Data Show In Vitro Potency Of Doripenem Against Resistant Bacteria

Ruzanna Harutyunyan's picture

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), today announced new study results that demonstrate doripenem (DORIBAX, doripenem for injection), a carbapenem antibiotic, was found to be more potent in vitro against certain strains of Enterobacteriaceae, including Extended-spectrum Beta-lactamases (ESBLs) than other commonly used carbapenems.

Enterobacteriaceae is a large group of bacteria that can cause infections of the digestive tract or other organs of the body and includes common bacteria strains such as E. coli. These new data were presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) / Infectious Diseases Society of America (IDSA) 46th annual meeting in Washington, D.C.

In the study, the incidence and susceptibility of extended-spectrum Beta-lactamase producing Enterobacteriaceae (ESBLE) and ciprofloxacin-resistant Enterobacteriaceae (CIPRE) to doripenem and relevant comparators was evaluated. The data analyzed was pooled from six large, multi-national Phase III clinical trials, including trials that focused on complicated urinary tract infections (cUTIs) and pyelonephritis(2); complicated intra-abdominal infections (cIAI) (2); nosocomial pneumonia (NP), including early-onset ventilator-associated pneumonia (VAP)(1); and VAP, both early- and late-onset (1). The study results showed:

-- Against ESBLE and CIPRE, doripenem was generally more potent in vitro than imipenem and ertapenem, and inhibited growth of CIPRE and ESBLE at very low drug concentrations.

-- Doripenem, imipenem and ertapenem, inhibited growth of >90% of ESBLE at concentrations of 0.25 micrograms/mL, 0.5 micrograms/mL, and 1 micrograms/mL, respectively.


-- Similarly, doripenem, imipenem and ertapenem inhibited the growth of >90% of CIPRE at concentrations of 0.5 micrograms/mL, 1 micrograms/mL, and 4 micrograms/mL, respectively.

Additionally, the study examined the incidence of ESBLE and CIPRE in baseline Enterobacteriaceae isolates in North America (NA), South America (SA), and Europe (EU). To evaluate these levels, minimum inhibitory concentrations (MICs) were determined for ESBLE and CIPRE. ESBLE were determined as Enterobacteriaceae that included Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs greater than or equal to 2 micrograms/mL. CIPRE were defined as Enterobacteriaceae with ciprofloxacin MIC greater than or equal to 4 micrograms/mL. The study results showed:

-- Relative incidence of ESBLE was highest in Europe (8% of all Enterobacteriaceae), and the relative incidence of CIPRE was highest in South America (16%).

-- In ESBLE from all regions combined, 68% were resistant to ciprofloxacin, while 98% had doripenem MICs less than or equal to 2 micrograms/mL.

-- In CIPRE from all regions combined, 99% had carbapenem MICs less than or equal to 4 micrograms/mL.

A second study, also presented at the 2008 ICAAC/IDSA Joint Meeting, that examined stored clinical Enterobacteriaceae isolates, found that overall susceptibility (less than or equal to 0.5 micrograms/mL) for doripenem among Enterobacteriaceae strains were 98.9% and 96.5% for strains expressing ESBL and AmpC Beta-lactamase enzymes, respectively. Both ESBL and AmpC Beta-lactamase are enzymes that destroy cephalosporins and other related antibiotics. Approximately, 32,990 Enterobacteriaceae isolates in four geographic locations (North America, Latin America, Europe and Asia-Pacific) were recovered from more than 60 medical centers, which participated in the global doripenem surveillance program from 2003 to 2007.

In this study, susceptibility testing was performed by the monitoring laboratory using Clinical and Laboratory Standards Institute (CLSI) methods and interpretive criteria. Overall, the Enterobacteriaceae doripenem-susceptibility rate (less than or equal to 0.5 micrograms/mL) was 98.9%. ESBLs were detected in 5.7, 17.3 and 4.8% of E. coli, Klebsiella spp. and P. mirabilis, respectively; AmpC-production rates were 1.6, 23.7, 2.2 and 2.7% for Citrobacter spp., Enterobacter spp., indole-positive Proteae and Serratia spp. ESBL and AmpC enzymes had little impact on doripenem MIC(50) potencies (up to two-fold). Sporadic occurrence of Bush group 2f carbapenemases (KPC) among Klebsiella spp. was detected along with rare metallo-Beta-lactamases in other Enterobacteriaceae, elevating carbapenem MICs.