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DORIPENEM: THE NEWEST
MEMBER OF THE
CARBAPENEM FAMILY

Fay S. Chan, Pharm. D. Candidate


The carbapenems are a class of broad-
spectrum p-lactam antibiotics used to treat serious or
life-threatening infections.1 The newest member of
this class (doripenem [dor' a p6n am], DoribaxTM
[dor' a bdks]) is still undergoing phase III/IV testing.
Doripenem is structurally similar to meropenem, and
unlike imipenem does not require concurrent admini-
stration of a renal enzyme inhibitor (cilastatin).
Spectrum of coverage includes gram-positive, gram-
negative and anaerobic pathogens similar to
imipenem/cilastatin and meropenem.2 This new par-
enteral antibiotic may offer slightly more activity
than meropenem against selected pathogens, includ-
ing coverage of some strains of Pseudomonas
aeruginosa not susceptible to other antipseudomonal
carbapenems.2 Research on this synthetic, carbap-
enem began in 1994 in Japan under Shionogi & Co,
Ltd. Currently Johnson & Johnson, holds US rights
for research and development and markets the prod-
uct through its subsidiary Ortho-McNeil, Inc.4'5 Fi-
nal FDA approval was granted on October 15th, 2007
within the "fast-track" designation. Doripenem is
indicated for the treatment of complicated intra-
abdominal infections (clAI) (i.e. complicated appen-
dicitis, bowel perforation, cholecystitis, solid organ
or intra-abdominal abscess, generalized peritonitis)


as well as for treatment of complicated urinary tract
infection (cUTI), including pyelonephritis. The fol-
lowing article will discuss the mechanism of action,
mechanisms of resistance, indications, pharmacology
and pharmacokinetics, spectrum of coverage, clinical
trials, adverse effects, drug interactions, contraindi-
cations and dosing of doripenem.

Mechanism of Action and Mechanisms of Resis-
tance
Doripenem inhibits bacterial cell wall forma-
tion and facilitates bacterial cell lysis. The effect is
mostly bactericidal as doripenem inhibits the final
step in cell wall synthesis by binding to specific
penicillin binding proteins (PBP) within the bacterial
cell walls. In E. coli and P. aeruginosa, doripenem
binds to PBP 2, involved in the maintenance of cell
shape, also to PBP 3, a key element in septum sepa-
ration of cells and PBP 4, believed to have a role in
secondary cross-linking of peptidoglycan.
Doripenem, meropenem, and ertapenem all
possess a 1-beta-methyl side chain that provides re-
sistance to the renal enzyme dehydropeptidase I.
Mechanisms such as drug inactivation by carbap-
enem-hydrolyzing enzymes, mutant or acquired





INSIDE THIS ISSUE:
DORIPENEM: THE NEWEST MEMBER OF THE
CARBAPENEM FAMILY




ll ^ I


mm


A9 PharmaNote


VOLUME 23, ISSUE 4 JANUARY 2008


Volume 23, Issue 4 January 2008


PharmaNote







penicillin binding proteins, decreased outer mem-
brane permeability, and active efflux can lead to
doripenem resistance. Doripenem is generally stable
to hydrolysis by most p-lactamases including penicil-
linases and cephalosporinases, but may be inacti-
vated by carbapenem hydrolyzing 3-lactamases.
Doripenem may also be inactivated by carbapenem-
resistant Acinetobacter sp. that possess metallo-p-
lactamases, which catalyze hydrolysis of the P-
lactam. Another mechanism for resistance is from
class D OXA-type p-lactamase enzymes which have
weak carbapenem-hydrolyzing activity (OXA en-
zymes include OXA-23, -24, -25, -26, -27).4-6 Cur-
rently some isolates resistant to either meropenem
and/or imipenem have not shown resistance to
doripenem.
In a 2005 study, Kobayashi examined syner-
gism between carbapenems and vancomycin or tei-
coplanin (unavailable in US) against MRSA, with an
emphasis on doripenem.7 Synergy with doripenem,
panipenem (unavailable in US), meropenem,
imipenem and teicoplanin was detected against 74%
of the strains tested. Initial results suggested that
combination therapy of vancomycin or teicoplanin
with doripenem, panipenem, meropenem or
imipenem would be effective for severe infections
due to carbapenem-resistant MRSA strains.

Pharmacokinetics and Pharmacodynamics
Doripenem is eliminated primarily as un-
changed drug in the kidneys. Mean plasma t/2,the
time required for the level of a drug in the body to be
reduced by half, in healthy, non-elderly adults is
about one hour while mean plasma clearance is 15.9
L/hour. Mean renal clearance is 10.8 L/hour. Ap-
proximately 70% of the dose is recovered over forty-
eight hours. Approximately 15% of the dose is recov-
ered in the urine as the metabolite. Accumulation of
doripenem does not occur following multiple doses
of 500 mg or 1 g IV every 8 hours for seven to ten
days in patients with normal renal function. When
giving doripenem and valproic acid concomitantly,
there is a significant decrease in the elimination of
doripenem suggesting that doripenem undergoes
glomerular filtration as well as active tubular secre-
tion. Doripenem has not been found to induce or in-
hibit CYP450 enzymes.4'5
Binding of doripenem to plasma proteins is
estimated at 8.1%, which is independent of plasma
drug concentrations. Penetration includes fluids and


tissues, specifically abdominal and renal. Ikawa and
colleagues evaluated peritoneal penetration of
doripenem in ten post-abdominal surgical patients
and found that it penetrated well into peritoneal exu-
dates.8 Average serum concentrations remained
higher in exudate than in serum after 0.81 hours
post-dose and the average drug-exposure times (T >
MIC) in serum and exudate were 73.6% and 78.2%
at an MIC of 1 mg/L; 37.0% and 41.5% at 4 mg/L;
and 12.7% and 13.1% at 16 mg/L, respectively.
Drug-exposure times were also greater than or equal
to those estimated from serum data. Similar to other
p-lactams, the time of unbound plasma concentration
above MIC corresponds with doripenem's antibiotic
effect.

Clinical Trials
Note: At this time, the only clinical trial data avail-
able on doripenem is not peer-reviewed nor has it
been publishedfor general use. Caution around the
interpretation of non-peer reviewed data is recom-
mended.

Complicated intra-abdominal infections (clAI)
Four clinical trials led to the approval of doripenem
by the FDA.4 In two multicenter, randomized dou-
ble-blind trials a combined total of 946 patients with
clAI were included.11,12,13
Solomkin and colleagues evaluated
doripenem (n=486) vs. meropenem (n=476) in a ran-
domized trial with an option for oral step-down ther-
apy in the treatment of clAI.11 Doripenem 500 mg
administered over 1 hour every 8 hours was com-
pared with meropenem 1 g administered over 3 5
minutes every 8 hours with the option to switch to
oral amoxicillin/clavulanate 875 mg/125 mg twice
daily after a minimum of nine doses of IV therapy
for a combined total of 5 14 days of IV and oral
treatment. Non-inferiority was determined if the
lower limit of the two-sided 95% confidence interval
(CI) of difference (doripenem subtracted mero-
penem) in cure rates was at least minusl5%. Clini-
cal cure rates in the microbiologically valuable
(ME) patients, defined as a subset of the clinically
valuable (CE) who had > 1 baseline intra-abdominal
bacterial pathogen susceptible to both study drugs;
were 84.6% (275/325) for doripenem and 84.1%
(260/309) in meropenem. In the microbiologically
modified intention-to-treat (mMITT) population, de-
fined as patients who received > 1 dose of study drug


PharmaNote Volume 23, Issue 4 January 2008


Volume 23, Issue 4 January 2008


PharmaNote







Table 1. In vitro activity of doripenem9


Organism
E. coli
K. pneumoniae
K. oxytoca
P. mirabilis
Citrobacter sp.
Enterobacter sp.
S. marcescens
Salmonella sp.
,l/i ,. Il/ sp.
A. baumannii
P. aeruginosa
Aeromonas sp.
H. influenza
P-lactamase-negative
P-lactamase-positive
M. catarrhalis
S. aureus
MSSA
MRSA
E. faecalis
Enterococcus sp.
S. pneumoniae
Penicillin-susceptible
Penicillin-intermediate
Penicillin-resistant
Viridans group streptococci
Penicillin-susceptible
Penicillin-intermediate
Penicillin-resistant
P-haemolytic streptococci
B. fragilis
Prevotella sp.
Other gram-negative sp.
C. difficHile
Other Clostridium sp.
Other Gram-positive so.


MIC Range
(ag/ml)
< 0.015 to 0.03
< 0.015 to 0.06
< 0.015 to 0.06
0.03 to 0.12
< 0.015 to 0.06
< 0.015 to 0.25
0.03 to 0.5
< 0.015 to 0.12
< 0.015 to 0.06
0.03 to > 32
0.06 to 1
< 0.015 to 0.25

< 0.015 to 1
0.12 to 1
< 0.015 to 0.03

0.32-0.125
4 -32
< 0.015 to >32
0.25 to > 32

< 0.015
< 0.015
0.25 to 2

< 0.015 to 0.12
< 0.015 to 2
0.25 to 4
< 0.015 to 0.12
0.12 to 1
0.03 to 1
< 0.015 to 4
1-2
< 0.015 to 0.25
< 0.015 to 0.5


Table 1. In vitro activity of doripenem9


MIC 50%
(gg/ml)
< 0.015
0.03
0.03
0.06
0.03
0.03
0.06
0.03
0.03
0.5
0.25
0.5

0.12
0.12
< 0.015

0.063
16
4
2

< 0.015
0.03
0.5

0.03
0.25
2
< 0.015
0.25
0.12
0.25
1
0.03
0.12


MIC 90%
(Jg/ml)
< 0.015
0.03
0.06
0.12
0.03
0.06
0.12
0.06
0.03
16
0.5


1
0.5
0.03

0.063
16
16
> 32

< 0.015
0.25
1

0.06
0.5
4
0.06
0.5
0.25
1
2
0.06
0.25


MSSA methicillin-susceptible S. aureus; MRSA methicillin-resistant S. aureus


and had a baseline bacterial pathogen identified re-
gardless of susceptibilities to both drugs, the clinical
cure rates were 76.2% (301/395) for doripenem vs.
77.3% for meropenem. (diff: -1.1%, 95% CI: -7.4%
to 5.1%). The microbiological cure rates against
common causative pathogens in clAI were 84.3%
(274/325) and 84.5% (261/309) for doripenem and
meropenem respectively. Solomkin concluded that
doripenem was non-inferior to meropenem in clAI,
and that doripenem was generally well-tolerated with
a safety profile similar to meropenem.11
A phase III study by Lucasti and associates,
doripenem (n=237) was compared to meropenem
(n=239) in hospitalized clAI patients.12 The dose of
doripenem was 500mg IV every 8 hours while mero-


penem was dosed at Ig every 8 hours. After 9 or
more doses of either study drug, there was an option
to step down therapy to oral amoxicillin/clavulanate
provided that patients met specific criteria. The du-
ration of study drug therapy (IV or IV + oral) ranged
from a minimum of 5 days to a maximum of 14 days.
Doripenem was found to be microbiologically active
against major causative pathogens of clAI (E. coli,
K. pneumoniae, P. aeruginosa, S. intermedius, E.
faecalis, B. caccae, B. thetaiotaomicron, B. fragilis,
andB. uniformss. Clinical cure rates in ME patients
were 85.9% (95% CI: -7.7% to 9.0%) for doripenem
and 85.3% for meropenem. Microbiologically evalu-
able patients were classified as clAI individuals who
received an adequate course of study drug therapy


PharmaNote Volume 23, Issue 4 January 2008


% Susceptible
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
75.8 (<4)
100.0 (< 4)
100.0 (< 4)


0.0 (>
0.0 (>
0.0 (>


0.0 (> 16)
0.0 (> 16)
13.3 (> 16)
20.0 (> 16)

0.0 (> 16)
0.0 (> 16)
0.0 (> 16)

0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
61.5
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)


% Resistant

0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
0.0 (> 16)
21.2 (> 16)
0.0 (> 16)
0.0 (> 16)


100.0 (< 4)
100.0 (< 4)
100.0 (<4)

100.0 (< 4)
100.0 (< 4)
80.0 (< 4)
70.0 (< 4)

100.0 (< 4)
100.0 (< 4)
100.0 (< 4)

100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
23.1
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)
100.0 (< 4)


Volume 23, Issue 4 January 2008


PharmaNote







and had a measurable outcome at a test of cure visit.
In the mMITT population, cure rates were 77.9% for
doripenem and 78.9% (150/190) for meropenem
(95% CI: -9.7% to 7.7%). Lucasti concluded that
doripenem was clinically effective in clAI and thera-
peutically non-inferior to meropenem.12

Complicated urinary tract infections (cUTI) includ-
ingpyelonephritis
A total of 1171 adults with cUTIs partici-
pated in two multicenter, randomized studies evalu-
ating the safety and efficacy of doripenem.4 Only one
of the studies, DORI-5 is currently available for re-
view.14 DORI-5 was a double-blind, randomized
comparison trial of IV doripenem 500 mg adminis-
tered over 1 hour every 8 hours to IV levofloxacin
250 mg once every 24 hours.14 The option to switch
to oral levofloxacin after a minimum of three days of
IV therapy was available for a total 10-14 days of
treatment. Most patients transitioned to oral therapy
but 11% of doripenem patients and 18% of levoflox-
acin patients received only IV therapy. Non-
inferiority in the microbiological cure of cUTI was
defined as +10% of levofloxacin cure rates. Primary
co-efficacy points were microbiological cure rates in
the ME population and in the mMITT group. Micro-
biologically valuable was classified as patients that
followed study protocol who had an interpretable
urine culture resulting from a specimen in the test of
care (TOC) timeframe at the TOC visit (5 11 days
following the last dose of study medication). Micro-
biological modified ITT were derived from patients
in the ITT, (n=748) who had a qualifying pretreat-
ment urine culture with growth of at least one, but
not exceeding two, bacterial pathogens. Secondary
endpoints included microbiological cure rate in ME
patients infected with E. coli and the clinical cure
rates in the CE patients (patients who had a clinical
outcome assessment obtained in the appropriate TOC
window) at TOC visit. The eradication rate of E.
coli in the ME, was comparatively non-significant at
84.4% of patients in the doripenem arm and 87.2% in
the levofloxacin arm (p=0.83, 95% CI: -10.0% to
4.5%). Clinical cure rates in the CE population fa-
vored doripenem 95.1% over levofloxacin 90.2%
(95% CI: 0.2% to 9.6%). Safety was also addressed,
as adverse effects were reported in 240 (63.8%) sub-
jects in the doripenem arm and 222 (59.7%) of the
levofloxacin group. Serious adverse effects were
experienced by forty-three (5.7%) patients with


doripenem and fifteen patients (4.0%) in the
levofloxacin group, however none were considered
related to study drug. The authors concluded that
doripenem demonstrated non-inferiority to IV
levofloxacin in ME patients with cUTIs and that the
use of doripenem was generally safe and well-
tolerated.14

Nosocomial pneumonia (NP), including ventilator-
associated pneumonia (VAP)
One randomized, open label, multinational,
multicenter study by Rea-Neto and colleagues
(DORI-9) involved 448 adult patients with clinically
or radiologically confirmed nosocomial pneumo-
nia.15 The population also included early onset VAP
within the first 5 days of ventilation (n=55).
Doripenem IV 500 mg over 4 hours every 8 hours
was compared to IV piperacillin/tazobactam (PIP/
TAZ) 4.5 g every 6 hours. Patients were allowed to
switch to oral levofloxacin 750 mg daily after a mini-
mum of 3 days of IV therapy for a total of 7 14
days of combined oral and IV therapy. Adjunctive
anti-pseudomonal therapy was begun in 80% of CE
patients. Comparisons were made focusing on effi-
cacy and safety profiles of IV doripenem vs. PIP/
TAZ in NP. Clinical cure rates in CE patients, were
81.3% with doripenem and 79.8% with PIP/TAZ
(95% CI: -9.1% to 12.1%). In the clinical mITT
population (n=429), clinical cure rates were 69.5%
doripenem and 64.1% PIP/TAZ (95% CI: -4.1% to
14.8%). Resistance to doripenem was lower than
PIP/TAZ particularly with P. aeruginosa (8%
doripenem vs. 27% PIP/TAZ in the mMITT set) and
K. pneumoniae (0% with doripenem and 44% PIP/
TAZ also in the mMITT population). In addition,
microbiological outcomes against gram-negative
pathogens were more favorable with doripenem.
The authors concluded that doripenem was well-
tolerated and therapeutically non-inferior to PIP/TAZ
in hospitalized patients with NP.15
Another study examined 531 adults with
clinically and radiologically confirmed early- and
late-onset VAP (DORI-10).16 Like DORI-9, this trial
was a randomized, international multi-center, open-
labeled study. Chastre and associates (DORI-10),
evaluated the efficacy and safety of doripenem vs.
imipenem/cilastin for VAP.16 This large, multi-
centered, open-label, phase III trial randomized adult
VAP ICU patients to 7 14 days of either extended
IV infusion of doripenem 500 mg every 8 hours, or


PharmaNote Volume 23, Issue 4 January 2008


Volume 23, Issue 4 January 2008


PharmaNote







standard IV imipenem/cilastin 500 mg every 6 hours
or 1000 mg every 8 hours. Co-primary endpoints
were clinical cure rates 7 14 days after completion
of treatment in CE patients who were per protocol
eligible, and the cMITT population (patients who
received any amount of study drug and met the defi-
nition of pneumonia). Clinical cure rates were
68.3% doripenem and 64.8% imipenem/cilastin in
CE patients (95% CI: -9.1 to 16.6). Cure rates in the
cMITT group were 59.0% doripenem and 57.8%
imipenem/cilastin (95% CI: -7.9 to 10.3%). Baseline


or emergent pseudomonal resistance was signifi-
cantly more frequent with imipenem/cilastin therapy.
Clinical cure rates for patients with P. aeruginosa
were 65% doripenem vs. 36% imipenem/cilastin
(p<0.05) while 18% of P. aeruginosa strains in the
doripenem group were resistant or developed resis-
tance. This was in contrast to 56% in the imipenem/
cilastin group (p<0.05 for both arms). Overall 14%
of the pseudomonal strains in the doripenem arm and
52% in the imipenem/cilastin arm were either resis-
tant at baseline or became resistant during the study.


Table 2. Summary of clinical trials
Study N Strategy Results Statistics Conclusions


Naber et al.
(DORI-5)14




Lucasti et al.
(DORI-7)12




Malafia et al.
(DORI-8)13




Rea-Neto et al.
(DORI-9)15






Solomkin et
al.1







Chastre et al.16


IV doripenem vs
IV levofloxacin
648 with oral step-
down therapy in
cUTI

Doripenem vs mer-
openem in compli-
476 cated intra-
abdominal infec-
tions (clAI)


486 Doripenem vs mer-
openem in clAI



Efficacy and safety
448 of IV doripenem vs
Pip/Tazo in NP




Doripenem vs.
962 meropenem with
oral step-down
therapy in clAI





Efficacy of
531 doripenem vs
imipenem in pa-
tients with VAP


CE cure rates of doripenem were
95.1% vs. levofloxacin 90.2%.




CCR in ME patients were 85.9%
(140/163), doripenem and 85.3%
(133/156) meropenem.


CCR in ME at TOC was 83.3%
doripenem vs. 83% meropenem,
demonstrating non-inferiority
(15% margin).

CCR in CE were 81.3%
doripenem and 79.8% Pip/Tazo.
Resistance was higher with Pip/
Tazo.




ME cure rates were 84.6%
doripenem and 84.1% mero-
penem.





CCR in CE patients was 68.3%
doripenem vs. 64.8% imipenem.
Seizures in doripenem 1.1% and
imipenem 3.8%


95% CI:
0.2 to
9.6%



95% CI:
-7.7% to
9.0%



95% CI:
-8.6% to
9.2%


95% CI:
-9.1% to
12.1%




95% CI;
-5.5% to
6.4%






95% CI:
-9.1% to
16.1%


Doripenem was microbio-
logically and clinically effec-
tive in cUTI and non-inferior
to levofloxacin.

Doripenem was clinically
effective in clAI, therapeuti-
cally non-inferior to mero-
penem and well-tolerated
overall.

Doripenem was clinically
effective in clAI with clinical
cure rates similar to mero-
penem and well-tolerated.

Doripenem was safe and well
tolerated in NP. Doripenem
was non-inferior to Pip/Tazo
for clinical and microbiologi-
cal cure of NP.

Doripenem was clinically
effective in patients with
clAI and non-inferior to mer-
openem. Microbiological
eradication rates and safety
profile was similar to mero-
penem.

Doripenem was clinically
effective in VAP patients and
non-inferior to imipenem.
The clinical cure rate of
doripenem was > the CCR of
imipenem in more seriously
ill patients.


CI confidence interval; VAP ventilator-associated pneumonia; CE clinically valuable; ME microbiologically valuable; cIAI complicated intra-abdominal
infections; cUTI complicated urinary tract infections; NP nosocomial pneumonia; PIP/TAZ piperacillin/tazobactam; CCR clinical cure rate


P h ar m a___teV olu me_2 3, Iss ue_4_Ja n u ary_2 0 0 8


Volume 23, Issue 4 January 2008


PharmaNote







Table 3. Summary of adverse effects occurring at a rate > 1% in three phase III clinical trials4,11,12,14


Adverse effect



Headache
Phlebitis
Nausea
Diarrhea
Anemia
Renal impairment/failure
Pruritus
Rash
Hepatic enzyme
elevation
Oral candidiasis
Vulvomycotic infection
UTI urinary tract infection


Complicated UTI14
Doripenem 500 Levofloxacin
mg Q8H (n=376) 250 mg IV Q24H
vs. (n=372)


16%
4%
4%
6%
2%
< 1%
< 1%
1%


15%
4%
6%
10%
1%
0%
1%
1%


Complicated intra-abdominal infections' 11,12


Doripenem
500 mg Q8H
(n=476)
45%
8%
12%
11%
10%
1%
3%
5%


Meropenem
1 g Q8H
(n=469)
5%
6%
9%
11%
5%
< 1%
2%
2%


2%
< 1%


Doripenem was found to be non-inferior to
imipenem/cilastin in terms of clinical cure rates of
VAP. Baseline or emergent pseudomonal resistance
was found to occur significantly more often with
imipenem/cilastin therapy. Furthermore, the clinical
cure rate of doripenem was greater than imipenem/
cilastatin in seriously ill patients as defined by
APACHE II scores.17

Adverse Reactions
The most common adverse reactions (> 5%)
observed in clinical trials were headache, nausea,
diarrhea, rash and phlebitis.4'5 Adverse reaction data
was compiled from 853 adult patients treated with
doripenem in three comparative studies.11'12,14 The
most common causes of discontinuation were nausea
(0.2%), vulvomycotic infection (0.1%) and rash
(0.1%). In an animal study18 comparing carbap-
enems for neurotoxicity and convulsive activity,
doripenem was the only carbapenem that did not in-
cite neurogenic activity. Doripenem at doses of 100
mg, 300 mg and 1000 mg in dogs demonstrated no
effects on EEG or behavior. Conversely after 100mg
of imipenem, seizure discharges with clonic conver-
sions, vomiting and multiple spike complexes were
observed in the hippocampus. Imipenem did not
generate any behavior changes. Meropenem exhib-
ited similar attributes to imipenem.
Anaphylaxis reactions are rare with
doripenem. Reactions are more likely to occur in
patients with a history of sensitivity to allergens. If
doripenem is used in a penicillin or p-lactam allergic
patient, use caution because known cross-reactivity


PharmaNote


is well established between p-lactam antibiotics.
The frequency and causality of doripenem anaphy-
lactoid reactions has not been established in clinical
practice. Possible serious adverse reactions include
Stevens-Johnson syndrome, interstitial pneumonia,
toxic epidermal necrolysis and increased seizure
risk.4
Clostridium difficile-associated diarrhea
(CDAD) has been reported with almost all antibacte-
rial agents especially with potent antibiotics or long-
term use. Doripenem utilization may result in dis-
ruption of gastrointestinal intrinsic flora and lead to
C. difficile growth. Diarrhea may significantly affect
morbidity and mortality. Caution must be employed
in patients who develop diarrhea after or during anti-
biotic use, cases of C. difficile have been reported
even after two months post-antibiotics.4

Drug Interactions and Contraindications
Valproic Acid
Concurrent administration of valproic acid
and doripenem may result in subtherapeutic plasma
concentrations of valproic acid, ultimately leading to
loss of seizure control.4'5 Monitor serum valproate
concentrations frequently if doripenem therapy is
used. Substitute forms of seizure control should be
implemented if serum valproic acid concentrations
cannot be maintained at an effective level.
Probenecid
Interactions between probenecid and
doripenem may result in increased doripenem plasma
concentrations.4'5 The administration of probenecid
and doripenem is not recommended.


Volume 23, Issue 4 January 2008







Table 4. Doripenem dosing and administration4'5
Infection Dose Frequency Infusion time Duration

Complicated intra-abdominal
Co d il 500 mg Q 8 hours 1 hour 5-14 days
infection

Complicated UTI, including
Complicated UTI, including 500 mg Q 8 hours 1 hour 10 days
pyelonephritis


Other antimicrobial agents
Doripenem has a small potential to interact
with other antibiotics and should not inhibit or in-
duce drugs such as, but not limited to levofloxacin,
amikacin, trimethoprim-sulfamethoxazole, daptomy-
cin, linezolid or vancomycin.4'5 In vitro studies in
human liver microsomes and hepatocytes indicate
that doripenem does not inhibit the major cyto-
chrome P450 isoenzymes (CYP1A2, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, CYP3A4/5 and CYP4A11). As a result,
when giving these antibiotics concurrently with
doripenem, the clearance and metabolism of either
drug should not be significantly affected.4
Hepatic Impairment
Doripenem does not appear to be hepatically
metabolized but the pharmacokinetics on patients
with hepatic impairment has not been tested. It is
expected that patients with impairment will not need
dose adjustments.

Cost
The average wholesale price (AWP) of a
doripenem 500mg IV vial is $47.91, in terms of cost
per unit. Pricing information was obtained courtesy
of the Red Book, manufacturer's information and the
McKesson database.19

Summary
Doripenem has similar attributes and much of
the same coverage as meropenem, but possibly more
coverage against Pseudomonas and other carbap-
enem-resistant isolates. The potential role of


doripenem will unfold as the peer-reviewed literature
is released and more clinical experience with the
drug is documented. Doripenem may provide en-
hanced activity against non-fermentative gram-
negative bacilli, may have bactericidal activity
against most pathogens, appears to be stable to both
human renal dehydropeptidases and to common bac-
terial p-lactamases including extended-spectrum 3-
lactamases, possesses a post-antibiotic effect against
Pseudomonas aeruginosa, and appears to possess
activity against penicillin-resistant streptococci.20

References
1. Sakyo S, Tomita H, Tanimoto K, et al. Potency
of carbapenems for the prevention of carbap-
enem-resistant mutants of Pseudomonas aerugi-
nosa: the high potency of a new carbapenem
doripenem. J Antibiot 2006; 59: 220-8.
2. Anderson DL. Doripenem. Drugs of Today 2006;
42: 399-404.
3. Zhanel GG, Wiebe R, Dilay L, et al. Compara-
tive review of the carbapenems. Drugs 2007; 67:
1027-52.
4. Doribax (doripenem) Full prescribing informa-
tion. Ortho-McNeil Pharmaceuticals, Inc; Rari-
tan, NJ: October 2007.
5. Doripenem. Clinical Pharmacology. Gold Stan-
dard Inc. 2007.
6. Afzal-Shah M, Woodford N, Livermore D. Char-
acterization of OXA-25, OXA-26, and OXA-27,
molecular class D P-Lactamases associated with
carbapenem resistance in clinical isolates of
Acinetobacter baumannii. Antimicrob Agents
Chemother 2001; 45: 583-8.


Table 5. Doripenem dosing in renal impairment4',
Estimated creatinine clearance Dose adjustment
> 50 mL/min No dosage adjustment necessary
> 30 to 50 mL/min 250 mg IV (over 1 hour) every 8 hours
> 10 to 30 mL/min 250 mg IV (over 1 hour) every 12 hours
*Doripenem is hemodialyzable, but due to insufficient data, no recommendations on dosing can be made

PharmaNote Volume 23, Issue 4 January 2008







7. Kobayashi Y. Study of the synergism between
carbapenems and vancomycin or teicoplanin
against MRSA, focusing on S-4661, a carbap-
enem newly developed in Japan. J Infect Chemo-
ther 2005; 11: 259-61.
8. Ikawa K, Morikawa N, Urakawa N, et al. Perito-
neal penetration of doripenem after intravenous
administration in abdominal-surgery patients. J
Antimicrob Chemother 2007; 60: 1395-7.
9. Jones R, Huynh H, Biedenbach D, et al.
Doripenem (S-4661), a novel carbapenem: com-
parative activity against contemporary pathogens
including bactericidal action and preliminary in
vitro methods evaluations. J Antimicrob Chemo-
ther 2004; 54: 144-54.
10. Drugs.com. FDA drug approvals. http://
www.drugs.com/newdrugs/fda-approves-
doribax-complicated-intra-abdominal-
complicated-urinary-tract-infections-674.html.
Accessed November 11, 2007.
11. Solomkin J, Umeh O, Jiang J, et al. Doripenem
versus meropenem with an option for oral step-
down therapy in the treatment of complicated
intra-abdominal infections. [poster] Presented at
the 47th Annual Interscience Conference on An-
timicrobial Agents and Chemotherapy (ICAAC),
Chicago, Illinois, September 17-20, 2007.
12. Lucasti C, Jasovich A, Umeh O, et al. Treatment
of complicated intra-abdominal infections:
doripenem vs. meropenem. [Abstract 1733_332].
Presented at the 17th European Congress of
Clinical Microbiology and Infectious Diseases
(ECCMID), Munich, Germany, April 1-4 2007.
13. Malafaia O, Umeh O, Jiang J. Doripenem vs.
meropenem for the treatment of complicated in-
tra-abdominal infections. [poster]. Presented at
the 47th Annual Interscience Conference on An-
timicrobial Agents and Chemotherapy (ICAAC),
Chicago, Illinois, September 17-20, 2007.
14. Naber K, Redman R, Kotey P, et al. Intravenous
therapy with doripenem vs. levofloxacin with an
option for oral step-down therapy in the
treatment of complicated urinary tract infection
and pyelonephritis. [abstract 1733_331].
Presented at the 17th European Congress of
Clinical Microbiology and Infectious Diseases
(ECCMID), Munich, Germany, Apr 1-4 2007.
15. Rea-Neto A, Niederman M, Lee M, et al.
Efficacy and safety of intravenous doripenem vs.
piperacillin/tazobactam in nosocomial pneumo-


nia [poster]. Presented at the 47th Annual Inter-
science Conference on Antimicrobial Agents and
Chemotherapy (ICAAC); Chicago, Illinois; Sep-
tember 17-20, 2007.
16. Chastre J, Wunderink R, Prokocimer P, et al.
Efficacy and safety of doripenem versus
imipenem for ventilator-associated pneumonia
[poster]. Presented at the 47th Annual Inter-
science Conference on Antimicrobial Agents and
Chemotherapy (ICAAC); Chicago, Illinois; Sep-
tember 17-20, 2007.
17. Postier R, Clavel M, Prokocimer P, et al.
[poster]. Presented at the 47th Annual Inter-
science Conference on Antimicrobial Agents and
Chemotherapy (ICAAC); Chicago, Illinois; Sep-
tember 17-20, 2007.
18. Horiuchi M, Kimura M, Tokumura M, et al. Ab-
sence of convulsive liability of doripenem, a new
carbapenem antibiotic, in comparison with b-
lactam antibiotics. Toxicology 2006; 222: 114-
24.
19. Doripenem. Hopkins Antibiotics Guide. http://
prod.hopkinsabxguide.org/antibiotics/
antibacterial/carbapenem/doripenem.html. Ac-
cessed December 17, 2007.
20. Doripenem A new broad-spectrum carbapenem
antibiotic. http://www.drugdevelopment-
technology.com/projects/doripenem. Accessed
November 16, 2007.



The PharmaNote is Published by:
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Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida



John G. Gums Editor
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