International Journal of Antimicrobial Agents 43 (2014) 353–360
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
A PROspective study on the Usage patterns of Doripenem in the Asia-Pacific region (PROUD study) Mahiran Mustafa a,∗ , Wai Ming Chan b , Christopher Lee c , Eddy Harijanto d , Chian Min Loo e , Nguyen Van Kinh f , Nguyen Dat Anh g , Jemelyn Garcia h a
Department of Medicine, Hospital Raja Perempuan Zainab II, 15000 Kota Bharu, Kelantan, Malaysia Adult Intensive Care Unit, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Road, Hong Kong c Department of Medicine, ID Unit and Department of Medicine, Hospital Sungai Buloh, Selangor 47000, Malaysia d Department of Anesthesiology, Dr Cipto Mangunkusumo Hospital, Diponegoro St No. 71, Kenari Village, Senen, Central Jakarta City 10430, Indonesia e Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Outram Road, Singapore 169608, Singapore f Intensive Care Unit, National Hospital for Tropical Diseases, Giai Phong Street, Hanoi, Vietnam g Emergency Department, Bach Mai Hospital, 78 Duong Giai Phong, Phuong Mai, Dong Da, Hanoi, Vietnam h Janssen Pharmaceutica, A Division of Johnson & Johnson Pte Ltd., Edison Road, Barrio Ibayo, Para˜ naque City 1700, Philippines b
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Article history: Received 17 June 2013 Accepted 2 January 2014 Keywords: Doripenem Asia-Pacific Medical 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) and complicated urinary tract infections (cUTIs). Clinical usage of doripenem (500 mg intravenously, infused over 1 h or 4 h every 8 h for 5–14 days) in APAC was evaluated in a prospective, open-label, noncomparative, 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%); and 19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64 g/mL, respectively. Doripenem was used most commonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinically evaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7–14 days after EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. The median 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 VAP patient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most common treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viable option 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.
1. Introduction The increasingly endemic nature of multidrug-resistant Gram-negative bacilli in healthcare settings [1,2], especially in the Asia-Pacific (APAC) region [3,4], has paved the way for carbapenems in the treatment of nosocomial infections [5]. Carbapenems possess broad-spectrum in vitro activity both against Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter spp. and extendedspectrum -lactamase (ESBL)-producing Enterobacteriaceae [6].
∗ Corresponding author. Tel.: +60 19 911 9155; fax: +60 9745 2546. E-mail address: [email protected] (M. Mustafa).
Medical societies and infectious diseases experts have published evidence-based treatment guidelines in which they recommend a carbapenem for empirical treatment of hospital-acquired and ventilator-associated pneumonia (VAP) when a Gram-negative pathogen is suspected [7,8], for healthcare-associated complicated intra-abdominal infections (cIAIs) [9] and for complicated urinary tract infections (cUTIs) due to antibiotic-resistant Gram-negative bacteria, including AmpC- and ESBL-producing strains [10]. Doripenem is the newest carbapenem approved in the APAC region for treatment of adults with nosocomial pneumonia (NP) including VAP, cIAI and cUTI. It is therefore important to evaluate and describe the current usage patterns for doripenem in the APAC region [11]. Thus, the PROspective study on the Usage patterns of Doripenem (PROUD) was designed to determine not only the types
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.017 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
354
M. Mustafa et al. / International Journal of Antimicrobial Agents 43 (2014) 353–360
of patients and indications for which doripenem is selected as treatment in APAC but also clinical and microbiological outcomes and medical resource utilisation associated with its usage. 2. Materials and methods An ethics committee at each site approved the protocol and informed consent form before study initiation (ClinicalTrials.gov registration no. NCT 00986102; http://www.clinicaltrials.gov). Patients or their legally acceptable representatives provided written informed consent before any study-related activity. 2.1. Patients Adults (≥18 years of age) hospitalised in an intensive care unit (ICU) or ward with a diagnosis of NP, VAP, cIAI or cUTI and who were candidates for carbapenem therapy were enrolled. A NP diagnosis required clinical signs/symptoms of de novo infection after ≥48 h of hospitalisation [7]. Patients on mechanical ventilation for ≥48 h before developing pneumonia were considered to have VAP. NP/VAP patients were required to have at least two of the following: cough; new onset or worsening purulent respiratory secretions; auscultatory findings on pulmonary examination of rales and/or consistent with consolidation; tachypnoea (≥30/min); and/or hypoxaemia [partial pressure of oxygen in arterial blood (PaO2 ) ≤60 mmHg or pulse oximetry < 90% on room air]; plus new or worsening infiltrate on chest radiography and either fever (oral >38 ◦ C)/hypothermia (rectal/core 15 mmHg from baseline); tachycardia (>100 bpm)/tachypnoea; and/or hypoxaemia; as well as physical signs of IAI (i.e. at least one of abdominal pain/tenderness, localised or diffuse guarding, abdominal wall rigidity, abdominal mass and/or ileus). A cUTI diagnosis required a positive pre-treatment cleancatch midstream urine culture (>105 CFU/mL) and either acute pyelonephritis or lower urinary tract symptoms together with one of the following: indwelling catheter or intermittent catheterisation; incomplete voiding (>100 mL of residual urine post-voiding); neurogenic bladder; obstructive uropathy; azotemia due to intrinsic renal disease; vesicoureteral reflux; other urological abnormalities; diabetes mellitus; or immunosuppression. Across these indications, exclusion criteria were creatinine clearance (CLCr ) ≤10 mL/min, dialysis, oliguria (14 days of antibiotics for the index infection; n = 17). 3.2. Demographic and other baseline clinical characteristics Demographic and clinical characteristics of patients in the ITT data set are summarised by infection type in Table 1. Most patients were Malay (55.6%) or Chinese (25.9%). Approximately two-thirds (64.0%) were critical care (ICU) patients. The mean APACHE II score at baseline (assessed in 207 patients) was 11.0, with 54 patients (26.1%) having a score ≥15. 3.3. Baseline culture results A total of 39 patients (27.7% of 141 mMITT patients) had a positive baseline blood culture, including 8 (30.8%), 15 (23.8%), 10 (23.8%) and 6 (60.0%) mMITT patients in the NP, VAP, cIAI and cUTI groups, respectively. Coagulase-negative staphylococci [15 patients (10.6%) of the mMITT data set] was the most common
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pathogen isolated from blood cultures, followed by Klebsiella pneumoniae (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 the infection site (i.e. not blood): Acinetobacter baumannii was the most common pathogen isolated from these specimen cultures (43 mMITT patients; 30.5%), followed by Escherichia coli (30 mMITT patients; 21.3%), K. pneumoniae (30 mMITT patients; 21.3%) and P. aeruginosa (29 mMITT patients; 20.6%); some patients had more than one pathogen. The most common pathogen detected from NP and VAP patients was A. baumannii [6 patients (23.1%) and 34 patients (54.0%), respectively]. The most common pathogen detected from cUTI and cIAI patients was E. coli [3 patients (30.0%) and 24 patients (57.1%), respectively]. MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of doripenem/imipenem/meropenem for P. aeruginosa, A. baumannii, E. coli and K. pneumoniae were 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 four pathogens [US Food and Drug Administration (FDA) breakpoints:
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
A PROspective study on the Usage patterns of Doripenem in the Asia-Pacific region (PROUD study) Mahiran Mustafa a,∗ , Wai Ming Chan b , Christopher Lee c , Eddy Harijanto d , Chian Min Loo e , Nguyen Van Kinh f , Nguyen Dat Anh g , Jemelyn Garcia h a
Department of Medicine, Hospital Raja Perempuan Zainab II, 15000 Kota Bharu, Kelantan, Malaysia Adult Intensive Care Unit, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Road, Hong Kong c Department of Medicine, ID Unit and Department of Medicine, Hospital Sungai Buloh, Selangor 47000, Malaysia d Department of Anesthesiology, Dr Cipto Mangunkusumo Hospital, Diponegoro St No. 71, Kenari Village, Senen, Central Jakarta City 10430, Indonesia e Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Outram Road, Singapore 169608, Singapore f Intensive Care Unit, National Hospital for Tropical Diseases, Giai Phong Street, Hanoi, Vietnam g Emergency Department, Bach Mai Hospital, 78 Duong Giai Phong, Phuong Mai, Dong Da, Hanoi, Vietnam h Janssen Pharmaceutica, A Division of Johnson & Johnson Pte Ltd., Edison Road, Barrio Ibayo, Para˜ naque City 1700, Philippines b
a r t i c l e
i n f o
Article history: Received 17 June 2013 Accepted 2 January 2014 Keywords: Doripenem Asia-Pacific Medical 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) and complicated urinary tract infections (cUTIs). Clinical usage of doripenem (500 mg intravenously, infused over 1 h or 4 h every 8 h for 5–14 days) in APAC was evaluated in a prospective, open-label, noncomparative, 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%); and 19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64 g/mL, respectively. Doripenem was used most commonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinically evaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7–14 days after EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. The median 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 VAP patient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most common treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viable option 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.
1. Introduction The increasingly endemic nature of multidrug-resistant Gram-negative bacilli in healthcare settings [1,2], especially in the Asia-Pacific (APAC) region [3,4], has paved the way for carbapenems in the treatment of nosocomial infections [5]. Carbapenems possess broad-spectrum in vitro activity both against Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter spp. and extendedspectrum -lactamase (ESBL)-producing Enterobacteriaceae [6].
∗ Corresponding author. Tel.: +60 19 911 9155; fax: +60 9745 2546. E-mail address: [email protected] (M. Mustafa).
Medical societies and infectious diseases experts have published evidence-based treatment guidelines in which they recommend a carbapenem for empirical treatment of hospital-acquired and ventilator-associated pneumonia (VAP) when a Gram-negative pathogen is suspected [7,8], for healthcare-associated complicated intra-abdominal infections (cIAIs) [9] and for complicated urinary tract infections (cUTIs) due to antibiotic-resistant Gram-negative bacteria, including AmpC- and ESBL-producing strains [10]. Doripenem is the newest carbapenem approved in the APAC region for treatment of adults with nosocomial pneumonia (NP) including VAP, cIAI and cUTI. It is therefore important to evaluate and describe the current usage patterns for doripenem in the APAC region [11]. Thus, the PROspective study on the Usage patterns of Doripenem (PROUD) was designed to determine not only the types
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.017 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
354
M. Mustafa et al. / International Journal of Antimicrobial Agents 43 (2014) 353–360
of patients and indications for which doripenem is selected as treatment in APAC but also clinical and microbiological outcomes and medical resource utilisation associated with its usage. 2. Materials and methods An ethics committee at each site approved the protocol and informed consent form before study initiation (ClinicalTrials.gov registration no. NCT 00986102; http://www.clinicaltrials.gov). Patients or their legally acceptable representatives provided written informed consent before any study-related activity. 2.1. Patients Adults (≥18 years of age) hospitalised in an intensive care unit (ICU) or ward with a diagnosis of NP, VAP, cIAI or cUTI and who were candidates for carbapenem therapy were enrolled. A NP diagnosis required clinical signs/symptoms of de novo infection after ≥48 h of hospitalisation [7]. Patients on mechanical ventilation for ≥48 h before developing pneumonia were considered to have VAP. NP/VAP patients were required to have at least two of the following: cough; new onset or worsening purulent respiratory secretions; auscultatory findings on pulmonary examination of rales and/or consistent with consolidation; tachypnoea (≥30/min); and/or hypoxaemia [partial pressure of oxygen in arterial blood (PaO2 ) ≤60 mmHg or pulse oximetry < 90% on room air]; plus new or worsening infiltrate on chest radiography and either fever (oral >38 ◦ C)/hypothermia (rectal/core 15 mmHg from baseline); tachycardia (>100 bpm)/tachypnoea; and/or hypoxaemia; as well as physical signs of IAI (i.e. at least one of abdominal pain/tenderness, localised or diffuse guarding, abdominal wall rigidity, abdominal mass and/or ileus). A cUTI diagnosis required a positive pre-treatment cleancatch midstream urine culture (>105 CFU/mL) and either acute pyelonephritis or lower urinary tract symptoms together with one of the following: indwelling catheter or intermittent catheterisation; incomplete voiding (>100 mL of residual urine post-voiding); neurogenic bladder; obstructive uropathy; azotemia due to intrinsic renal disease; vesicoureteral reflux; other urological abnormalities; diabetes mellitus; or immunosuppression. Across these indications, exclusion criteria were creatinine clearance (CLCr ) ≤10 mL/min, dialysis, oliguria (14 days of antibiotics for the index infection; n = 17). 3.2. Demographic and other baseline clinical characteristics Demographic and clinical characteristics of patients in the ITT data set are summarised by infection type in Table 1. Most patients were Malay (55.6%) or Chinese (25.9%). Approximately two-thirds (64.0%) were critical care (ICU) patients. The mean APACHE II score at baseline (assessed in 207 patients) was 11.0, with 54 patients (26.1%) having a score ≥15. 3.3. Baseline culture results A total of 39 patients (27.7% of 141 mMITT patients) had a positive baseline blood culture, including 8 (30.8%), 15 (23.8%), 10 (23.8%) and 6 (60.0%) mMITT patients in the NP, VAP, cIAI and cUTI groups, respectively. Coagulase-negative staphylococci [15 patients (10.6%) of the mMITT data set] was the most common
355
pathogen isolated from blood cultures, followed by Klebsiella pneumoniae (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 the infection site (i.e. not blood): Acinetobacter baumannii was the most common pathogen isolated from these specimen cultures (43 mMITT patients; 30.5%), followed by Escherichia coli (30 mMITT patients; 21.3%), K. pneumoniae (30 mMITT patients; 21.3%) and P. aeruginosa (29 mMITT patients; 20.6%); some patients had more than one pathogen. The most common pathogen detected from NP and VAP patients was A. baumannii [6 patients (23.1%) and 34 patients (54.0%), respectively]. The most common pathogen detected from cUTI and cIAI patients was E. coli [3 patients (30.0%) and 24 patients (57.1%), respectively]. MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of doripenem/imipenem/meropenem for P. aeruginosa, A. baumannii, E. coli and K. pneumoniae were 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 four pathogens [US Food and Drug Administration (FDA) breakpoints:
