New Antibiotics for Healthcare-Associated Pneumonia

Elizabeth A. Neuner, Pharm.D.; David J. Ritchie, Pharm.D.; Scott T. Micek, Pharm.D.

Disclosures

Semin Respir Crit Care Med. 2009;30(1):92-101. 

In This Article

Doripenem

Doripenem is a new parenteral carbapenem that has bactericidal activity against many gram-positive and gram-negative aerobic organisms encountered in patients with HCAP. Data from in vitro evaluations suggest gram-positive activity similar to imipenem, including methicillin-sensitive S. aureus (MSSA) and Streptococcus pneumoniae. Like imipenem, doripenem is inactive against MRSA.[2] Doripenem has in vitro activity against a broad scope of gram-negative HCAP pathogens that is similar in nature to meropenem. Importantly, doripenem demonstrates potent bactericidal activity against P. aeruginosa and often retains activity against isolates resistant to imipenem and meropenem.[3] The high binding affinity of doripenem to PBP-2 and -3 is felt to enhance its activity against drug-resistant P. aeruginosa.[4] Doripenem has in vitro activity similar to imipenem against wild-type isolates of Acinetobacter baumannii.[3] Doripenem, like other carbapenems, is stable to the extended-spectrum ß-lactamases (ESBLs) produced by Escherichia coli and Klebsiella species.[5] In addition, doripenem is stable to AmpC ß-lactamases and does not select for AmpC-derepressed mutants from inducible populations of organisms, including Enterobacter species, Serratia species, and Citrobacter fruendii.[5]

Doripenem also has activity against other pathogens associated with HCAP, including non-AmpC ß-lactamase producing Enterobacteriaceae and Haemophilus influenzae.[2,6]

Although doripenem is stable against many ß-lactamases, it is vulnerable to certain acquired ß-lactamases, including the class B metallo-ß-lactamases produced by some P. aeruginosa isolates and carbapenemases produced by some Enterobacteriaceae and Acinetobacter species.[5,7] Additionally, P. aeruginosa isolates that do not possess the porin OprD have increased minimum inhibitory concentration (MIC) values for doripenem. Fortunately, pseudomonal resistance to doripenem requires multiple resistance mechanisms to be present; typically, loss of membrane permeability combined with functioning AmpC ß-lactamases or overexpression of multidrug efflux pumps.[7] The propensity to select for resistant P. aeruginosa mutants in vitro was lower for doripenem than for the other carbapenems.[8]

The volume of distribution for doripenem is 17 L, approximating extracellular fluid volume, and the protein binding (8.9%) is comparable to meropenem (2%). Doripenem distributes to many body fluids and tissues, including peritoneal fluid and bile; distribution into lung epithelial lining fluid is unknown.[9] The estimated elimination half-life of doripenem is ~0.95 hour, and 75% of the drug is excreted unchanged in the urine.[10] In subjects with renal impairment, drug exposure was increased, necessitating reduced dosing.[11]

In a neutropenic mouse-thigh infection model, the pharmacokinetic-pharmacodynamic (PK-PD) parameter that correlated best with efficacy of doripenem was the proportion of the dosing interval for which drug concentrations exceed the MIC of the targeted microorganism (T > MIC).[10] In a Monte-Carlo simulation, the dose of 500 mg intravenously (IV) every 8 hours as a 1-hour infusion resulted in > 99% probability of achieving the target attainment (T > MIC > 35%) for organisms with MIC values ≤ 2 mg/L.[10] For organisms with higher MICs, extending the duration of the infusion without increasing the total daily dose increased the likelihood of achieving the target PK-PD parameter.

Doripenem has low affinity for the γ-aminobutyric acid (GABA) receptor compared with other carbapenems and produced no convulsive activity in preclinical animal studies.[12] However, seizures were reported in 1.1 to 1.3% of patients in clinical trials. Allergic reactions ranging in severity from rash and urticaria to anaphylaxis and severe hypersensitivity have occurred with doripenem.

Doripenem received FDA approval based on data from clinical trials demonstrating noninferiority to levofloxacin for the treatment of complicated urinary tract infections and meropenem for intraabdominal infections.[13,14,15] Additionally, recent studies evaluated doripenem for the treatment of hospital-acquired pneumonia (HAP). The first randomized, open-labeled, phase III trial compared doripenem to piperacillin/tazobactam for the treatment of nosocomial or early-onset (< 5 days) ventilator-associated pneumonia (VAP).[16] Patients were randomized to receive doripenem 500 mg IV every 8 hours as a 1-hour infusion or piperacillin/tazobactam 4.5 g IV every 6 hours as a 30-minute infusion. Step-down therapy to oral levofloxacin was allowed after ≥ 72 hours of study drug, for a complete treatment course of 7 to 14 days. The clinical cure rates in the clinically evaluable (CE) population were 81.3% (109/134) and 79.8% (95/119) and in the clinical modified intention-to-treat (cMITT) population were 69.5% (148/213) and 64.1% (134/209) in the doripenem and piperacillin/tazobactam arm, respectively (p = NS). Overall microbiological cure rates were 84.5% for doripenem and 80.7% for piperacillin/tazobactam.

A second randomized, open-labeled, phase III trial in patients solely with VAP compared doripenem to imipenem.[17] In this trial, patients received doripenem 500 mg IV every 8 hours as 4-hour extended infusion or imipenem 500 mg IV every 6 hours or 1000 mg IV every 8 hours as standard infusions for 7 to 14 days. The clinical cure rates were 68.3% for doripenem versus 64.2% for imipenem and 59.0% for doripenem versus 57.8% for imipenem in the CE and cMITT populations, respectively. Doripenem met the predefined criteria for noninferiority to imipenem for the treatment of VAP. In a subgroup analysis of patients with P. aeruginosa, there was a nonstatistically significant trend toward higher clinical cure rates with doripenem 80.0% versus imipenem 42.9%.

The broad gram-positive and gram-negative activity, in addition to supportive clinical trial data, gives doripenem appeal as a first-line empirical agent in combination with an anti- MRSA drug for HCAP. Alternatively, doripenem could be reserved for HCAP caused by resistant gram-negative organisms, including P. aeruginosa. The optimal dosing strategy for doripenem in the treatment of HCAP remains to be determined.

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