Ceftobiprole and Doripenem: New Antibiotics for Potential Use in Critical Illness

Basirat Sanuth, PharmD, BCPS*
Critical Care Pharmacy Resident
University of Toledo Medical Center
Toledo, Ohio, USA

Martin J. Ohlinger, PharmD, BCPS**
Clinical Assistant Professor of
Pharmacy Practice
Residency Program Director, Critical Care
University of Toledo, College of Pharmacy
Toledo, Ohio, USA

Steven Martin, PharmD, BCPS, FCCM***
University of Toledo
College of Pharmacy
Toledo, Ohio, USA


Antimicrobial resistance, a common problem faced by clinicians, has limited the use of many antimicrobial classes in the critical care setting.(1) In the past decade, Gram-positive bacterial resistance, such as methicillin-resistant Staphylococcus aureus (MRSA), has increased worldwide, including in the United States where its prevalence is over 50%.(2) Also, the emergence of multidrug-resistant Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, has complicated the treatment of healthcare-associated infections. Ceftobiprole, a new broad-spectrum cephalosporin with activity against MRSA, is pending approval by the U.S. Food and Drug Administration (FDA). Doripenem is a new carbapenem with potent activity against multidrug-resistant P. aeruginosa. This review will focus on the use of both drugs within the intensive care population.

Ceftobiprole
Ceftobiprole is the first of a new generation of cephalosporins with activity against MRSA. Although current phase 3 studies have focused on the treatment of complicated skin and soft tissue infections (cSSTIs) and lower respiratory tract infections, such as healthcare-associated and community-acquired pneumonia, potential applications for compounds such as ceftobiprole may include many infections commonly observed in critically ill patients.(1,3) Ceftobiprole is an extended-spectrum β-lactam with in vitro activity against many Gram-positive, Gram-negative, and anaerobic bacteria.(3,4)

Ceftobiprole is unique in its activity as the first cephalosporin to demonstrate clinical efficacy in MRSA.(5) It has a strong affinity for penicillinbinding protein (PBP) 2a and PBP2x, which are responsible for resistance in staphylococci and streptococci, respectively.(1,6) Its activity against Gram-positive bacteria includes Staphylococcus aureus (methicillin-resistant, vancomycin-intermediate, and resistant strains), methicillin-resistant Staphylococcus epidermidis, penicillin-susceptible and -resistant Streptococcus pneumoniae, and Enterococcus (ampicillin-susceptible E. faecalis and E. faecium as well as vancomycin-resistant E. faecalis).(3,4) Studies have reported that ceftobiprole has a minimum inhibitory concentration (MIC) for methicillinsusceptible S. aureus ranging from <0.12 to 1 μg/mL (MIC required to kill 90% of organisms [MIC90], 0.5 μg/mL) and for MRSA ranging from 0.25 to 4 μg/mL (MIC90, 1 μg/mL).(7) MIC90 values for common Gram-positive and Gram-negative pathogens are shown in Table 1.

Ceftobiprole also has in vitro activity against most Enterobacteriaceae, P. aeruginosa, Fusobacterium nucleatum and Clostridium perfringens.(3,4) It demonstrates antimicrobial activity similar to that of third- and fourth-generation cephalosporins (such as ceftazidime, ceftriaxone and cefepime) by its stability against most commonly occurring class A and some class C β-lactamases. Its activity against ESBL-producing organisms is limited and may preclude clinical use in situations of suspected resistance.(1) Analysis of in vitro activity against a collection of Enterobacteriaceae from hospitalized patients (n=273) reported 93% of pathogens had MIC ≤4 μg/mL. In vitro activity of ceftobiprole against P. aeruginosa also has been shown to be comparable to that of cefepime and ceftazidime. In a study assessing 741 isolates of P. aeruginosa, 72%, 68% and 73% of isolates were inhibited by ≤4 μg/mL of ceftobiprole, cefepime and ceftazidime, respectively.(5)

The pharmacokinetics of ceftobiprole have been evaluated in healthy individuals. The agent is administered as the water-soluble prodrug ceftobiprole medocaril, which is rapidly and nearly completely converted by plasma esterases to the active drug, ceftobiprole. The active drug binds minimally to plasma proteins (16%) and has a volume of distribution approximately equal to extracellular fluid volume in adults (18.4 L).(3) Ceftobiprole undergoes minimal hepatic metabolism and is primarily excreted unchanged in the urine.(2,3) Its terminal half-life is three to four hours. At a dosing regimen of 500 mg administered every eight hours as a two-hour infusion, ceftobiprole is likely to be effective in the empiric treatment of Gram-positive and Gram-negative infections.(3)

A phase 3 study compared ceftobiprole to vancomycin in patients with cSSTIs due to suspected or proven Gram-positive infection. Ceftobiprole 500 mg intravenously every 12 hours or vancomycin 1 g intravenously every 12 hours was administered for seven to 14 days. In the microbiologically evaluable patients, staphylococci were the predominant causative organisms with >25% of the pathogens caused by MRSA. Of the clinically evaluable patients, 93.3% of patients treated with ceftobiprole, versus 93.5% of patients treated with vancomycin, were cured at the test-of-cure visit (95% confidence interval [CI], -4.4% to 3.9%). The cure rates for patients with MRSA infections were 91.8% with ceftobiprole and 90.0% with vancomycin (95% CI, -8.4% to 12.1%).(8) A second trial compared ceftobiprole (500 mg intravenously every eight hours) monotherapy to ceftazidime plus vancomycin for the treatment of cSSTIs caused by either Grampositive or Gram-negative bacteria. Staphylococci were the predominant causative organisms, with MRSA cultured from approximately 20% of the microbiologically evaluable patients. Among the clinically evaluable group, 90.5% of ceftobiprole and 90.2% of the comparator-treated groups were cured at the test-of-cure visit (95% CI, -4.2% to 4.9%). The cure rates for patients with MRSA infections were 89.7% and 86.1% for the ceftobiprole and comparator-treated group, respectively (95% CI, -8.0% to 19.7%).(9) Ceftobiprole was well tolerated in both studies, with nausea, vomiting and taste disturbances being the most common adverse effects. (8,9,10)

Two phase 3 clinical trials have been completed for the treatment of cSSTIs. Ongoing studies include phase 3 clinical trials for pneumonia and febrile neutropenia associated with chemotherapy administration. A phase 2 trial involving S. aureus bacteremia is also underway.(11) Once available, ceftobiprole may be used effectively as empiric therapy for Gram-positive and Gram-negative infections in the intensive care population. It offers the advantage of methicillin-resistant S. aureus, P. aeruginosa and anaerobic coverage compared to current regimens.

Doripenem
Doripenem is a parenteral carbapenem recently approved for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections, such as pyelonephritis in adults.(15) It has also been studied in healthcare-associated and ventilator-associated pneumonia (VAP) and bacteremia, but these indications are not yet approved by the FDA.11 Doripenem exhibits bactericidal activity similar to that in the carbapenem class. It has broad-spectrum activity against Gram-positive, Gramnegative and anaerobic bacteria, similar to imipenem and meropenem.(16) However, doripenem has greater potency against P. aeruginosa than these two agents, making it a potentially useful alternative to other carbapenems in critically ill patients. Doripenem and imipenem are more potent against Gram-positive organisms than meropenem.

Unlike imipenem, doripenem does not require co-administration of cilastatin to prevent resistance to the renal enzyme dehydropeptidase-1 and is stable in intravenous solution for up to eight hours at room temperature.(17) Doripenem exhibits low protein binding (8.1%) and has a volume of distribution similar to theextracellular fluid volume in adults
(18.2 L). Doripenem is primarily eliminated unchanged by the kidneys.(15) For this agent as well other carbapenems, the concentration of drug must exceed the MIC of the organism for at least 40% of the dosing interval to maximize bactericidal activity.(18)

Doripenem is active against multidrug-resistant Enterobacteriaceae.(16) MIC90 values for common Grampositive and Gram-negative pathogens are shown in Table 2. Traczewski et al demonstrated a lower in vitro MIC90 for doripenem than for imipenem, levofloxacin, piperacillin, ceftazidime, aztreonam, tobramycin, or cefepime against 160 isolates of P. aeruginosa (82 from cystic fibrosis patients). Doripenem also was shown to have activity against Burkholderia cepacia, a common pathogen found in patients with cystic fibrosis.(19) Doripenem has been shown to retain in vitro activity against Gram-negative bacteria expressing ESBL and derepressed or inducible AmpC.(20) All carbapenems are active in vitro against ESBL-producing Escherichia coli and Klebsiella pneumoniae, but none possess any useful activity against Stenotrophomonas maltophilia due to its production of metallo-β-lactamases.(21) Resistance was also observed with doripenem and other carbapenems in Acinetobacter isolates expressing metallo-β-lactamases or OXA-carbapenemases. Doripenem demonstrated lower propensity to select for resistant mutants than meropenem.(20)

A non-blinded, non-inferiority trial compared doripenem 500 mg (every eight hours infused over 60 minutes) to piperacillin/tazobactam 4.5 g (every six hours infused over 30 minutes) in patients with healthcareassociated pneumonia. In the study, patients could be switched to oral levofloxacin 750 mg once daily after three days of intravenous therapy, though the planned duration of therapy was seven to 14 days. The clinical cure rates for the clinically evaluable patients were 81.3% and 79.8% in the doripenem and piperacillin/tazobactam groups, respectively, at the test-of-cure visit (95% CI, -9.1 to 12.1).(22) A second phase 3 trial conducted in patients with VAP compared doripenem (500 mg every eight hours via four-hour infusion) to imipenem (500 mg every six hours or 1 g every eight hours via 30- or 60-minute infusion, respectively) for seven to 14 days.(23) The four-hour infusion has been shown to optimize the duration of time the drug concentration remains above the MIC.(24) Clinical cure rates were 68.3% (13 of 20) for doripenem versus 64.8% (4 of 14) for imipenem (P = not significant [NS]). In patients with P. aeruginosa, clinical cure rates were 80% for doripenem versus 42.9% for imipenem (P = NS); the microbiological eradication rate was 65% versus 35.7%, respectively (P = NS).(23)

Doripenem also has been evaluated in the treatment of cIAIs. In two identical, randomized, double-blind, noninferiority trials in cIAIs requiring parenteral antibiotics, the efficacy of doripenem (500 mg every eight hours infused over 60 minutes) was compared to meropenem (1 g every eight hours bolus over three to five minutes). The duration of therapy was five to 14 days. E. coli was the most common pathogen.(25,26) An analysis of combined results from these two trials showed clinical cure rates of 85.3% and 86.2% for doripenem and meropenem, respectively, in the clinically evaluable population. Microbiological cure rates were similar in the two treatment groups for E. coli (87.5% and 84.4% for doripenem and meropenem, respectively) and other pathogens. Doripenem was generally well tolerated.(27)

In the treatment of complicated lower urinary tract infections or pyelonephritis, the efficacy of doripenem 500 mg (every eight hours intravenously) was compared to that of levofloxacin 250 mg (every 24 hours intravenously for 10 days). Patients could be switched to oral levofloxacin after a minimum of three days of intravenous therapy. E. coli was the pathogen isolated most often. In the clinically evaluable patients, the clinical cure rates were 95.1% and 90.2% in the doripenem and levofloxacin groups, respectively (95% CI, 0.2 to 9.6). Microbiological cure rates were similar in the two groups for E. coli (84.4% and 87.2% for doripenem and levofloxacin, respectively).(28)

Although, doripenem currently is not approved for the treatment of nosocomial pneumonia, it has a potential role in the treatment of healthcare associated pneumonia such as VAP.

Summary
Ceftobiprole and doripenem represent two muchneeded options for managing infection in critical illness. Ceftobiprole is the first broad-spectrum cephalosporin with clinically useful activity against MRSA. Doripenem expands the class of carbapenems and may be a preferred alternative to currently available agents given its superior activity against P. aeruginosa. Novel dosing strategies extending the infusion interval may be the key to improved anti-pseudomonal outcomes.

References:

1. Fritsche TR, et al. Antimicrobial activity of ceftobiprole, a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, tested against contemporary pathogens: results from the SENTRY Antimicrobial Surveillance Program (2005-2006). Diagn Microbiol Infect Dis. 2008;61:86-95.

 Disclosures:

*Author has no disclosures to report

**Author has no disclosures to report

***Author has disclosure