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

Cefpirome is a parenteral fourth-generation cephalosporin antibiotic (aminothiazolemethoxyimine cephalosporin). Like cefepime, it shows broad-spectrum activity against many Gram-positive and Gramnegative bacteria, including most species of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus (Hancock et al., 1992; Wiseman and Lamb, 1997). Its use has been greatly overshadowed by that of cefepime in recent years, and the reader is referred to the cefepime chapter for a more detailed examination of fourth generation cephalosporins (see Chapter 32, Cefepime). In India, cefpirome has been combined with tazobactam (Livermore et al., 2008) – this combination has not become available elsewhere and will not be discussed in detail.

The molecular weight of cefpirome is 612.67 and its chemical formula is C22H22N6O5S2  H2SO4. Its structure is illustrated in Figure 31.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

There are very few recent data published regarding the activity of cefpirome against the most frequently detected Gram-positive and Gram-negative clinical isolates (Table 31.1). The majority of recent multicenter studies have reported epidemiologic information only regarding cefepime (as a representative antibiotic of the fourthgeneration cephalosporins). In general, cefpirome MICs for Grampositive and Gram-negative clinical isolates are similar to those of cefepime (Wiseman et al., 1997).

Gram-positive aerobic bacteria

Cefpirome is universally active against oxacillin-susceptible staphylococci (Ishii et al., 2008). It also has activity against most streptococci, including Streptococcus pneumoniae. Cefpirome is inactive against methicillin-resistant S. aureus (MRSA) and enterococci.

Gram-negative aerobic bacteria

Cefpirome has similar activity to cefepime against most of the Enterobacteriaceae. However, isolates of P. aeruginosa were more susceptible to ceftazidime (8.7% resistance) and cefepime (8.9%) than cefpirome (16.2%) in one recent evaluation (Ishii et al., 2008).

Cefoperazone/sulbactam, cefepime, and ceftazidime show a susceptibility advantage over cefpirome for Acinetobacter spp. as well (Ishii et al., 2008).

Anaerobic bacteria

Cefpirome lacks clinically useful activity against anaerobic bacteria. However, combination of cefpirome with tazobactam has excellent activity against anaerobes (Jones et al., 1990), suggesting that much of the resistance to cefpirome alone is a result of beta-lactamase production.

b. Emerging resistance and cross-resistance

In general, cefpirome is stable to the effects of AmpC beta-lactamases (Hanson, 2003). However, novel AmpC beta-lactamases which are able to hydrolyze cefpirome have been described (Ahmed and Shimamoto, 2008). Some extended-spectrum beta-lactamases also hydrolyze cefpirome, leading to clinically apparent resistance. c. In vitro synergy and antagonism The addition of beta-lactamase inhibitors to cefpirome has the potential to expand its spectrum of activity.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

According to the manufacturer’s instructions, the following scheduled dosages should be used for the cefpirome treatment: complicated upper and lower urinary tract infections (1 g every 12 hours), skin and soft-tissue infections (1 g every 12 hours), lower respiratory tract infections (1–2 g every 12 hours), bacteremia (2 g every 12 hours), severe infections in intensive care unit (ICU)-patients (2 g every 12 hours), and infections in neutrbopenic and immunocompromised patients (2 g every 12 hours)

b. Newborn infants and children

There is very limited dosing information on cefpirome in premature neonates, infants, and children.

c. Altered dosages

Impaired renal function

Since cefpirome is eliminated from the body via the kidneys, the dosage should be reduced in these patients to compensate for the slower excretion. Elimination half-lives after single i.v. doses of 2 g to patients with creatinine clearance W50 ml/min, 20–50 ml/min, 10–20 ml/min and o10 ml/min were 2.6, 9.2, 9.8, and 14.5 hours, respectively. Consequently, dose adjustments are required in renally impaired patients at creatinine clearance levels below 50 ml/min. If the glomerular filtration rate is 20–50 ml/min, dosage should be reduced to 50% of usual quantity.

Impaired hepatic function

There are no data to suggest that dosing regimens should be altered in patients with impaired hepatic function.

Premature neonates

There are no data to guide dosing in premature neonates. 

The elderly

No dose adjustments are required in the elderly, unless renal impairment is present.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cefpirome is not absorbed after oral administration; therefore, it has to be given either by the intramuscular or intravenous routes. Serum protein binding is less than 10% (Wiseman and Lamb, 1997).

b. Drug distribution

After a 1 g i.m. dose of cefpirome, the average peak (Cmax) serum level was 23.2 mg/ml, and this was reached 1.9 hours after the injection; 12 hours later the serum level was less than 1 mg/ml. Doubling the dose doubles the Cmax serum level, but does not significantly prolong the serum level beyond 12 hours. The half-life of cefpirome was 2 hours (Meyer et al., 1992). In another study, the Cmax level after 1 hours i.v. infusion of 1 g cefpirome was approximately 60 mg/ml. If a 2-g dose was administered, the peak level was doubled (i.e. 119 mg/ml). The average half-life was again 2 hours, and the level approached 1 mg/ml after 12 hours. There was no accumulation of cefpirome after multiple 12-hourly doses (Craig, 1993). In patients older than 65 years, the Cmax serum level after a single i.v. dose of 2 g to healthy elderly subjects was 174 mg/ml. The elimination half-life was 3.4 hours, and urinary excretion of the unchanged product was 71% after 24 hours. After i.v. repeated doses of 1 and 2 g, Cmax amounted to 127 and 231 mg/ml, respectively. The elimination half-life after the same doses was approximately 4.5 hours (Wiseman and Lamb, 1997).

c. Clinically important pharmacokinetic and pharmacodynamic features

Like other cephalosporins, cefpirome is a time-dependent killer. The pharmacodynamics of cefpirome in critically ill populations have been extensively studied by Lipman et al. (2001). Standard dose recommendations of cefpirome, such as other b-lactams, in ICUpatients without renal dysfunction, can result in very low levels of antibiotic at the end of the dosing intervals (Lipman et al., 2001). In fact, creatinine clearance, which is the principal determinant of cephalosporin clearance, may be more than the assumed normal range in the critically ill patients as a result of high glomerular filtration. 

d. Excretion

Cefpirome is eliminated in the urine by glomerular filtration. The urinary recovery at 24–48 hours ranges from 66% to 100%. More than 95% of the administered dose can be recovered from the urine. The drug is not metabolized in the body to any appreciable extent. Less than 4% of drug may be eliminated in the feces, presumably because of biliary excretion (Meyer et al., 1992; Craig, 1993).

e. Drug interactions

There is no evidence that cefpirome negatively affects renal function at normal therapeutic dosages. Probenecid interferes with the renal tubular transfer of cephalosporins, delaying their extraction and thus increasing their plasma concentration (Wiseman and Lamb, 1997).

TOXICITY

Cefpirome is generally well tolerated. The overall incidence of adverse events possibly related to treatment (12.5%) was similar to that of other cephalosporins used in the clinical trials. Cefpirome was discontinued in 5.1% of cases (5% for comparator cephalosporins). The following adverse events have been reported: hypersensitivity reactions (angioedema, bronchospasm, malaise, possibly culminating in shock, may rarely occur); cutaneous (rash, pruritus, urticaria, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis); gastrointestinal tract (nausea, vomiting, abdominal pain, diarrhea, pseudomembranous colitis); renal function (slight increases in serum creatinine, acute renal failure in rare cases); liver function (increased plasma levels of transaminases, g-GT, LDH, bilirubin and/or alkaline phosphatase); blood constituents (thrombocytopenia, eosinophilia, and very rarely hemolytic anemia); local reactions (phlebitis, thrombophlebitis and pain at the site of injection); central nervous system (very few cases of convulsions, reversible encephalopathy, impairment of consciousness, abnormal movements, convulsions); cardiovascular system (hemorrhage, ecchymosis and altered rhythm); respiratory (dyspnea); headache, fever, taste, and/or smell disturbances shortly after injection (Donaubauer and Mayer, 1992; Wiseman and Lamb, 1997).

CLINICAL USES OF THE DRUG

Cefpirome is indicated in various parts of the world for lower respiratory tract infections, complicated urinary tract infections, skin and soft-tissue infections, bacteremia–septicemia, and infections in neutropenic and immunocompromised patients (Sanders et al., 1996). 

a. Empiric management of fever in neutropenic patients

Cefpirome, by virtue of its enhanced antimicrobial activity against Gram-positive pathogens, b-lactamase stability, and activity against P. aeruginosa, is an option among broad-spectrum b-lactams for use in the empiric treatment of febrile episodes in neutropenic patients. In a recent analysis, 132 neutropenic patients received a dose of cefpirome of 2 g every 12 hours i.v. Overall, clinical outcome improved after treatment in 89% of patients. The mean time of fever resolution was 3.1 days (Su et al., 2007). In another study, 208 febrile neutropenic episodes were randomized to treatment using either cefpirome 2 g every 12 hours (105 cases) or piperacillin–tazobactam 4 g every 8 hours (103 cases). Two days after initiation of antibiotics, clinical (fever disappearance) and microbiologic (culture negative) success rates were 62% and 50% for cefpirome versus 61% and 55% for piperacillin–tazobactam, respectively. At the end of protocol, success rate was 59% with cefpirome versus 50% with piperacillin/tazobactam (p=0.27) (Bauduer et al., 2001).

b. Empiric management of serious infection in non-neutropenic patients

Cefpirome showed equivalent efficacy and safety to ceftazidime in the empirical treatment of suspected bacteremia or sepsis. A multicenter, randomized trial was performed to compare cefpirome at a dose of 2 g every 12 hours with ceftazidime (2 g every 8 hours) in the empirical treatment of suspected bacteremia in patients with severe sepsis. The majority of patients had community-acquired infections. In patients with a positive blood culture treated Z48 hours, the clinical success rates were 77% for cefpirome and 67% for ceftazidime, with no significant difference between the two. In patients with bacteriologically proven infection, 89% of patients treated were assessed as cured independently of the drug used (Norrby et al., 1998).

c. Hospital-acquired and ventilator-associated pneumonia

In an international multicenter open-label randomized comparative study, adult patients in ICUs were enrolled to receive i.v. 2 g every 12 hours cefpirome or i.v. ceftazidime 2 g every 8 hours for the empiric treatment of pneumonia. Of the 400 enrolled patients, 201 received cefpirome (monotherapy, 56%) and 199 received ceftazidime (monotherapy, 51%). Pneumonia was hospital-acquired for 75% of the patients. For the cefpirome and ceftazidime groups, there were 35% versus 30% clinical failures among monotherapy-stratified patients, respectively, and 34% versus 42% clinical failures among combination therapy-stratified patients, respectively. The mortality rates within 2 weeks after the end of treatment were similar (cefpirome group, 31%; ceftazidime group, 26%), as were the percentages of patients with at least one treatment-related adverse event (17% and 19%, respectively). Therefore, an empiric treatment strategy with cefpirome at 2 g every 12 hours is equivalent in terms of efficacy and tolerance to ceftazidime at 2 g every 8 hours for the treatment of pneumonia in patients in ICUs (Wolff, 1998).

d. Urinary tract infection

In clinical trials, patients with complicated urinary tract infections have responded to cefpirome at least as well as to ceftazidime (Norrby et al., 1988; Carbon and Cefpirome Study Group, 1992; Norrby and Geddes, 1993).

References

Ahmed AM, Shimamoto T (2008). Emergence of a cefepime- and cefpiromeresistant Citrobacter freundii clinical isolate harbouring a novel chromosomally encoded AmpC beta-lactamase, CMY-37. Int J Antimicrob Agents 32: 256–61.
Baldwin DR, Maxwell SRJ, Honeybourne D et al. (1991). The penetration of cefpirome into the potential sites of pulmonary infection. J Antimicrob Chemother 28: 79.
Barry AL, Brown SD, Novick WJ (1995). In vitro activities of cefotaxime, ceftriaxone, ceftazidime, cefpirome, and penicillin against Streptococcus pneumoniae isolates. Antimicrob Agents Chemother 39: 2193.
Bauduer F, Cousin T, Boulat O et al. (2001). A randomized prospective multicentre trial of cefpirome versus piperacillin-tazobactam in febrile neutropenia. Leuk Lymphoma 42: 379.
Carbon C (1992). Prospective randomized phase II study of intravenous cefpirome 1 g or 2 g b.d. in the treatment of hospitalized patients with different infections. Cefpirome Study Group. J Antimicrob Chemother 29 (Suppl A): 87.
Craig WA (1993). The pharmacokinetics of cefpirome-rationale for a twelvehour dosing regimen. Scand J Infect Dis Suppl 91: 33.
Donaubauer HH, Mayer D (1992). Toxicity of cefpirome: an overview. J Antimicrob Chemother 29 (Suppl A): 71.
Fremaux A, Sissia G, Spicq C, Geslin P (1998). In vitro activity of cefpirome against Streptococcus pneumoniae strains with decreased susceptibility to cefotaxime. Diagn Microbiol Infect Dis 31: 501.
Friedland IR, Sultan E, Lehr KH, Lenfant B (1998). Concentrations of cefpirome in cerebrospinal fluid of children with bacterial meningitis after a single intravenous dose. Antimicrob Agents Chemother 42: 199.
Hanson ND (2003). AmpC beta-lactamases: What do we need to know for the future? J Antimicrob Chemother 52: 2.
Herkner H, Mu¨ller MR, Kreischitz N et al. (2002). Closed-chest microdialysis to measure antibiotic penetration into human lung tissue. Am J Respir Crit Care Med 165: 273.
Hollenstein U, Brunner M, Mayer BX et al. (2000). Target site concentrations after continuous infusion and bolus injection of cefpirome to healthy volunteers. Clin Pharmacol Ther 67: 229.
Ishii Y, Alba J, Kimura S, Yamaguchi K (2006). Evaluation of antimicrobial activity of beta-lactam antibiotics by Etest against clinical isolates from 100 medical centers in Japan (2004). Diagn Microbiol Infect Dis 55: 143.
Ishii Y, Tateda K, Yamaguchi K, Japan Antimicrobial Resistance Surveillance Participants Group (2008). Evaluation of antimicrobial activity of betalactam antibiotics by Etest against clinical isolates from 100 medical centers in Japan (2006). Diagn Microbiol Infect Dis 60: 177–83.

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