Imipenem outdoes doripenem in ventilator associated pneumonia

---according to a recent announcement.

Before getting into the report this might be a good time to compare some attributes of the four “penem” antibiotics approved in the U.S.

Imipenem (Primaxin)---from rxlist:

Approved for:

Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae*, Klebsiella species, Serratia marcescens

Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus vulgaris*, Providencia rettgeri*, Pseudomonas aeruginosa

Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species,Clostridiumspecies, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis, Fusobacterium species

Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species*, Escherichia coli, Gardnerella vaginalis, Klebsiella species*, Proteus species, Bifidobacterium species*, Peptococcus species*, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis*

Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species*, Bacteroides species including B. fragilis*

Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa

Skin and skin structure infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri*, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species*

Endocarditis. Staphylococcus aureus (penicillinase-producing strains)

Polymicrobic infections. PRIMAXIN I.V. (imipenem and cilastatin for injection) is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillinG.

Off label antimicrobial susceptibility:

Gram-positive aerobes

Bacillus spp.

Listeria monocytogenes

Nocardia spp.

Staphylococcus saprophyticus

Group C streptococci

Group G streptococci

Viridans group streptococci

Gram-negative aerobes

Aeromonas hydrophila

Alcaligenes spp.

Capnocytophaga spp.

Haemophilus ducreyi

Neisseria gonorrhoeae including penicillinase-producing strains

Pasteurella spp.

Providencia stuartii

Gram-negative anaerobes

Prevotella bivia

Prevotella disiens

Prevotella melaninogenica

Veillonella spp.

Though not mentioned in the labeling imipenem has activity against Listeria.

Advantages, disadvantages, comments:

Much broader range of approved indications compared to the other penems.

Experience with a wider range of antibiotic susceptibility.

Dosing information in product labeling extremely difficult to use.

May have higher seizure risk.

Meropenem (Merrem)---from Rx list:

Approved for:

Skin and Skin Structure Infections. Complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase and non-β- lactamase producing, methicillin susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Intra-abdominal Infections

Complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (Pediatric patients ≥ 3 months only)

Bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (β-lactamase and non-β-lactamase-producing isolates), and Neisseria meningitidis.

Off label antimicrobial susceptibility:

Aerobic and facultative Gram-positive microorganisms

Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing, methicillin-susceptible isolates only).

Aerobic and facultative Gram-negative microorganisms

Acinetobacter species

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter diversus

Citrobacter freundii

Enterobacter cloacae

Haemophilus influenzae (ampicillin-resistant, non-β-lactamase-producing isolates[BLNAR isolates])

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis (β-lactamase andnon-β-lactamase-producingisolates)

Morganella morganii

Pasteurella multocida

Proteus vulgaris

Salmonella species

Serratia marcescens

Shigella species

Yersinia enterocolitica

Anaerobic microorganisms

Bacteroides distasonis

Bacteroides ovatus

Bacteroides uniformis

Bacteroides ureolyticus

Bacteroides vulgatus

Clostridium difficile

Clostridium perfringens

Eubacterium lentum

Fusobacterium species

Prevotella bivia

Prevotella intermedia

Prevotella melaninogenica

Porphyromonas asaccharolytic

Propionibacterium acnes

Although not mentioned in the product labeling meropenem has activity against Listeria.

Advantages, disadvantages, comments:

May have lower seizure risk than imipenem.

Labeling is user friendly.

May have less cross sensitivity in PCN allergic patients.

Narrow range of approved indications compared to imipenem.

Doripenem (Doribax)---from Rx list:

Approved for:

Complicated Intra-Abdominal Infections

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

Complicated Urinary Tract Infections, Including Pyelonephritis

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Off label antimicrobial susceptibility:

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

Advantages, disadvantages, comments:

Labeling is user friendly.

Narrow range of approved uses compared to imipenem.

Ertapenem (Invanz)---from Rx list:

Approved for:

Complicated Intra-Abdominal Infections

INVANZ is indicated for the treatment of complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.

Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis

INVANZ is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies].

Community Acquired Pneumonia

INVANZ is indicated for the treatment of community acquired pneumonia due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis.

Complicated Urinary Tract Infections Including Pyelonephritis

INVANZ is indicated for the treatment of complicated urinary tract infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae.

Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post Surgical Gynecologic Infections

INVANZ is indicated for the treatment of acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecological infections due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia.

Prevention

INVANZ is indicated in adults for:

Prophylaxis of Surgical Site Infection Following Elective Colorectal Surgery

INVANZ is indicated for the prevention of surgical site infection following elective colorectal surgery.

Off label antimicrobial susceptibility:

Gram-positive bacteria:

Staphylococcus epidermidis (methicillin susceptible isolates only)

Streptococcus pneumoniae (penicillin-intermediate isolates)

Note: Methicillin-resistant Staphylococcus epidermidis are resistant to ertapenem.

Gram-negative bacteria:

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella oxytoca (excluding ESBL producing isolates)

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

Anaerobic bacteria:

Bacteroides vulgatus

Clostridium perfringens

Fusobacterium spp.

Advantages, disadvantages, comments:

Broader range of approved uses than meropenem and doripenem but the narrowest spectrum of all available penems in the U.S. (Not appropriate as your initial big gun if the patient has risk factors for highly resistant pathogens such as Pseudomonas).

So that brings us back to the FDA report on ventilator associated pneumonia. From Medscape Medical News:

Johnson and Johnson has halted its clinical trial of the antibiotic drug doripenem (Doribax) for patients with ventilator-associated pneumonia after interim results showed a higher death rate among patients receiving the drug compared with those receiving other antibiotics...

The trial, conducted at sites in several countries as part of a postmarketing commitment to the European Medicines Agency, involved 274 participants. It was designed to compare a fixed, 7-day course of doripenem with a fixed, 10-day course of imipenem-cilastatin...

Interim results showed patients receiving doripenem had an all-cause mortality rate of 21.5% at 28 days compared with 14.8% in the control group. In addition, patients in the doripenem group had a 11.2% lower rate of being cured compared with patients in the alternative drug group.

"(The trial) demonstrated excess mortality and a numerically poorer clinical cure rate among subjects treated with Doribax compared to those treated with imipenem-cilastatin," the FDA said in a press statement.

Imipenem seems to come out on top. From what I read about this trial and from the labeling comparisons above I don't know the reason why.

This is an example of comparative effectiveness research but is it also an example of the type of flawed design that is unique to and often creeps into CER? Specifically, why 10 days of imipenem and only 7 days of doripenem? There are other details I'd like to see if this study ever gets published. But for now these are the results and we must make what we can of them.

So for VAP should we be saying “gimme good ole imi”? However you slice it it seems to have the best track record among the penems. (If there've been any direct comparative studies involving meropenem I'm not aware of them).

Can we extrapolate these findings to non-VAP HCAP? Is it worth the down side of possible increased seizure risk and more difficult dosing? Who knows?