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251（ 31 ）Efficacy and safety of doripenem for sepsis
with neutropenia in Japanese patientswith hematologic diseases
NOBU AKIYAMA1, AKIHISA KANAMARU2, KAZUO TAMURA3,
MITSUNE TANIMOTO4, KAZUMA OHYASHIKI5, YASUNORI NAKAGAWA6,
AKIO URABE7 and TORU MASAOKA8
1

Department of Internal Medicine, Teikyo University School of Medicine
2
Kinki University School of Medicine
3
Division of Medical Oncology, Hematology and Infectious Diseases,
Fukuoka University Hospital
4
Division of Hematology and Oncology, Okayama University Hospital
5First Department of Internal Medicine (Division of Hematology),
Tokyo Medical University
6
Department of Oncology and Hematology,
Japanese Red Cross Medical Center
7
NTT Medical Center Tokyo
8
Osaka Medical Center for Cancer and Cardiovascular Disease(Received for publication May 23, 2012)

Doripenem (DRPM) is one of the carbapenems which has a broad-spectrum andstrong activity against Pseudomonas aeruginosa. This observational study was
conducted between April 2006 and March 2007 in Japan to evaluate the ef¿cacy andsafety of DRPM 0.5 g three times a day for sepsis with neutropenia in patients withhematologic diseases. One hundred-nineteen patients were enrolled from 34 medical
institutes, comprising 117 patients for safety evaluation and 104 for ef¿cacy
evaluation. Monotherapy of DRPM 0.5 g three times a day (DRPM monotherapy)
was evaluated in 73 patients. The response rates of DRPM monotherapy at 72 hours
and at Day 7 were 31.5% (23/73) and 67.1% (49/73), respectively. The incidence ofadverse reactions including abnormal changes in laboratory values was 23.1%, andhepatic toxicity was most common. All of these adverse events were judged by theinvestigators as non-serious and tolerable. These results suggest that DRPM is usefulfor sepsis with neutropenia, though further study may be warranted.

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1. Introduction
Doripenem (DRPM) is a carbapenem antibiotic with broad-spectrum and potent antibacterial
activity against Pseudomonas aeruginosa1〜3). DRPM was primarily approved in Japan in July
2005, and then in the United States in October 2007. The European Union marketing authorization for DRPM was granted in July 2008. Febrile neutropenia (FN) in association with hematologic diseases is potentially fatal. Empiric therapy with appropriate antibiotics should be instituted as soon as possible, when FN occurs. In the Infectious Diseases Society of America (IDSA)
Guidelines published in 2011, monotherapy with either an antipseudomonal ȕ-lactam or a carbapenem or piperacillin-tazobactam is recommended as the ¿rst-line empiric therapy for high risk
FN patients4). It has been demonstrated that imipenem/cilastatin (IMP/CS), panipenem/betamipron (PAPM/BP), and meropenem (MEPM) are effective in FN5〜8). The ef¿cacy rate of
DRPM for sepsis without neutropenia was 100% (9/9) in the clinical trial before the government
approval9). DRPM has been expected to be effective for sepsis even with neutropenia as well. In
this study, the safety and ef¿cacy of DRPM in treatment of sepsis in neutropenic patients with hematologic diseases was evaluated.

2. Patients and Methods
2.1. Subjects
Patients eligible for study inclusion were those with hematologic diseases, diagnosed withsepsis or suspicion of sepsis, treated with DRPM 0.5 g three times a day, meeting the inclusion
criteria and lacking the exclusion criteria. In each institute, eligible patients were consecutively
registered. Inclusion criteria were as follows: inpatients aged 16 years or older, body temperature侒37.5°C at axilla, neutrophil count either ＜500/ȝL or ＜1000/ȝL with predictable decrease to＜500/ȝL. Exclusion criteria were as follows: history of shock or hypersensitivity against any of
the components of DRPM, history of hypersensitivity against carbapenem, penicillin, or cephalosporin antibiotics, treatment with sodium valproate, severe hepatic or renal disorder, and infection
due to causative organisms resistant to DRPM like methicillin-resistant Staphylococcus aureus(MRSA).
2.2. Study design
This study was an open-label, prospective and non-randomized clinical study. Patients wereenrolled within three days after initiation of DRPM. DRPM 0.5 g was intravenously administeredover 30 minutes every eight hours. The observation period was from the start of DRPM administration to seven days after completing treatment. If the duration of treatment was less than sevendays, the observation period was 14 days from the start of treatment.

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253（ 33 ）Fig. 1. Distribution of patients.

The following variables were collected: clinical characteristics (age, sex, weight, underlying
disease, past history, history of allergy, and complications), treatment factors (prior and concomitant medications), clinical symptoms (temperature, blood pressure, pulse rate, disturbed consciousness, dyspnea), laboratory ¿ndings (urinalysis, complete blood counts, blood chemistrypro¿les, C-reactive protein (CRP), ȕ-D-glucan, endotoxin, blood cultures), and adverse events.
Severity of infection was determined according to the grade of CTCAE v3.0, as correspondenceof moderate and severe to grade 3 and 4, respectively.
Response to treatment was evaluated at 72 hours and at Day 7. “Effective” in the evaluation
at 72 hours was de¿ned as follows: the daily maximum temperature dropped to less than 37.0°C
within 72 hours after the initiation of DRPM therapy (Criteria I), or fell by at least 1.0°C to less

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Table 1. Characteristics of patients in DRPM monotherapy.

than 37.5°C within 72 hours (Criteria II), and this state persisted for at least three days. “Effective” in the evaluation at Day 7 was de¿ned as follows: the daily maximum temperature dropped
to less than 37.0°C, or fell by at least 1.0°C to less than 37.5°C within seven days, this state persisted for at least three days, and any symptoms derived from infection were absent at Day 7.
Treatment response other than the de¿nition of “effective” was judged as “not effective”.

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255（ 35 ）2.3. Statistical analysis
For the ef¿cacy evaluation, the response rate was calculated as percentage of “effective” responses in the evaluation at 72 hours and at Day 7. For safety evaluation, the incidence of adverse
reactions was calculated. The Clopper-Pearson method was used to calculate the con¿dence intervals of ratios. The Ȥ2 test was used to compare the ef¿cacy rates between categories of each variable, and for the purpose of this test the categories “unknown” and “missing data” were excluded.
Ordinal variables were tested for trend with the Cochran-Armitage test. The presence of a linear
trend in the ef¿cacy rate in association with an increase in the category was evaluated, and the
goodness of ¿t of the linear trend was also evaluated. For all tests, the level of signi¿cance wasset at p＜0.05, two-sided.

3. Results
3.1. Distribution and characteristics of patients
Distribution of patients is shown in Figure 1. One hundred-nineteen patients from 34 institutes in Japan were enrolled in the study. The safety and overall ef¿cacy were evaluated in 117
and 104 patients, respectively. Thirty-one patients were excluded from the overall ef¿cacy evaluation set, and the ef¿cacy of DRPM monotherapy was evaluated in 73 patients, eventually. Theircharacteristics are shown in Table 1. All of the excluded cases violated the study protocol, thusef¿cacy could not be evaluated. In particular, one death case was excluded from the ef¿cacy evaluation set of DRPM monotherapy, since the patient died of intracranial hemorrhage due to progression of acute myeloid leukemia within three days after initiation of DRPM.
3.2. Ef¿cacy
3.2.1. Overall response rates
The overall response rates of the 104 patients at 72 hours and at Day 7 were 27.9% (29/104)
and 57.7% (60/104), respectively.
3.2.2. Response rates of DRPM monotherapy
The response rates of the 73 patients with DRPM monotherapy are shown in Table 2. The response rates at 72 hours and at Day 7 were 31.5% (23/73) and 67.1% (49/73), respectively. Noneof the characteristics affected the response rates at 72 hours and at Day 7.
3.2.3. Recurrent fever
The day of defervescence was de¿ned as the ¿rst day when a patient was assessed as “effective” according to the ef¿cacy criteria. Up to Day 7, fever over 37.5°C recurred in six out of 23
cases evaluated as effective at 72 hours. These cases comprised three out of eleven and three outof twelve cases judged by Criteria I and Criteria II, respectively. The rate of recurrence was notdifferent between these two groups (p＝0.725).

Table 3. Impact of prior antibiotics on response rate of DRPM monotherapy.

Table 2. Response rates of DRPM monotherapy.

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Table 4. Response rate by neutrophil count at 72 hours.

Table 5. Response rate by neutrophil count at day 7.

Table 6. Response rate by causative organisms.

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3.2.4. Impact of prior therapy on ef¿cacy of DRPM monotherapy
The response rates strati¿ed by prior use of parenteral antibiotics are shown in Table 3. In allof the cases with prior antibiotics, the antibiotics were switched to DRPM because of treatment
failure. The response rates at 72 hours in patients with and without prior antibiotics were 30.8%(8/26) and 31.9% (15/47) respectively, and at Day 7 were 61.5% (16/26) and 70.2% (33/47) respectively. There was no signi¿cant difference in response rates between these two groups at bothof 72 hours and at Day 7.
Fluoroquinolone (FQ) prophylaxis did not inÀuence the ef¿cacy of DRPM at 72 hours andDay 7, as well.
3.2.5. Impact of neutrophil count on ef¿cacy of DRPM monotherapy
The ef¿cacy at 72 hours and at Day 7 strati¿ed according to neutrophil count before andafter DRPM monotherapy is shown in Tables 4 and 5. The response rates at 72 hours were notsigni¿cantly different among three groups classi¿ed by the pre-treatment neutrophil count (p＝0.3303), and among the four categories of neutrophil count at 72 hours (p＝0.2531). In comparison with neutrophil counts before and 72 hours after DRPM initiation, there were no signi¿cantdifferences in the response rates among the three categories (increased, decreased, and unchanged
neutrophil counts) (p＝0.1589).
The response rates at Day 7 were not signi¿cantly different among the groups classi¿ed by
the pre-treatment neutrophil count (p＝0.7147). In contrast, there was a signi¿cant difference inthe response rates among the four categories of neutrophil count at Day 7 (p＝0.0307). In the patients with neutrophil count over 100/ȝL at Day 7, the response rate was signi¿cantly higher thanin those with neutrophil count ＜100/ȝL at Day 7 (p＝0.0039). In the patients with pre-treatment
neutrophil count ＜100/ȝL, the increase in neutrophil count to 100/ȝL or more at Day 7 resulted
in a signi¿cantly higher response rate (p＝0.0011). Among the three categories (increased, decreased, and unchanged neutrophil counts), the response rate of the increasing tendency in neutrophils was signi¿cantly higher than the others (p＝0.0338).
3.2.6. Ef¿cacy by causative organism of DRPM monotherapy
Bacteria were isolated from the blood in 11 out of 73 cases. Response rate by causative organism is shown in Table 6. Overall response rates after 72 hours and Day 7 were 36% and 73%,
respectively.
3.2.7. Fatal outcomes of DRPM monotherapy
Three deaths out of 73 cases occurred during the study period (Table 7). A 78 year-old
woman with myelodysplastic syndromes died of sepsis with unknown etiology at day 4 of DRPM
monotherapy. In this case, DRPM followed administration of cefepime (CFPM) for ¿ve days
which failed to ameliorate sepsis, and the patient went into septic shock and multi-organ failure.
Two cases of death were caused by non-infectious complications including intracranial
bleeding and an underlying disease, respectively.

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259（ 39 ）Table 7. Fatal cases.

Table 8. Adverse reactions.

3.3. Adverse reactions
The adverse reactions in 117 patients included in the safety evaluation set are listed in Table
8. Incidence of adverse reactions was 23.1% (27/117). The most common adverse reaction was

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hepatic toxicity, occurring in 18.0% (21/117). There were no serious adverse reactions corresponding to Grade 3 or 4 of CTCAE v3.0, except for asymptomatic grade 3 toxicity of increased
aspartate aminotransferase (AST) and hypopotassemia in two individual cases.

4. Discussion
Either of an antipseudomonal cephalosporin or a carbapenem or piperacillin-tazobactam isrecommended for empiric therapy of FN in the practical guidelines for FN4). Five carbapenems
including IMP/CS, MEPM, PAPM/BP, biapenem (BIPM) and DRPM are available in Japan. Prospective randomized studies on the ef¿cacy of CFPM, MEPM and PAPM/BP against FN, whichwere conducted by the Japanese FN Study Group, demonstrated that overall response rates after
three and seven days of treatment were about 30% and 50%, respectively, and were not different
among these three agents10,11). The response rate of BIPM during the ¿rst seven days was reported
as 67.9% in FN patients with hematopoietic diseases12). The present study preliminarily demonstrated that the response rates of overall patients and those with DRPM monotherapy at 72 hours
and Day 7 were considered comparable to those of CFPM, MEPM and PAPM/BP, though a randomized control trial should be needed to prove non-inferiority or equality of DRPM to thoseagents for FN.
New evaluation criteria for ef¿cacy were introduced in this study. The de¿nition of signi¿cant fever is 37.5°C or more at axillary temperature in Japan. However, traditionally defervescence has been de¿ned as below 37.0°C. Body temperature between 37.0 and 37.5°C was grayzone in the evaluation of ef¿cacy. The majority of patients whose body temperature fell to between 37.0 and 37.5°C with improvement of clinical symptoms did not need to change the ¿rstline antibiotic therapy. In this study, the defervescence was de¿ned as below 37.0°C (Criteria I) or
37.5°C with decrease over 1.0°C (Criteria II). The determination of “with decrease over 1.0°C”
was added to prevent from misjudgment of dropping down below 37.5°C due to circadian Àuctuation and measurement error as defervescence. The rate of recurrent fever in the patients evaluatedas “effective” at 72 hours by Criteria II was equal to that of Criteria I. Consequently, the effectiveness assessed by Criteria II is considered as equivalent to that by Criteria I. The de¿nition ofdefervescence as dropping below 37.5°C when body temperature was decreased by at least 1°C is
reasonable in clinical practice.
The response rates at 72 hours and at Day 7 were compared between patients with and without prior parenteral antibiotics therapy. It was demonstrated that prior parenteral antibiotics did
not inÀuence these response rates, and that DRPM was effective in 61.5% of patients with priorantibiotic therapy at Day 7. The IDSA guidelines on FN recommend the shift from an initial
cephalosporin to a carbapenem as well as by the addition of an aminoglycoside, ciproÀoxacin, or
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261（ 41 ）therapy failed in clinically unstable FN patients without a clear source of fever4). Although ef¿cacy of carbapenems in the second-line empiric therapy has not been established yet, DRPM may
be considered as one of promising agents for the second-line empirical therapy in FN.
FQs are often used for prevention of bacterial infection in high-risk neutropenic patients withhematologic diseases. FQs were reported to enhance the mutation conferring carbapenem resistance in Pseudomonas aeruginosa, in vitro. Carbapenem-resistant mutants were selected in thepresence of carbapenems after pre-incubation with subinhibitory concentration of a FQ (ciproÀoxacin and oÀoxacin). The frequency of the isolation of the mutants was higher in the selection with
MEPM than DRPM, which completely inhibited growth of the mutants13). In the present study, theef¿cacies of DRPM were equivalent in patients with and without prior Àuoroquinolone. DRPM issuggested to be a promising antibacterial agent for patients with FQ prophylaxis, as well.
Neutrophil counts before DRPM monotherapy had little effect on the response rates at 72
hours and Day 7. Neutrophil counts at 72 hours did not inÀuence the response rate at 72 hours.
By contrast, the response rate at Day 7 in patients with neutrophil count ＜100/ȝl at Day 7 wassigni¿cantly lower than that with neutrophil count 侒100/ȝl. This indicates that neutrophil count＜100/ȝl at Day 7 is a risk factor for treatment failure. The IDSA guidelines proposed that neutrophil count ＜100/ȝl over 7 days is one of the determinants for high risk FN patients4). Our data,thus, agreed with the proposal of IDSA.
In this study the incidence of adverse reactions during administration of DRPM was 23.1%.
The most common adverse reaction observed with DRPM was hepatic toxicity, like other carbapenems. All of adverse reactions observed with DRPM were judged to be not serious by the investigator and all were considered tolerable. These ¿ndings suggest that administration of 0.5 g
three times a day of DRPM is considered as safe for the majority of Japanese patients.
In conclusion, the present study suggests that DRPM is considered to be one of the promising agents as an empiric therapy in neutropenic patients with fever and sepsis with neutropenia.
Further phase 3 study is warranted to con¿rm the ef¿cacy and safety of this agent.
Acknowledgement
Doripenem Sepsis Research Group was organized with 34 institutions are listed below. Asahikawa Medical College Hospital, Sapporo Hokuyu Hospital, Osaki Citizen Hospital, Iwate Medical University Hospital, Iwaki Kyouritsu Hospital, Teikyo University Hospital, Kanto Medical
Center NTT EC, Japanese Red Cross Medical Center, Tokyo Womenʼs Medical University Hospital, Tokyo Medical University Hospital, Kyorin University Hospital, St. Marianna University
School of Medicine Hospital, Mito Saiseikai General Hospital, Tsukuba University Hospital, Niigata University Medical & Dental Hospital, Aichi Medical University Hospital, Mie University
Hospital, Hamamatsu University School of Medicine Hospital, Kanazawa University Hospital,
Osaka City University Hospital, Osaka Medical College Hospital, Kinki University School of262（ 42 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Medicine Hospital, Nara Medical University Hospital, Takeda Hospital, Okayama University
Hospital, Hiroshima University Hospital, Kagawa University Hospital, Matsuyama Red Cross
Hospital, Ehime University Hospital, Fukuoka University Hospital, National Kyushu Cancer
Center, University of Occupational and Environmental Health Hospital, Nagasaki University
Hospital, Ryukyu University Hospital.
This research was sponsored by Shionogi & Co. Ltd.

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