumonia patients, the response rates were also not significantly different. The author concluded that cefoperazone–sulbactam may be as good as imipenem–cilastatin for the treatment of Acinetobacter bacteremia.

f. Extended-spectrum 

beta-lactamase producing organisms Bin et al. (2006) analyzed the outcome of different antibiotic treatments for bacteremia due to CTX-M-type ESBL-producing E. coli. Of seven patients treated with cefoperazone-sulbactam, five (71.4%) achieved cure (MIC range 0.5–8 mg/ml). Few other published data exist on treabtment of ESBL producers with cefoperazone– sulbactam.

TOXICITY

Similar to other cephalosporins, allergic rashes occasionally occur with cefoperazone (Gordon and Phyfferoen, 1983). Diarrhea follows parenteral cefoperazone therapy more commonly than after other parenteral cephalosporins (File et al., 1982; File et al., 1983; Gordon and Phyfferoen, 1983). In one study, diarrhea occurred in 12 of 52 patients treated with cefoperazone, and in five C. difficile and its toxin was found in the feces; in another 11, stools were looser than normal, and C. difficile and its toxin were present in three (Carlberg et al., 1982). Cefoperazone therapy can be associated with major changes in fecal flora. There is suppression of anaerobic cocci, Gram-negative anaerobes and Enterobacteriaceae, and acquisition of enterococci, Candida spp., and, in some patients, C. difficile (Mulligan et al., 1982; Alestig et al., 1983). This is because the drug is excreted mainly through the bile into the gut.

The nephrotoxic potential of cefoperazone appears to be low, and it has been used with furosemide or aminoglycosides, such as gentamicin, without encountering renal toxicity (Trollfors et al., 1982; Gordon and Phyfferoen, 1983). In common with cefamandole, cefotetan, and moxalactam, cefoperazone contains an N-methylthiotetrazole side-chain, and it may cause hypoprothrombinemia and bleeding, particularly in elderly malnourished, vitamin K-deficient patients.
Administration of parenteral vitamin K may prevent this complication (Carlberg et al., 1982; Gordon and Phyfferoen, 1983; Smith and Lipsky, 1983), and this is routinely performed in some centers. In one patient reported by Parker et al. (1984), cefoperazone caused coagulopathy and clinical bleeding, despite previous administration of i.v. vitamin K. Cefoperazone can inhibit ADP-induced platelet aggregation, but this only occurs with very high serum levels (Bang and Kammer, 1983).

Mild elevations of transaminases have occasionally been noted with cefoperazone usage (Carlberg et al., 1982). Eosinophilia, reversible neutropenia, and a positive direct Coombs’ test have been reported (Strausbaugh and Llorens, 1983; Warren et al., 1983). Cefoperazone inhibits neutrophil chemotaxis in vitro, but the clinical significance of this is not known (Fietta et al., 1983). Cephalosporins with an N-methylthiotetrazole side-chain, such as cefoperazone, have shown adverse effects in the testes of neonatal rats (Lipsky, 1986).

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