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

Cefoperazone is referred to as an extended-spectrum or thirdgeneration cephalosporin. It is stable to some beta-lactamases, particularly those produced by Gram-negative bacteria, and has potency against most wild-type Enterobacteriaceae. It also has moderate to good activity against Pseudomonas aeruginosa (Dunn, 1982). The molecular weight of cefoperazone is 667.65; its formula is C25H27N9O8S2 and its structure is shown in Figure 25.1.
The addition to cefoperazone of the beta-lactamase inhibitor, sulbactam (see Chapter 12, Sulbactam), expands the spectrum to include Acinetobacter baumannii and some Gram-negative organisms with broader spectrum beta-lactamases. In particular, the combination of cefoperazone and the beta-lactamase inhibitor sulbactam is more resistant to attack by class A beta-lactamases but remains vulnerable to isolates producing class C beta-lactamases (Williams, 1997; Bijie et al., 2005).

Figure 25.1 Chemical structure of cefoperazone.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility Gram-positive aerobic bacteria

Cefoperazone is about as active as cefotaxime against Staphylococcus aureus and coagulase-negative staphylococci, but methicillin-resistant strains are resistant to cefoperazone. Streptococcus pneumoniae, including strains relatively resistant and highly resistant to penicillin G, need slightly higher concentrations of cefoperazone than of cefotaxime for inhibition (Ward and Moellering, 1981; Tweardy et al., 1983). Compared with cefotaxime, its activity against S. pyogenes is similar, but group B streptococci and most viridans streptococci are slightly less susceptible (Jacobs et al., 1982; Jones and Barry, 1983a). Enterococcus faecalis is resistant and Listeria monocytogenes is moderately resistant.

Gram-negative aerobic bacteria

Meningococci are quite susceptible to cefoperazone, but slightly less so than to ceftriaxone or cefotaxime (Scribner et al., 1982). This also applies to gonococci including beta-lactamase-producing strains, but the reported degree of sensitivity of the latter has varied (MICs for non-beta-lactamase-producing strains are r0.004–0.5 and for betalactamase-producing strains 0.125–0.5 mg/ml (Rodrı`guez et al., 1983).

Cefoperazone is active against nearly all wild-type strains of the Enterobacteriaceae, though to a lesser degree than other thirdgeneration cephalosporins such as cefotaxime and ceftriaxone (Hall et al., 1980; Jones et al., 1980; Magnussen et al., 1982; Jones and Barry, 1983a; Sykes and Bush, 1983). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of cefoperazone against many Enterobacteriaceae are inoculum dependent (Hinkle et al., 1980; Lang et al., 1980). Overall, in the group of Enterobacteriaceae with cefoperazone MICs between 2 and 32 mg/ml, sulbactam enhanced the activity of cefoperazone against 56% of tested strains (Fass et al., 1992). When cefoperazone MICs were 64 mg/ml or greater, sulbactam enhanced the activity of cefoperazone against 80– 90% of strains (Fass et al., 1992), indicating some activity against extended-spectrum beta-lactamases (ESBLs). A recent trial from Turkey reported results concerning 1196 Gram-negative clinical isolates, mostly cultured from blood, urine, and respiratory secretions. Resistance of isolates to cefoperazone–sulbactam was 6% for Escherichia coli (26% of which were ESBL positive) and 17.7% for Klebsiella pneumoniae (32% of which were ESBL positive) (Akova 2008).

Against Haemophilus influenzae, cefoperazone is not quite as active as ceftriaxone or cefotaxime. Cefoperazone shows inoculum-dependent decreases in inhibitory and bactericidal activity when tested against beta-lactamase-producing strains (Bulger and Washington, 1980; Wise et al., 1981); H. parainfluenzae is also cefoperazone-susceptible. Bordetella pertussis, Pasteurella multocida, Aeromonas hydrophila, and the Moraxella spp. are usually susceptible to cefoperazone. Flavobacterium and Legionella pneumophila typically lack susceptibility (Edelstein and Meyer, 1980; Fass et al., 1980; Jones and Barry, 1983a).

Acinetobacter spp. are cefoperazone resistant. Sulbactam, however, has direct activity against Acinetobacter because it has high affinity to the organism’s penicillin-binding protein 2 (Akova 2008). Thus, even in settings with a high proportion of multidrug-resistant A. baumannii strains, at least 60% are susceptible to cefoperazone–sulbactam (Akova 2008).

Cefoperazone has a moderately high degree of activity against P. aeruginosa. Historically, approximately 50% of all isolates are inhibited by 4 mg/ml, and 90% by 32 mg/ml (Kurtz et al., 1980; Mitsuhashi et al., 1980; Gillett, 1982; File and Tan, 1983). Thereby, amongst beta-lactams, the drug has about the same potency as piperacillin, but slightly less activity than ceftazidime. The MICs of cefoperazone against P. aeruginosa increase if the sensitivity tests are carried out with large inocula. An increase in inoculum concentration from 105 to 107 cells/ml results in a significant loss of activity (Hinkle et al., 1980). The addition of sulbactam enhances the in vitro antipseudomonal activity of cefoperazone in about 25% of strains (Fass et al., 1980).

Usually Burkholderia cepacia is moderately resistant to cefoperazone. Cefoperazone is similar to other beta-lactams in activity against Stenotrophomonas maltophilia (Fass, 1980; Appelbaum et al., 1982).

Anaerobic bacteria

Some Gram-positive anaerobes, such as Peptococcus and Propionibacterium spp. and Clostridium perfringens, are cefoperazone susceptible; C. difficile is resistant (Rolfe and Finegold, 1981; Denys et al., 1983). Some of the anaerobic Gram-negative bacilli, such as Prevotella and Fusobacterium spp., are usually cefoperazone susceptible. Organisms of the B. fragilis group are variable in their cefoperazone susceptibility. Some strains are inhibited by low cefoperazone concentrations, but 50% and 90% require 64 and 128 mg/ml, respectively, for inhibition (Rolfe and Finegold, 1981; Muytjens and Van der Ross-van de Repe, 1982; Sutter, 1983). Sulbactam adds considerably to the antianaerobic activity of cefoperazone. Not only does sulbactam inhibit some betalactamases produced by B. fragilis, it also may have direct activity on the penicillin-binding protein 2 of the organism (Akova 2008).

c. In vitro synergy and antagonism

Cefoperazone, when combined with aminoglycosides such as amikacin, frequently exhibits in vitro synergism against many Enterobacteriaceae (Hinkle et al., 1980; Jones and Packer, 1982; Van Laethem et al., 1983). In a study by Isenberg et al. (1999), combinations of cefoperazone with ciprofloxacin were found to be synergistic against 50% of the S. maltophilia isolates, and combination with levofloxacin showed significant synergy against 50% B. cepacia isolates (Fass, 1980; Appelbaum et al., 1982; Isenberg et al., 1999).

MECHANISM OF DRUG ACTION

Cefoperazone acts in a manner similar to other cephalosporins. As noted above, sulbactam is a betalactamase inhibitor so ‘‘protects’’ cefoperazone from the effects of some (but not all) beta-lactamases. Sulbactam also has direct effects on penicillin-binding protein 2 of Acinetobacter spp. and Bacteroides fragilis. 

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

The usual adult dosage of cefoperazone is 1–2 g, given i.m. or i.v. 12-hourly. For serious infections, the total daily adult dose can be increased to 6–12 g, given in two, three, or four divided doses. Cefoperazone can be given i.m. dissolved in a 0.5% lignocaine solution. Individual i.v. doses can be administered over 3–5 minutes, or infused more slowly over intervals of 30–60 minutes (Balant et al., 1980; Gordon and Phyfferoen, 1983; Lyon, 1983).

b. Newborn infants and children

The cefoperazone dosage for children is 50–100 mg/kg body weight per day, given in two divided doses; for serious infections, up to 200 mg/kg/ day has been used, administered in two, three, or four divided doses.

In newborn infants aged 1–7 days, the cefoperazone half-life is prolonged about 3-fold, and a single dose of 50 mg/kg body weight produces high serum levels for 24 hours. As cefoperazone is mainly eliminated via the liver, prolongation of its half-life is probably a result of immaturity of hepatic function in neonates (Rosenfeld et al., 1983). According to Bosso et al. (1983), a 50 mg/kg dose every 12 hours may be safe and effective for the treatment of serious infections in newborn and premature infants.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The pharmacokinetics of cefoperazone have been reviewed (Craig and Gerber, 1981). Neither cefoperazone nor sulbactam is well absorbed after oral administration. Srinivasan et al. (1981) administered 2 g cefoperazone doses to volunteers as a 30-minute i.v. infusion. At the end of the infusion, the mean serum level was 256 mg/ml, and, at 1, 4, 6, 8, and 12 hours after, infusion levels were 108, 20, 11, 4.2, and 0.25 mg/ml, respectively. These results were similar to those obtained by Standiford et al. (1982). Cefoperazone produces high serum levels early because of its smaller volume of distribution in the ‘‘central compartment’’ of the body compared with many other cephalosporins. Cefoperazone’s smaller distribution may be related to its higher protein binding, which is 90%. Drugs with longer half-lives may have higher concentrations than those of cefoperazone after 4 hours, because the longer half-life counterbalances cefoperazone’s larger volume of distribution.

Co-administration of sulbactam with cefoperazone did not significantly alter the pharmacokinetics of either drug (Reitberg et al., 1988b), suggesting that co-administration of sulbactam will not affect the usual dosing regimen for cefoperazone (Foulds et al., 1983). The safety profiles are similar to those for the individual agents administered separately. The only pharmacokinetic alteration observed when comparing individual to combination drug administration was a minor (about 10%) but statistically significant decrease in sulbactam renal clearance for the combination, resulting in a similar decrease in total body clearance (Reitberg et al., 1988a).

b. Drug distribution

Cefoperazone penetrates into most body fluids and tissues (Lyon, 1983). After usual therapeutic doses, adequate concentrations were attained in skeletal muscle and surgical wound drainage fluid (Muder et al., 1984). Mean sputum concentrations of 0.08–6.1 mg/ml were detected in patients treated for respiratory tract infections. Adequate levels were reached in ascitic fluid, and the drug crossed the placenta (Shimizu, 1980). After a 2 g i.m. dose, concentration of the drug in pelvic tissue was some 20 mg/g, approximately 3 hours later (Bawdon et al., 1982).

Cefoperazone does not penetrate into normal cerebrospinal fluid (CSF) to any extent, but it does in animals with induced bacterial meningitis (Perfect and Durack, 1981; Schaad et al., 1981; McCracken et al., 1982). In neonates given a single i.v. dose of 50 mg/kg body weight, CSF levels in those with bacterial meningitis were in the range 2.8–9.5 mg/ml, whereas, for those without meningitis, this value was 1–7 mg/ml (Rosenfeld et al., 1983). Ten children and five adults with bacterial meningitis were given cefoperazone, either as a single dose of 50 mg/kg, a single dose of 100 mg/kg, or three doses of 100 mg/kg, 8 hourly. Of 44 CSF samples, only 26 had detectable cefoperazone levels (range o0.8–11.5 mg/ml). In summary, cefoperazone may not reach the CSF of patients with bacterial meningitis as well as other third-generation cephalosporins (Cable et al., 1983).

c. Excretion

Only 20–30% of an administered dose of cefoperazone is excreted in the urine as the unchanged drug. Nevertheless, therapeutic urinary levels of the active drug are achieved; they exceed 25 mg/ml during the first 8 hours after a 2 g i.v. dose (Srinivasan et al., 1981; Standiford et al., 1982). Renal excretion of cefoperazone is mainly by glomerular filtration; tubular secretion appears to play a minor role.

Cefoperazone is metabolized in the body only to a minor extent. The principal metabolite is cefoperazone A, which has an antibacterial activity some 16-fold less than the parent drug. Small amounts of this metabolite are found in human bile (Jones and Barry, 1983b). The major excretory pathway for cefoperazone is via the bile in its active form. In animals, biliary recovery accounts for 79% of an administered dose (Greenfield et al., 1983). In humans, probably some 60–80% of the administered dose is excreted via the bile, a percentage higher than for any other available cephalosporin. This may be because cefoperazone has the highest molecular weight (Turnidge and Craig, 1983). It has been difficult to confirm that such a high percentage of the drug is eliminated by bile in humans. Kemmerich et al. (1983) found that 18.5% (range 3.8– 37.5%) of an administered dose was excreted in bile, but these estimations were made in patients with T-tube drainage following biliary surgery, in whom there was still some element of hepatic dysfunction, which would affect biliary excretion. A prolonged half-life and compensatory increase in urine elimination of cefoperazone indicated significant hepatic dysfunction in these patients. Very high peak biliary concentrations of cefoperazone (481–6598 mg/ml) are attained in patients with T-tubes and relatively normal hepatic function (Shimizu, 1980; Greenfield et al., 1983; Kemmerich et al., 1983). Although high biliary levels of cefoperazone imply significant biliary excretion, the total amount of the drug eliminated by this pathway has not been adequately determined for humans (Greenfield et al., 1983). Biliary tract obstruction stops cefoperazone excretion via the bile, but 24 hours after relief of obstruction, passive excretion of the drug in bile occurs, even though the active excretion mechanism has not yet recovered (Leung et al., 1990).

d. Drug interactions

As cefoperazone, like cefamandole and moxalactam, has an N-methylthiotetrazole side-chain, it can cause a disulfiram-like reaction if alcoholic beverages are ingested during, or several days after cessation of its administration (Buening and Wold, 1982). Concomitant administration of probenecid only causes slight elevation of the serum levels of cefoperazone, and prolongation of its half-life from 92 to 109 minutes (Shimizu, 1980).

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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