AA

MCa

b

c

d

e

f

g

h

a

ARA

KDAM

1

GicCaPs

h0

International Journal of Antimicrobial Agents 43 (2014) 353–360

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journa l homepage: ht tp : / /www.e lsev ier .com/ locate / i jant imicag

PROspective study on the Usage patterns of Doripenem in thesia-Pacific region (PROUD study)

ahiran Mustafaa,∗, Wai Ming Chanb, Christopher Leec, Eddy Harijantod,hian Min Looe, Nguyen Van Kinhf, Nguyen Dat Anhg, Jemelyn Garciah

Department of Medicine, Hospital Raja Perempuan Zainab II, 15000 Kota Bharu, Kelantan, MalaysiaAdult Intensive Care Unit, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Road, Hong KongDepartment of Medicine, ID Unit and Department of Medicine, Hospital Sungai Buloh, Selangor 47000, MalaysiaDepartment of Anesthesiology, Dr Cipto Mangunkusumo Hospital, Diponegoro St No. 71, Kenari Village, Senen, Central Jakarta City 10430, IndonesiaDepartment of Respiratory and Critical Care Medicine, Singapore General Hospital, Outram Road, Singapore 169608, SingaporeIntensive Care Unit, National Hospital for Tropical Diseases, Giai Phong Street, Hanoi, VietnamEmergency Department, Bach Mai Hospital, 78 Duong Giai Phong, Phuong Mai, Dong Da, Hanoi, VietnamJanssen Pharmaceutica, A Division of Johnson & Johnson Pte Ltd., Edison Road, Barrio Ibayo, Paranaque City 1700, Philippines

r t i c l e i n f o

rticle history:eceived 17 June 2013ccepted 2 January 2014

eywords:oripenemsia-Pacificedical resource utilisation

a b s t r a c t

Doripenem is approved in the Asia-Pacific (APAC) region for treating nosocomial pneumonia (NP)including ventilator-associated pneumonia (VAP), complicated intra-abdominal infections (cIAIs) andcomplicated urinary tract infections (cUTIs). Clinical usage of doripenem (500 mg intravenously, infusedover 1 h or 4 h every 8 h for 5–14 days) in APAC was evaluated in a prospective, open-label, non-comparative, multicentre study of inpatients (≥18 years) with NP, VAP, cIAI or cUTI. A total of 216[intention-to-treat (ITT)] patients received doripenem: 53 NP (24.5%); 77 VAP (35.6%); 67 cIAI (31.0%); and19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichiacoli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64 �g/mL, respectively. Doripenem was used mostcommonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinicallyevaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7–14 daysafter EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. Themedian duration of hospital stay, intensive care unit (ICU) stay and mechanical ventilation was 20, 12

and 10 days, respectively. Of 146 discharged patients, 7 were re-admitted within 28 days of EOT; 1 VAPpatient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most com-mon treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viableoption for treating APAC patients with NP, VAP, cIAI or cUTI.

[ClinicalTrials.gov: NCT 00986102].© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

. Introduction

The increasingly endemic nature of multidrug-resistantram-negative bacilli in healthcare settings [1,2], especially

n the Asia-Pacific (APAC) region [3,4], has paved the way forarbapenems in the treatment of nosocomial infections [5].arbapenems possess broad-spectrum in vitro activity both

gainst Gram-positive and Gram-negative pathogens, includingseudomonas aeruginosa, Acinetobacter spp. and extended-pectrum �-lactamase (ESBL)-producing Enterobacteriaceae [6].

∗ Corresponding author. Tel.: +60 19 911 9155; fax: +60 9745 2546.E-mail address: mahiranmustafa@hotmail.com (M. Mustafa).

ttp://dx.doi.org/10.1016/j.ijantimicag.2014.01.017924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights

Medical societies and infectious diseases experts have publishedevidence-based treatment guidelines in which they recommenda carbapenem for empirical treatment of hospital-acquired andventilator-associated pneumonia (VAP) when a Gram-negativepathogen is suspected [7,8], for healthcare-associated complicatedintra-abdominal infections (cIAIs) [9] and for complicated urinarytract infections (cUTIs) due to antibiotic-resistant Gram-negativebacteria, including AmpC- and ESBL-producing strains [10].

Doripenem is the newest carbapenem approved in the APACregion for treatment of adults with nosocomial pneumonia (NP)

including VAP, cIAI and cUTI. It is therefore important to evaluateand describe the current usage patterns for doripenem in the APACregion [11]. Thus, the PROspective study on the Usage patterns ofDoripenem (PROUD) was designed to determine not only the types

reserved.

3 l of An

omm

2

irPt

2

(w

ivetri(rpfsp≥f

vtel>aoa

cpotnia

c2rdbplgpwo

2

t

54 M. Mustafa et al. / International Journa

f patients and indications for which doripenem is selected as treat-ent in APAC but also clinical and microbiological outcomes andedical resource utilisation associated with its usage.

. Materials and methods

An ethics committee at each site approved the protocol andnformed consent form before study initiation (ClinicalTrials.govegistration no. NCT 00986102; http://www.clinicaltrials.gov).atients or their legally acceptable representatives provided writ-en informed consent before any study-related activity.

.1. Patients

Adults (≥18 years of age) hospitalised in an intensive care unitICU) or ward with a diagnosis of NP, VAP, cIAI or cUTI and whoere candidates for carbapenem therapy were enrolled.

A NP diagnosis required clinical signs/symptoms of de novonfection after ≥48 h of hospitalisation [7]. Patients on mechanicalentilation for ≥48 h before developing pneumonia were consid-red to have VAP. NP/VAP patients were required to have at leastwo of the following: cough; new onset or worsening purulentespiratory secretions; auscultatory findings on pulmonary exam-nation of rales and/or consistent with consolidation; tachypnoea≥30/min); and/or hypoxaemia [partial pressure of oxygen in arte-ial blood (PaO2) ≤60 mmHg or pulse oximetry < 90% on room air];lus new or worsening infiltrate on chest radiography and eitherever (oral >38 ◦C)/hypothermia (rectal/core <35 ◦C) or leukocyto-is (≥10 000/mm3)/leukopenia (≤4500/mm3). In addition, eligibleatients were hospitalised for ≥48 h, had a prior hospitalisation of48 h within the prior 7 days or were resident of a chronic care

acility and admitted for pneumonia.A cIAI diagnosis required infection extending beyond the

iscus of origin into the peritoneal space with abscess forma-ion or peritonitis [12]. cIAI patients had systemic infection asvidenced by at least one of the following: fever/hypothermia;eukocytosis; hypotension (systolic blood pressure decreased by15 mmHg from baseline); tachycardia (>100 bpm)/tachypnoea;nd/or hypoxaemia; as well as physical signs of IAI (i.e. at leastne of abdominal pain/tenderness, localised or diffuse guarding,bdominal wall rigidity, abdominal mass and/or ileus).

A cUTI diagnosis required a positive pre-treatment clean-atch midstream urine culture (>105 CFU/mL) and either acuteyelonephritis or lower urinary tract symptoms together with onef the following: indwelling catheter or intermittent catheterisa-ion; incomplete voiding (>100 mL of residual urine post-voiding);eurogenic bladder; obstructive uropathy; azotemia due to

ntrinsic renal disease; vesicoureteral reflux; other urologicalbnormalities; diabetes mellitus; or immunosuppression.

Across these indications, exclusion criteria were creatininelearance (CLCr) ≤10 mL/min, dialysis, oliguria (<20 mL/h over4 h), hypersensitivity to a carbapenem or �-lactam antibiotic,eceived another carbapenem within 2 weeks of the first doripenemose, treatment failure with other carbapenems, infection causedy doripenem-resistant pathogen(s) and poor prognosis. NP/VAPatients were excluded if they had cavitary lung disease, primary

ung cancer, metastatic lung disease or pneumonia due to fun-al, viral or atypical pathogen (i.e. Pneumocystis jiroveci, Legionellaneumoniae or Mycoplasma pneumoniae), as were cUTI patientsith infection caused by Mycobacterium tuberculosis, fungi or other

rganisms not susceptible to doripenem.

.2. Study design

This phase 4, prospective, open-label, non-comparative, mul-icentre study was conducted between July 2009 and September

timicrobial Agents 43 (2014) 353–360

2011 at centres in Malaysia (n = 9), Indonesia (n = 5), Vietnam (n = 3),Singapore (n = 2) and Hong Kong (n = 1). The study had three phases:(i) a pre-treatment phase with a 1-day screening/baseline visit; (ii)a treatment phase; and (iii) a post-treatment phase consisting ofan end-of-treatment (EOT)/early withdrawal visit ≤24 h after thelast dose of antibiotic [intravenous (i.v.) + oral], a test-of-cure (TOC)visit 7–14 days after EOT, and a late follow-up visit 28 days afterthe conclusion of treatment (to assess mortality status and ICU andhospital re-admission rates).

2.3. Study drug therapy

Doripenem 500 mg was administered via a 1-h or 4-h i.v. infu-sion (4-h i.v. infusion was recommended for NP/VAP patientsat risk of infection with less-susceptible pathogens), every 8 h,either alone or in combination with protocol-specified antibacte-rial agents (i.e. vancomycin for meticillin-resistant staphylococcalinfection; amikacin or another aminoglycoside for P. aeruginosainfection). For patients with renal dysfunction, the doripenemdosage was reduced according to protocol-specified adjustments.The recommended duration of doripenem treatment was 5–14days, with switch to an appropriate oral antibiotic possible after≥72 h of i.v. doripenem for patients who were clinically improved.For VAP patients, i.v. study drug administration was to be discon-tinued if the Clinical Pulmonary Infection Score (CPIS) [13] haddecreased by 2 points relative to baseline for ≥2 days. If the CPIShad not met these criteria by Day 14, the patient was considered aclinical failure and study drug was discontinued.

2.4. Efficacy procedures/outcome definitions

The Acute Physiology and Chronic Health Evaluation (APACHE)II score [14] was computed at baseline for all ICU patients. Clini-cal signs and symptoms, physical examination and vital signs wereassessed at baseline, daily during treatment with study drug as wellas at the EOT and TOC visits. For NP/VAP patients, a chest radiographwas obtained at baseline, EOT and TOC, and more frequently if clin-ically indicated. For VAP patients only, the CPIS was calculated atbaseline, Day 3, Day 5 and then every other day until the EOT orextubation.

Blood samples were collected for culture from all patients atbaseline, Days 3 and 5, and every other day thereafter until theEOT or a negative result was reported. In patients with NP or VAP,respiratory secretion samples were obtained at baseline, EOT andat other time points as clinically indicated. Samples for ventilatedpatients were obtained by bronchoscopy with bronchoalveo-lar lavage or protected-specimen brush, mini-bronchoalveolarlavage, or deep suction by endotracheal tube. Expectorated sam-ples containing <10 squamous epithelial cells and >25 leukocytesper low-power field were considered suitable for non-ventilatedpatients. An intra-operative tissue specimen was obtained fromcIAI patients (and cUTI patients who required surgery) for Gramstain and culture. For cUTI patients, urine was collected asepti-cally at baseline and at other time points as clinically indicated forGram stain and quantitative culture. Local laboratories performedall culture and susceptibility testing for specified antibiotics (usingthe Etest method). Medical resource utilisation data were collectedthroughout the study.

Investigators classified clinical response at the EOT and TOCvisits as cure, failure, relapse or indeterminate outcome. Cure wasdefined by resolution of signs/symptoms of infection or sufficientimprovement such that further antibacterial therapy was unnec-

essary. Death or lack of response leading to administration ofnon-study antibacterial agents after ≥48 h of treatment definedfailure. Clinical cure at the EOT followed by recurrence of infec-tion was classified as relapse at TOC. Per-patient microbiological

l of An

ra

2

Te

2

2

wbhfio

2

sdo

3

3

ltmcpptts

tfdoudt

3

dw(a(

3

i(cp

M. Mustafa et al. / International Journa

esponse rates and per-pathogen microbiological outcomes werelso determined.

.5. Adverse event assessments

Adverse events were monitored from informed consent throughOC, or through 30 days after completion of study drug for seriousvents.

.6. Statistical methods

.6.1. Sample size determinationSince no previous epidemiological study had been performed

ith doripenem, the target sample size was 208 completed patientsased on an assumption that 50% of doripenem-treated patientsad NP/VAP and 50% were treated as monotherapy, with precision

or real proportions as 7% of half-width of their 95% confidencentervals (CIs). Adjusting for a 20% drop-out rate, the target numberf enrolled patients was ca. 260.

.6.2. Statistical analysesSummary statistics were determined for all endpoints. Two-

ided exact CIs were calculated for endpoints associated withoripenem usage (mode and duration of therapy) and proportionsf cure.

. Results

.1. Patient disposition and completion

A total of 217 patients were enrolled; 216 patients received ateast one dose of doripenem and were included in the intention-o-treat (ITT) data analysis set. Patients with an indeterminate or

issing clinical outcome response were excluded from the clini-ally evaluable data set, resulting in 165 and 140 clinically evaluableatients at the EOT and TOC visits, respectively. Moreover, 75 ITTatients (27 NP, 14 VAP, 9 cUTI and 25 cIAI) were excluded fromhe modified microbiological ITT (mMITT) data analysis set becausehey had no pathogen isolated from a baseline (blood or other)pecimen, resulting in 141 mMITT patients.

The majority of enrolled patients (212/217; 97.7%) completedhe study; 3 patients withdrew consent and 2 patients were lost toollow-up. Of the 216 ITT patients, 61 (28.2%) discontinued studyrug prematurely due primarily to adverse events (n = 22), isolationf a doripenem-resistant pathogen at baseline (n = 14), clinical fail-re (n = 8) and other reasons (e.g. CLCr ≤10 mL/min, patient requiredialysis after enrolment, patient required >14 days of antibiotics forhe index infection; n = 17).

.2. Demographic and other baseline clinical characteristics

Demographic and clinical characteristics of patients in the ITTata set are summarised by infection type in Table 1. Most patientsere Malay (55.6%) or Chinese (25.9%). Approximately two-thirds

64.0%) were critical care (ICU) patients. The mean APACHE II scoret baseline (assessed in 207 patients) was 11.0, with 54 patients26.1%) having a score ≥15.

.3. Baseline culture results

A total of 39 patients (27.7% of 141 mMITT patients) had a pos-

tive baseline blood culture, including 8 (30.8%), 15 (23.8%), 1023.8%) and 6 (60.0%) mMITT patients in the NP, VAP, cIAI andUTI groups, respectively. Coagulase-negative staphylococci [15atients (10.6%) of the mMITT data set] was the most common

timicrobial Agents 43 (2014) 353–360 355

pathogen isolated from blood cultures, followed by Klebsiella pneu-moniae (8 patients; 5.7%) and Staphylococcus aureus (5 patients;3.5%).

At baseline, 129 patients (91.5% of 141 mMITT patients)had culture-positive results from specimens collected from theinfection site (i.e. not blood): Acinetobacter baumannii was themost common pathogen isolated from these specimen cultures(43 mMITT patients; 30.5%), followed by Escherichia coli (30 mMITTpatients; 21.3%), K. pneumoniae (30 mMITT patients; 21.3%) andP. aeruginosa (29 mMITT patients; 20.6%); some patients had morethan one pathogen. The most common pathogen detected fromNP and VAP patients was A. baumannii [6 patients (23.1%) and34 patients (54.0%), respectively]. The most common pathogendetected from cUTI and cIAI patients was E. coli [3 patients (30.0%)and 24 patients (57.1%), respectively].

MIC90 values (minimum inhibitory concentration required toinhibit 90% of the isolates) of doripenem/imipenem/meropenemfor P. aeruginosa, A. baumannii, E. coli and K. pneumoniaewere 32/32/24, 32/32/32, 0.094/0.38/0.094 and 0.64/8/0.94 �g/mL,respectively. The susceptibility rates to doripenem of these fourpathogens [US Food and Drug Administration (FDA) breakpoints:<2 �g/mL for P. aeruginosa and <1 �g/mL for the other threepathogens] were 70.6%, 16.9%, 97.7% and 91.7%, respectively.

3.4. Doripenem usage patterns

Doripenem was used most often for VAP (n = 77, 35.6%; 95% CI29.3–42.4%), NP (n = 53, 24.5%; 95% CI 19.0–30.8%) and cIAI (n = 67,31.0%; 95% CI 24.9–37.7%) and less often for cUTI (n = 19, 8.8%; 95%CI 5.4–13.4%).

Among the NP patients treated with doripenem, 23 (10.6% ofITT patients) were treated with doripenem for early-onset NP (<5days after hospitalisation) and 30 (13.9%) were treated for late-onset NP (≥5 days after hospitalisation). Among the VAP patients,32 patients (14.8%) and 45 patients (20.8%) were treated for early-onset VAP (<5 days after mechanical ventilation) and late-onsetVAP (≥5 days after mechanical ventilation), respectively. In thecIAI group, doripenem was used most commonly for perforatedappendicitis (n = 24; 11.1% of ITT patients), intestinal perfora-tion (n = 8; 3.7% of ITT patients) and large intestine perforation(n = 7; 3.2% of ITT patients). Among cUTI patients, doripenem wasused most commonly for acute pyelonephritis (n = 11; 5.1% of ITTpatients), complicated lower urinary tract infection (n = 2; 0.9% ofITT patients) and urosepsis (n = 2; 0.9% of ITT patients).

3.5. Mode and duration of doripenem therapy

In most cases, doripenem was used as monotherapy [187/216(86.6%) ITT patients] (Table 2). Doripenem was initiated as second-line treatment for approximately two-thirds of patients (62.0%).

The mean duration of doripenem therapy was 7.9 days, withthe shortest and longest mean therapy duration observed inthe cIAI/cUTI groups (each 6.9 days) and VAP group (9.2 days),respectively. When treatment with follow-on oral antibiotics wasconsidered, the mean total duration of antibiotic therapy was 8.8days (range of means, 7.5 days for NP to 9.9 days for VAP).

3.6. Clinical cure

At the EOT, clinical cure was achieved in 86.7% of 165 clinicallyevaluable patients (Table 3). The highest and lowest clinical curerates at that visit were observed among cIAI patients (88.5%) and

NP patients (82.5%), respectively. The clinical cure at TOC was 87.1%for clinically evaluable patients, with the highest and lowest ratesobserved among cIAI patients (93.9%) and VAP patients (79.6%),respectively. Seven patients (five VAP and one each for NP and cUTI)

356 M. Mustafa et al. / International Journal of Antimicrobial Agents 43 (2014) 353–360

Table 1Demographic and clinical characteristics by infection (intention-to-treat data set).

NP (n = 53) VAP (n = 77) cUTI (n = 19) cIAI (n = 67) Total (n = 216)

Age (years)Mean ± S.D. 54.1 ± 17.52 44.4 ± 19.17 58.2 ± 13.23 49.2 ± 16.13 49.5 ± 17.88Median 56 45 59 51 52Range 21–91 16–85 29–81 17–79 16–91

Sex [n (%)]Male 37 (69.8) 58 (75.3) 6 (31.6) 43 (64.2) 144 (66.7)Female 16 (30.2) 19 (24.7) 13 (68.4) 24 (35.8) 72 (33.3)

Race [n (%)]Chinese 8 (15.1) 13 (16.9) 7 (36.8) 28 (41.8) 56 (25.9)Malay 33 (62.3) 44 (57.1) 8 (42.1) 35 (52.2) 120 (55.6)Indian 2 (3.8) 3 (3.9) 2 (10.5) 0 (0.0) 7 (3.2)Other 10 (18.9) 17 (22.1) 2 (10.5) 4 (6.0) 33 (15.3)

Patient’s location in the hospital upon enrolment [n (%)]ICU 30 (56.6) 69 (89.6) 9 (47.4) 29/65 (44.6) 137/214 (64.0)Non-ICU 23 (43.4) 8 (10.4) 10 (52.6) 36/65 (55.4) 77/214 (36.0)Missing 0 0 0 2 2

APACHE II scoreMean ± S.D. 12.1 ± 6.43 13.4 ± 6.08 10.4 ± 5.72 7.6 ± 5.37 11.0 ± 6.38Median 11 12 10 7 10Range 2–32 2–34 3–22 0–20 0–3495% CI of mean 10.2–13.9 12.0–14.8 7.2–13.6 6.3–9.0 10.2–11.9

APACHE II score [n (%)]≤14 34/49 (69.4) 50 (64.9) 11/15 (73.3) 58/66 (87.9) 153/207 (73.9)15–19 8/49 (16.3) 15 (19.5) 3/15 (20.0) 6/66 (9.1) 32/207 (15.5)20–24 4/49 (8.2) 7 (9.1) 1/15 (6.7) 2/66 (3.0) 14/207 (6.8)25–29 2/49 (4.1) 4 (5.2) 0 (0.0) 0 (0.0) 6/207 (2.9)≥30 1/49 (2.0) 1 (1.3) 0 (0.0) 0 (0.0) 2/207 (1.0)Missing 4 0 4 1 9

N ated ud valua

wIe

idApw2mdiAK

3

d

TM

Ni

P, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cUTI, compliceviation; ICU, intensive care unit; APACHE, Acute Physiology and Chronic Health E

ere confirmed as ‘relapsed’ at this visit. Clinical cure rates in theTT and mMITT populations were lower than those in the clinicallyvaluable data set.

Among the patients in the mMITT population who were clin-cal failures at the EOT: 2 of 4 NP patients were infected withoripenem-resistant pathogens (both infected with resistant. baumannii and 1 with resistant P. aeruginosa); 7 of 7 VAPatients were infected with doripenem-resistant pathogens [4ith resistant A. baumannii, 3 with resistant P. aeruginosa andwith resistant K. pneumoniae (2 patients were infected withultiple pathogens)]; 1 of 1 cUTI patient was infected with

oripenem-resistant K. pneumoniae; and 2 of 4 cIAI patients werenfected with doripenem-resistant pathogens [1 with resistant. baumannii, 1 with resistant P. aeruginosa and 1 with resistant. pneumoniae (1 patient was infected with multiple pathogens)].

.7. Microbiological outcomes

The most common bacterial isolates and their susceptibility tooripenem are shown by infection type in Fig. 1.

able 2ode and duration of doripenem therapy by infection (intention-to-treat data set).

NP (n = 53) VAP (n = 77)

Monotherapy or combination therapy [n (%)]Monotherapy 41 (77.4) 66 (85.7)Combination therapy 12 (22.6) 11 (14.3)Monotherapy 95% CI 63.8–87.7 75.9–92.7Combination therapy 95% CI 12.3–36.2 7.4–24.1

First-line therapy or second-line therapy [n (%)]First-line therapy 16 (30.2) 33 (42.9)Second-line therapy 37 (69.8) 44 (57.1)First-line therapy 95% CI 18.3–44.3 31.6–54.7Second-line therapy 95% CI 55.7–81.7 45.4–68.4

P, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cUTI, complicated unterval.

rinary tract infection; cIAI, complicated intra-abdominal infection; S.D., standardtion; CI, confidence interval.

The microbiological eradication rate (i.e. documented erad-ication or presumed eradication based on absence of signs andsymptoms of infection and source of infection to culture) at EOTwas 56.0% overall, the lowest rate for VAP (Fig. 2). The microbiolog-ical outcome was indeterminate for 17.0% of the mMITT patients.The eradication rate was highest for E. coli (63.3%) and lowest forA. baumannii (46.7%) (Fig. 3).

3.8. Medical resource utilisation

The median length of hospital stay was 20 days, with the longesthospital stay observed among VAP patients (33 days), followedby NP, cUTI and cIAI patients at 21, 13 and 12 days, respectively(Table 4). The median length of ICU stay was 12 days, with the samegeneral trend for duration of ICU stay based on infection type (VAP17 days, NP 8 days, cIAI 7 days and cUTI 4 days). The median dura-tion of mechanical ventilation was 10 days for all patients, with

VAP patients requiring the longest duration (median 15 days) ofsuch respiratory assistance. Of 146 patients who were dischargedduring the study, 7 required re-admittance during the initial 28days following EOT. And, of the 34 patients who remained in the

cUTI (n = 19) cIAI (n = 67) All patients (n = 216)

18 (94.7) 62 (92.5) 187 (86.6)1 (5.3) 5 (7.5) 29 (13.4)

74.0–99.9 83.4–97.5 81.3–90.80.1–26.0 2.5–16.6 9.2–18.7

3 (15.8) 30 (44.8) 82 (38.0)16 (84.2) 37 (55.2) 134 (62.0)

3.4–39.6 32.6–57.4 31.5–44.860.4–96.6 42.6–67.4 55.2–68.5

rinary tract infection; cIAI, complicated intra-abdominal infection; CI, confidence

M. Mustafa et al. / International Journal of Antimicrobial Agents 43 (2014) 353–360 357

Table 3Clinical response at end-of-treatment (EOT) and test-of cure (TOC) visits.

NP VAP cUTI cIAI All patients

Clinically evaluable data setEOT [n (%)] n = 40 n = 56 n = 17 n = 52 n = 165

Clinical cure 33 (82.5) 49 (87.5) 15 (88.2) 46 (88.5) 143 (86.7)Clinical failure 7 (17.5) 7 (12.5) 2 (11.8) 6 (11.5) 22 (13.3)95% CI of clinical cure rate 67.2–92.7 75.9–94.8 63.6–98.5 76.6–95.7 80.5–91.5

TOC [n (%)] n = 27 n = 49 n = 15 n = 49 n = 140Clinical cure 25 (92.6) 39 (79.6) 12 (80.0) 46 (93.9) 122 (87.1)Clinical failure 1 (3.7) 5 (10.2) 2 (13.3) 3 (6.1) 11 (7.9)Relapse 1 (3.7) 5 (10.2) 1 (6.7) 0 (0.0) 7 (5.0)95% CI of clinical cure rate 75.7–99.1 65.7–89.8 51.9–95.7 83.1–98.7 80.4–92.2

ITT data setEOT [n (%)] n = 53 n = 77 n = 19 n = 67 n = 216

Clinical cure 33 (62.3) 49 (63.6) 15 (78.9) 46 (68.7) 143 (66.2)Clinical failure 7 (13.2) 7 (9.1) 2 (10.5) 6 (9.0) 22 (10.2)Indeterminate outcome 5 (9.4) 15 (19.5) 1 (5.3) 10 (14.9) 31 (14.4)Missing 8 (15.1) 6 (7.8) 1 (5.3) 5 (7.5) 20 (9.3)95% CI of clinical cure rate 47.9–75.2 51.9–74.3 54.4–94.0 56.2–79.4 59.5–72.5

TOC [n (%)]Clinical cure 25 (47.2) 39 (50.6) 12 (63.2) 46 (68.7) 122 (56.5)Clinical failure 1 (1.9) 5 (6.5) 2 (10.5) 3 (4.5) 11 (5.1)Relapse 1 (1.9) 5 (6.5) 1 (5.3) 0 (0.0) 7 (3.2)Indeterminate outcome 4 (7.5) 8 (10.4) 1 (5.3) 4 (6.0) 17 (7.9)Missing 22 (41.5) 20 (26.0) 3 (15.8) 14 (20.9) 59 (27.3)95% CI of clinical cure rate 33.3–61.4 39.0–62.2 38.4–83.7 56.2–79.4 49.6–63.2

mMITT data setEOT [n (%)] n = 26 n = 63 n = 10 n = 42 n = 141

Clinical cure 15 (57.7) 38 (60.3) 9 (90.0) 25 (59.5) 87 (61.7)Clinical failure 4 (15.4) 7 (11.1) 1 (10.0) 4 (9.5) 16 (11.3)Indeterminate outcome 4 (15.4) 13 (20.6) 0 (0) 8 (19.0) 25 (17.7)Missing 3 (11.5) 5 (7.9) 0 (0) 5 (11.9) 13 (9.2)95% CI of clinical cure rate 36.9–76.7 47.2–72.4 55.5–99.8 43.3–74.4 53.2–69.8

TOC [n (%)]Clinical cure 11 (42.3) 31 (49.2) 7 (70.0) 26 (61.9) 75 (53.2)Clinical failure 1 (3.8) 5 (7.9) 1 (10.0) 3 (7.1) 10 (7.1)Relapse 1 (3.8) 4 (6.3) 1 (10.0) 0 (0.0) 6 (4.3)Indeterminate outcome 3 (11.5) 7 (11.1) 0 (0.0) 4 (9.5) 14 (9.9)Missing 10 (38.5) 16 (25.4) 1 (10.0) 9 (21.4) 36 (25.5)95% CI of clinical cure rate 23.4–63.1 36.4–62.1 34.8–93.3 45.6–76.4 44.6–61.6

NP, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cUTI, complicated urinary tract infection; cIAI, complicated intra-abdominal infection; CI, confidenceinterval; ITT, intention-to-treat; mMITT, modified microbiological ITT.

Fig. 1. Most common bacterial isolates by infection type (modified microbiological intention-to-treat data set). Hatched colour block denotes number of strains susceptibleto doripenem; solid colour block denotes number of strains resistant to doripenem. NP, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cIAI, complicatedintra-abdominal infection; cUTI, complicated urinary tract infection. (For interpretation of the references to color in this figure legend, the reader is referred to the webversion of the article.)

358 M. Mustafa et al. / International Journal of Antimicrobial Agents 43 (2014) 353–360

0

10

20

30

40

50

60

70

NP (26) VAP (63) cIAI (42) cUTI (10) Total (141)Mic

rob

iolo

gic

al

ou

tco

me

(% o

f p

ati

ents

)

Treatment indication (n)

Eradication * Persistence ** Indeterminate

Fig. 2. Overall microbiological outcomes at end of treatment by indication (modified microbiological intention-to-treat data set). NP, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection. * Eradication or presumed eradication; ** persistence orpresumed persistence.

Table 4Summary of medical resource utilisation by infection (intention-to-treat data set).

NP VAP cUTI cIAI All patients

Length of hospital stayn (missing) 53 (0) 77 (0) 19 (0) 67 (0) 216 (0)Mean ± S.D. (days) 29.4 ± 25.89 40.4 ± 26.95 16.9 ± 12.19 19.6 ± 17.60 29.2 ± 24.77Median (days) 21 33 13 12 20

Length of ICU stayn (missing) 29 (24) 70 (7) 9 (10) 34 (33) 142 (74)Mean ± S.D. (days) 13.7 ± 14.40 23.2 ± 16.34 9.0 ± 9.76 10.1 ± 10.21 17.3 ± 15.44Median (days) 8 17 4 7 12

Duration of mechanical ventilationn (missing) 24 (29) 73 (4) 5 (14) 30 (37) 132 (84)Mean ± S.D. (days) 10.3 ± 11.88 21.5 ± 21.61 2.8 ± 1.92 7.5 ± 9.30 15.6 ± 18.62Median (days) 6 15 2 4 10

Time to hospital discharge a

n (missing) 53 (0) 77 (0) 19 (0) 67 (0) 216 (0)Mean ± S.D. (days) 17.8 ± 15.23 25.2 ± 18.96 10.9 ± 7.72 14.6 ± 16.42 18.9 ± 17.23Median (days) 13 19 8 9 13

N ated ud

ital.

ha

3

tgT

P, nosocomial pneumonia; VAP, ventilator-associated pneumonia; cUTI, compliceviation; ICU, intensive care unit; CI, confidence interval; S.D., standard deviation.a Time from first dose of the study drug until the date of discharge from the hosp

ospital 28 days after EOT, 1 VAP patient was re-admitted to an ICUfter TOC.

.9. All-cause mortality

The all-cause mortality rate was 22.7% (49/216 ITT patients);here were 18 deaths (34.0%) in the NP group, 18 (23.4%) in the VAProup, 12 (17.9%) in the cIAI group and 1 (5.3%) in the cUTI group.he mean APACHE II score was 15.3 in patients who died and 9.8

0

10

20

30

40

50

60

70

Acinetobacter baumannii (45)

Escherichia coli (30)Mic

robio

logic

al o

utc

om

e (%

)

Path

Eradication

Fig. 3. Microbiological outcome at end of treatment for most common

rinary tract infection; cIAI, complicated intra-abdominal infection; S.D., standard

in patients who survived. Most deaths were related to the indexinfection, secondary infections or a complication of the patient’sunderlying illness. The investigators considered two deaths to bepossibly related to the study drug. A 37-year-old female whoreceived 7 days of doripenem for NP developed sudden onset of

severe headache, vomiting and seizures 3 h after her last dose ofdoripenem. The cause of death may have been related to intracra-nial haemorrhage, with daily warfarin usage due to prior mitralvalve replacement surgery a contributing factor. The second death

Klebsiella pneumoniae (37)

Pseudomonas aeruginosa (31)

ogen

Persistence

pathogens (modified microbiological intention-to-treat data set).

l of An

ifh

3

tv

ledbri

4

tdm

PbcParohNbis(i

mt[rss1ccdtmndoMmHo

tdCtr9

M. Mustafa et al. / International Journa

nvolved a 78-year-old male with colon carcinoma who developed aungal wound superinfection (due to Zygomycetes sp.), which couldave contributed to multi-organ failure and death.

.10. Adverse events

Doripenem was generally well tolerated. The most commonreatment-related adverse events were diarrhoea (n = 3; 1.4%) andomiting (n = 3; 1.4%).

Of 216 ITT patients, 24 (11.1%) discontinued treatment ateast in part due to an adverse event(s); 6 patients with ninevents were classified by the investigator as possibly related tooripenem [1 each of increased alanine aminotransferase, throm-ocytosis, Stenotrophomonas (superinfection) sepsis, tachycardia,ash, thrombocytopenia, as well as seizure, headache and vomitingn the patient described above who died].

. Discussion

This prospective, open-label, non-comparative, multicen-re study provides important epidemiological information onoripenem usage, related clinical/microbiological outcomes, andedical resource utilisation among Asian patients.In this study, 83% of A. baumannii isolates and 29% of

. aeruginosa isolates were non-susceptible to doripenem ataseline. These findings are consistent with results of the recentlyonducted Comparative Activity of Carbapenem Testing (COM-ACT) II surveillance study in which carbapenem resistancemong A. baumannii and P. aeruginosa isolates was 73% and 30%,espectively [15]. Likewise, the Asian Network for Surveillancef Resistant Pathogens (ANSORP) surveillance study showed aigh prevalence of multidrug-resistant non-fermenters amongP/VAP patients in Asia, with resistance to imipenem of 67% for A.aumannii and 27% for P. aeruginosa [16]. Discordant initial empir-cal antimicrobial therapy (i.e. did not match the antibiogram)ignificantly increased the risk of pneumonia-related mortalityodds ratio = 1.5; 95% CI 1.1–2.1) [16], underscoring the clinicalmperative for appropriate initial antimicrobial selection.

A sizeable proportion of patients selected for doripenem treat-ent had late-onset NP or VAP, suitable candidates for carbapenem

herapy based on the burden of illness (i.e. morbidity and mortality17,18]) and the high probability of infection caused by antibiotic-esistant pathogens [18]. The relatively low frequency (3.7%) oftudy patients with an APACHE II score of ≥25 at study entry isurprising given that many were enrolled with NP/VAP, of whom9.2% were also bacteraemic at baseline. Doripenem was used mostommonly as monotherapy and as second-line therapy. Whilst thelinical utility of doripenem monotherapy has been established inifficult-to-treat infections caused by P. aeruginosa [19], such is nothe case for A. baumannii, which expresses multiple drug resistance

echanisms [20,21], resulting in few therapeutic options and theeed for empirical combination therapy. Furthermore, pharmaco-ynamic data suggest a higher 1 g dose infused over 4 h optimisesutcomes in patients infected with pathogens having a doripenemIC >4 �g/mL [22], as was seen with A. baumannii, the most com-on pathogen cultured from NP and VAP patients in this study.owever, further clinical study is needed to evaluate the 1 g dosef doripenem.

The clinical cure rates observed with doripenem, as used inhis study of clinical practice within APAC, are similar to thoseocumented in pivotal, phase 3 clinical trials of the carbapenem.

linical cure rates at TOC among clinically evaluable patients inhe PROUD study and phase 3 studies were 92.6% and 81.3% [23],espectively, for NP; 79.6% and 68.3% [24], respectively, for VAP; and3.9% and 86.7% [25], respectively, for cIAI. The cure rate observed

timicrobial Agents 43 (2014) 353–360 359

in PROUD for cUTI (80.0%) is lower than that in phase 3 studies[26,27], although the small number (n = 19) of cUTI patients in thecurrent study limits any conclusions from the comparison. Clini-cal cure rates in the ITT population were lower than those in theclinically evaluable population (66.2% at EOT and 56.5% at TOC). Asignificant proportion of patients in the ITT population had indeter-minate outcomes or missing assessments at EOT (23.6%) and TOC(35.2%) visits, which likely affected the overall proportion of clinicalcure.

The overall favourable microbiological outcome rate withdoripenem in PROUD was 56.0%, which compares with micro-biological eradication rates of 60–95% in phase 3 pivotal studies(of patients enrolled primarily in North America and Europe),depending on the type of infection [23–26]. Several factors mayhave contributed to this outcome, including sample size, severityof infection, laboratory procedures used and the use of centralvs. local laboratories. Furthermore, study inclusion/exclusioncriteria limited enrolment to a more homogeneous populationand excluded those not expected to survive. The microbiology andresistance rates in each country and in each study centre are alsofactors that could have affected the microbiological eradication ratein this study. The prevalence of carbapenem-non-susceptibilityamong Gram-negative pathogens causing serious infections (e.g.P. aeruginosa, A. baumannii) is higher in APAC than in other regionsof the world, including North America and Europe [28]. Thisdisparity is reflected in the high proportion of clinical failures whowere infected with a doripenem-resistant pathogen(s), includingone-half of the NP (2/4) and cIAI patients (2/4) and all of the VAP(7/7) and cUTI (1/1) patients who were clinical failures.

Doripenem 500 mg i.v. was generally well tolerated, with thetypes and frequencies of adverse events observed in the PROUDstudy similar to those in previous studies [23–26].

Estimates of the crude mortality for NP/VAP range from 30% to70% [7], with many of the deaths due to underlying disease ratherthan pneumonia. Mortality related to pneumonia (attributablemortality) is estimated to be between 33% and 50% [7]. In this study,the all-cause mortality rate was 34.0% in the NP group and 23.3% inthe VAP group.

The development of VAP increases medical resource utilisa-tion and attributable hospital costs [29]. Kollef et al. showed thatdoripenem reduced medical resource utilisation vs. comparatoragents in the treatment of VAP patients, including shorter mediandurations of hospitalisation (22 days vs. 26 days; P = 0.010), ICUstay (12 days vs. 13 days; P = 0.065) and mechanical ventilation (7days vs. 10 days; P = 0.008) [30]. In this study, the median lengthsof hospital stay (33 days), ICU stay (17 days) and mechanical ven-tilation (15 days) for VAP patients were longer than those reportedby Kollef et al., perhaps relating to differences between the studypopulations in severity of infection, co-morbidities, antimicrobialresistance and non-antimicrobial aspects of health care.

This study is limited by an open-label, non-comparative design,with bias in clinical response assessment and attribution of adverseevents possible. However, the main aim of this study was tocharacterise ‘real-life’ doripenem usage patterns and performance(efficacy, safety) in clinical practice, which is best accomplishedwithout the constraints of a blinded, comparative study.

Overall, the PROUD study results demonstrate that doripenemis a viable option for treating APAC patients with NP, VAP, cIAI orcUTI.

Acknowledgments

Sandra Norris, PharmD, provided writing assistance, and Brad-ford Challis, PhD (of Janssen Research & Development) providedadditional editorial assistance. The authors would like to thank

3 l of An

tsGPnMmSv((SSNa

o

aA

b

R

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

60 M. Mustafa et al. / International Journa

he investigators in each country who participated in the PROUDtudy (PROUD Asia-Pacific Study Group): Helen Oh (Changieneral Hospital, Singapore); Chow Ting Soo (Hospital Pulauinang, Malaysia); Balan Subrahmanyam (Hospital Sultanah Ami-ah, Malaysia); Jenny Tong May Geok (Hospital Tuanku Ja’afar,alaysia); Najahbinti Dato’ Haji Harussani (Hospital Raja Per-aisuri Bainun, Malaysia); Mohd Ridhwan Mohd Noor (Hospital

ultanah Nur Zahirah, Malaysia); Patrick Tan Seow Koon (Uni-ersity of Malaya Medical Centre, Malaysia); Raha Abdul RahmanUniversity of Kebangsaan, Malaysia); Bambang WahjuprajitnoRSUD Dr. Soetomo Surabaya, Indonesia); Ike Sri Redjeki (R.S. Hasanadikin, Bandung, Indonesia); Christian A. Johannes (RSPAD Gatotoebroto, Jakarta, Indonesia); April Retno Susilo (R.S. Pusat Jantungasional Harapan Kita, Jakarta, Indonesia); and Pham Hong Truongnd Tran Van Ngoc (Cho Ray Hospital, Vietnam).

Funding: This study was funded by Janssen Asia Pacific, a divisionf Johnson & Johnson Pte Ltd. (Singapore).

Competing interests: JG is a consultant of Janssen Pharmaceutica,division of Johnson & Johnson Asia Pacific (Manila, Philippines).ll other authors declare no competing interests.

Ethical approval: This study was approved for its ethical merity ethics committees at each of the study sites.

eferences

[1] Infectious Diseases Society of America, Spellberg B, Blaser M, Guidos RJ, BoucherHW, Bradley JS, Eisenstein BI, et al. Combating antimicrobial resistance: pol-icy recommendations to save lives. Clin Infect Dis 2011;52(Suppl. 5):S397–428.

[2] World Health Organization. WHO global strategy for the containment ofantimicrobial resistance. Geneva, Switzerland: WHO; 2001 http://www.who.int/drugresistance/guidance/en/index.html [accessed 02.08.12].

[3] Bouchillon SK, Iredell JR, Barkham T, Lee K, Dowzicky MJ. Comparative in vitroactivity of tigecycline and other antimicrobials against Gram-negative andGram-positive organisms collected from the Asia-Pacific Rim as part of theTigecycline Evaluation and Surveillance Trial (TEST). Int J Antimicrob Agents2009;33:130–6.

[4] Lagamayo EN. Antimicrobial resistance in major pathogens of hospital-acquired pneumonia in Asian countries. Am J Infect Control 2008;36(4Suppl.):S101–8.

[5] Nicolau DP. Carbapenems: a potent class of antibiotics. Expert Opin Pharma-cother 2008;9:23–37.

[6] Chen YH, Hsueh PR, Badal RE, Hawser SP, Hoban DJ, Bouchillon SK, et al.Antimicrobial susceptibility profiles of aerobic and facultative Gram-negativebacilli isolated from patients with intra-abdominal infections in the Asia-Pacificregion according to currently established susceptibility interpretive criteria. JInfect 2011;62:280–91.

[7] American Thoracic Society; Infectious Diseases Society of America. Guide-lines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med2005;171:388–416.

[8] Song JH. Asian Hospital Acquired Pneumonia Working Group. Treatmentrecommendations of hospital-acquired pneumonia in Asian countries: firstconsensus report by the Asian HAP Working Group. Am J Infect Control2008;36(4 Suppl.):S83–92.

[9] Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al.Diagnosis and management of complicated intra-abdominal infection in adultsand children: guidelines by the Surgical Infection Society and the InfectiousDiseases Society of America. Clin Infect Dis 2010;50:133–64.

10] Pallett A, Hand K. Complicated urinary tract infections: practical solutionsfor the treatment of multiresistant Gram-negative bacteria. J AntimicrobChemother 2010;65(Suppl. 3):iii25–33.

11] Dedhia HV, McKnight R. Doripenem position in clinical practice. Expert RevAnti Infect Ther 2009;7:507–14.

[

timicrobial Agents 43 (2014) 353–360

12] Solomkin JS, Mazuski JE, Baron EJ, Sawyer RG, Nathens AB, DiPiro JT, et al.Infectious Diseases Society of America. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis2003;37:997–1005.

13] Luna CM, Blanzaco D, Niederman MS, Matarucco W, Baredes NC, Desmery P,et al. Resolution of ventilator-associated pneumonia: prospective evaluation ofthe Clinical Pulmonary Infection Score as an early clinical predictor of outcome.Crit Care Med 2003;31:676–82.

14] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity ofdisease classification system. Crit Care Med 1985;13:818–29.

15] Kiratisin P, Chongthaleong A, Tan TY, Lagamayo E, Roberts S, Garcia J, et al.Comparative in vitro activity of carbapenems against major Gram-negativepathogens: results of Asia-Pacific surveillance from the COMPACT II study. IntJ Antimicrob Agents 2012;39:311–6.

16] Chung DR, Song JH, Kim SH, Thamlikitkul V, Huang SG, Wang H, et al. AsianNetwork for Surveillance of Resistant Pathogens Study Group. High prevalenceof multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia.Am J Respir Crit Care Med 2011;184:1409–17.

17] Vallés J, Pobo A, García-Esquirol O, Mariscal D, Real J, Fernández R. Excess ICUmortality attributable to ventilator-associated pneumonia: the role of early vslate onset. Intensive Care Med 2007;33:1363–8.

18] Werarak P, Kiratisin P, Thamlikitkul V. Hospital-acquired pneumonia andventilator-associated pneumonia in adults at Siriraj Hospital: etiology, clin-ical outcomes, and impact of antimicrobial resistance. J Med Assoc Thai2010;93(Suppl. 1):S126–38.

19] Ambruzs M, Sambrowski J, Kaul S, Khashab M, Xiang J, Peterson J, et al.Clinical outcome of nosocomial pneumonia (NP)/ventilator-associated pneu-monia (VAP), or healthcare associated pneumonia (HCAP) after treatment withdoripenem 1-g infused over 4 h every 8 h in a study protocol that enriched forinfection with P. aeruginosa. In: 49th Interscience Conference on Antimicro-bial Agents and Chemotherapy (ICAAC). San Francisco, CA. Washington, DC:American Society for Microbiology; 2009 [abstract 311].

20] Durante-Mangoni E, Zarrilli R. Global spread of drug-resistant Acinetobacterbaumannii: molecular epidemiology and management of antimicrobial resis-tance. Future Microbiol 2011;6:407–22.

21] Fournier PE, Vallenet D, Barbe V, Audic S, Ogata H, Poirel L, et al. Compara-tive genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genet2006;2:e7.

22] Samtani MN, Flamm R, Kaniga K, Nandy P. Pharmacokinetic–pharmacodynamic-model-guided doripenem dosing in critically ill patients.Antimicrob Agents Chemother 2010;54:2360–4.

23] Réa-Neto A, Niederman M, Lobo SM, Schroeder E, Lee M, Kaniga K, et al. Effi-cacy and safety of doripenem versus piperacillin/tazobactam in nosocomialpneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin2008;24:2113–26.

24] Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Effi-cacy and safety of intravenous infusion of doripenem versus imipenem inventilator-associated pneumonia: a multicenter, randomized study. Crit CareMed 2008;36:1089–96.

25] Lucasti C, Jasovich A, Umeh O, Jiang J, Kaniga K, Friedland I. Efficacy andtolerability of IV doripenem versus meropenem in adults with complicatedintra-abdominal infection: a phase III, prospective, randomized, double-blind,non-inferiority study. Clin Ther 2008;30:868–83.

26] Naber KG, Llorens L, Kaniga K, Kotey P, Hedrich D, Redman R. Intravenousdoripenem at 500 mg versus levofloxacin at 250 mg, with an option to switchto oral therapy, for treatment of complicated lower urinary tract infection andpyelonephritis. Antimicrob Agents Chemother 2009;53:3782–92.

27] Redman R, Damiao R, Kotey P, Kaniga K, Davies T, Naber KG. Safety and effi-cacy of intravenous doripenem for the treatment of complicated urinary tractinfections and pyelonephritis. J Chemother 2010;22:384–91.

28] Bertrand X, Dowzicky MJ. Antimicrobial susceptibility among Gram-negativeisolates collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa between 2004 and2009 as part of the Tigecycline Evaluation and Surveillance Trial. Clin Ther2012;34:124–37.

29] Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic conse-quences of ventilator-associated pneumonia: a systematic review. Crit Care

Med 2005;33:2184–93.

30] Kollef MH, Dilip N, Merchant S, Gast C, Quintana A, Ketter N. Medical resourceutilization among patients with ventilator-associated pneumonia: pooledanalysis of randomized studies of doripenem versus comparators. Clin Care2010;14:R84.