Doribax: Package Insert and Label Information (Page 3 of 4)

12.4 Microbiology

  • Mechanism of Action

Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa , doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

  • Mechanism(s) of Resistance

Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, with the exception of carbapenem hydrolyzing beta-lactamases. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.

  • Interaction with Other Antimicrobials

In vitro synergy tests with doripenem show doripenem has little potential to antagonize or be antagonized by other antibiotics (e.g., levofloxacin, amikacin, trimethoprim-sulfamethoxazole, daptomycin, linezolid, and vancomycin).

Doripenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)]

Facultative Gram-negative microorganisms
Acinetobacter baumannii
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Facultative Gram-positive microorganisms
Streptococcus constellatus
Streptococcus intermedius
Anaerobic microorganisms
Bacteroides caccae
Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Peptostreptococcus micros

At least 90 percent of the following microorganisms exhibit an in vitro minimal inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for doripenem of organisms of the same type shown in Table 6. The safety and efficacy of doripenem in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive microorganisms
Staphylococcus aureus
(methicillin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus pyogenes
Facultative Gram-negative microorganisms
Citrobacter freundii
Enterobacter cloacae
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Serratia marcescens
  • Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (1,3) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of doripenem powder. The MIC values should be interpreted according to the criteria provided in Table 6.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (2,3) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 µg of doripenem to test the susceptibility of microorganisms to doripenem. Results should be interpreted according to the criteria in Table 6.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doripenem as MICs should be determined by standardized test methods (4). The MIC values obtained should be interpreted according to the criteria in Table 6.

Table 6. Susceptibility Test Result Interpretive Criteria for Doripenem
Minimum Inhibitory Concentrations (µg/mL) Disk Diffusion(zone diameters in mm)
n/a = not applicable
*
The current absence of resistant isolates precludes defining any results other than “Susceptible”. Isolates yielding MIC or disk diffusion results suggestive of “Nonsusceptible” should be subjected to additional testing.
Pathogen Susceptible * Susceptible *
Enterobacteriaceae ≤0.5 ≥23
Pseudomonas aeruginosa ≤2 ≥24
Acinetobacter baumannii ≤1 ≥17
Streptococcus anginosus group (S. constellatus and S. intermedius) ≤0.12 ≥24
Anaerobes ≤1 n/a

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor the performance of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard doripenem powder should provide the MIC values provided in Table 7. For the diffusion techniques using a 10 µg doripenem disk, the criteria noted in Table 7 should be achieved.

Table 7. Acceptable Quality Control Ranges for Susceptibility Testing
QC Organism Minimum Inhibitory Concentrations (µg/mL) Disk Diffusion(zone diameters in mm)
n/a = not applicable
*
This organism may be used for validation of susceptibility test results when testing organisms of the Streptococcus anginosus group
Escherichia coli ATCC 25922 0.015–0.06 27–34
Pseudomonas aeruginosa ATCC 27853 0.12–0.5 28–34
Streptococcus pneumoniae ATCC 49619* 0.03–0.12 30–38
Bacteroides fragilis ATCC 25285 0.12–0.5 n/a
Bacteroides thetaiotaomicron ATCC 29741 0.12–1 n/a

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Because of the short duration of treatment and intermittent clinical use, long-term carcinogenicity studies have not been conducted with doripenem.

Doripenem did not show evidence of mutagenic activity in standard tests that included bacterial reverse mutation assay, chromosomal aberration assay with Chinese hamster lung fibroblast cells, and mouse bone marrow micronucleus assay.

Intravenous injection of doripenem had no adverse effects on general fertility of treated male and female rats or on postnatal development and reproductive performance of the offspring at doses as high as 1g/kg/day (based on AUC, greater than 1.5 times the exposure to humans at the dose of 500 mg administered every 8 hours).

14 CLINICAL STUDIES

14.1 Complicated Intra-Abdominal Infections

A total of 946 adults with complicated intra-abdominal infections were randomized and received study medications in two identical multinational, multi-center, double-blind studies comparing DORIBAX® (500 mg administered over 1 hour every 8 hours) to meropenem (1 g administered over 3–5 minutes every 8 hours). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg administered twice daily) after a minimum of 3 days of intravenous therapy for a total of 5–14 days of intravenous and oral treatment. Patients with complicated appendicitis, or other complicated intra-abdominal infections, including bowel perforation, cholecystitis, intra-abdominal or solid organ abscess and generalized peritonitis were enrolled.

DORIBAX® was non-inferior to meropenem with regard to clinical cure rates in microbiologically evaluable (ME) patients, i.e., in patients with susceptible pathogens isolated at baseline and no major protocol deviations at test of cure (TOC) visit, 25–45 days after completing therapy. DORIBAX® was also non-inferior to meropenem in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with baseline pathogens isolated regardless of susceptibility. Clinical cure rates at TOC are displayed by patient populations in Table 8. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 9.

Table 8. Clinical Cure Rates in Two Phase 3 Studies of Adults with Complicated Intra-Abdominal Infections
Analysis Populations DORIBAX® *n/N (%) Meropenem n/N (%) Treatment Difference(2-sided 95% CI §)
*
500 mg administered over 1 hour every 8 hours
n = number of patients in the designated population who were cured; N = number of patients in the designated population
1 g administered over 3 – 5 minutes every 8 hours
§
= confidence interval
ME = microbiologically evaluable patients
#
mMITT = microbiological modified intent-to-treat patients
Study 1:
ME 130/157 (82.8) 128/149 (85.9) -3.1 (-11.3; 5.2)
mMITT # 143/194 (73.7) 149/191 (78.0) -4.3 (-12.8; 4.3)
Study 2:
ME 128/158 (81.0) 119/145 (82.1) -1.1 (-9.8; 7.8)
mMITT # 143/199 (71.9) 138/186 (74.2) -2.3 (-11.2; 6.6)
Table 9. Microbiological Cure Rates by Infecting Pathogen in Microbiologically Evaluable Adults with Complicated Intra-abdominal Infections
Pathogen DORIBAX® Meropenem
N * n % N * n %
*
N = number of unique baseline isolates
n = number of pathogens assessed as cured
Gram-positive, aerobic
Streptococcus constellatus 10 9 90.0 7 5 71.4
Streptococcus intermedius 36 30 83.3 29 21 72.4
Gram-positive, anaerobic
Peptostreptococcus micros 13 11 84.6 14 11 78.6
Gram-negative, aerobic
Enterobacteriaceae 315 271 86.0 274 234 85.4
Escherichia coli 216 189 87.5 199 168 84.4
Klebsiella pneumoniae 32 25 78.1 20 19 95.0
Non-fermenters 51 44 86.3 39 28 71.8
Pseudomonas aeruginosa 40 34 85.0 32 24 75.0
Gram-negative, anaerobic
Bacteroides fragilis group 173 152 87.9 181 152 84.0
Bacteroides caccae 25 23 92.0 19 18 94.7
Bacteroides fragilis 67 56 83.6 68 54 79.4
Bacteroides thetaiotaomicron 34 30 88.2 36 32 88.9
Bacteroides uniformis 22 19 86.4 18 15 83.3
Non-fragilis Bacteroides 14 13 92.9 13 9 69.2
Bacteroides vulgatus 11 11 100.0 8 6 75.0

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