clinical evaluation of the need for carbapenems to treat community acquired and healthcare associated pneumonia

The clinical advantages of carbapenem in cases of pneumonia have not been certified and the need for antipseudomonal antimicrobial agents to treat healthcare-associated pneumonia HCAP rem

Original article

Clinical evaluation of the need for carbapenems to treat

community-acquired and healthcare-associated pneumonia

Kazuhiro Kamataa, Hiromichi Suzukia,*, Koji Kanemotob, Yasuharu Tokudac,

Seiji Shiotanid, Yumi Hirosee, Masatsune Suzukie, Hiroichi Ishikawab

a Division of Infectious Diseases, Department of Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan

b Department of Respiratory Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan

c Japan Community Healthcare Organization, Tokyo, Japan

d Department of Radiology, Tsukuba Medical Center Hospital, Tsukuba, Japan

e Department of General Medicine and Primary Care, Tsukuba Medical Center Hospital, Tsukuba, Japan

a r t i c l e i n f o

Article history:

Received 8 November 2014

Received in revised form

10 May 2015

Accepted 11 May 2015

Available online xxx

Keywords:

Healthcare-associated pneumonia

Community-acquired pneumonia

Carbapenem

Antimicrobial stewardship

a b s t r a c t Carbapenems have an overall broad antibacterial spectrum and should be protected against from the acquisition of drug resistance The clinical advantages of carbapenem in cases of pneumonia have not been certified and the need for antipseudomonal antimicrobial agents to treat healthcare-associated pneumonia (HCAP) remains controversial We introduced an antimicrobial stewardship program for carbapenem and tazobactam/piperacillin use and investigated the effects of this program on the clinical outcomes of 591 pneumonia cases that did not require intensive care unit management, mechanical ventilation or treatment with vasopressor agents [221 patients with community-acquired pneumonia (CAP) and 370 patients with HCAP] Compared with the pre-intervention period, age, comorbidities and the severity and etiology of pneumonia did not differ during the intervention period Carbapenems were rarely used during the intervention period in cases of pneumonia (CAP: 12% vs 1%, HCAP: 13% vs 1%), while antipseudomonal beta-lactam use was reduced from 33% to 8% among cases with HCAP This reduction in the rate of carbapenem administration did not have an impact on the prognosis in the cases

of CAP, and the in-hospital mortality was lower among the patients with HCAP during the intervention period (15% vs 5%, p¼ 0.013) The causes of death in the cases of HCAP were not directly related to pneumonia during the intervention period The current study shows that carbapenem use can be avoided

in cases of CAP or HCAP that are not in a critical condition The frequent use of antipseudomonal beta-lactams does not improve the clinical outcomes of HCAP

© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

Published by Elsevier Ltd All rights reserved

1 Introduction

Carbapenems have the broadest spectrum of activity against

Gram-positive and -negative bacteria among beta-lactam

antimi-crobials and are currently recognized as“last-line agents” in clinical

practice Since the discovery of thienamycin produced from

of treatment with imipenem/cilastatin [2], several carbapenems

(meropenem, doripenem, imipenem/cilastatin, ertapenem, biape-nem, panipenem/betamipron) have been released[3], and their use has increased globally by 45% in the last 10 years[4]

While carbapenems have strong potency for penicillin-binding proteins and are not hydrolyzed from many beta-lactamases,

frequently during the course of clinical use of these agents[5], with the production of carbapenase and/or mutations in outer mem-brane porin proteins Hence, the application of these drugs should

be avoided if alternative antimicrobial agents are available Pneumonia is the most common infectious disease in humans, with Streptococcus pneumoniae being the leading causative path-ogen, followed by Haemophilus influenzae, Klebsiella pneumoniae,

* Corresponding author Division of Infectious Diseases, Department of Medicine,

Tsukuba Medical Center Hospital, 1-3-1 Amakubo, Tsukuba, Ibaraki 305-8558,

Japan Tel.: þ81 (29) 851 3511; fax: þ81 (29) 858 2773.

E-mail address: hsuzuki@tmch.or.jp (H Suzuki).

Contents lists available atScienceDirect Journal of Infection and Chemotherapy

jo u rn a l h o m e p a g e :h t t p : / / w w w e l s e v i e r c o m / l o c a t e / j i c

http://dx.doi.org/10.1016/j.jiac.2015.05.002

1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Published by Elsevier Ltd All rights reserved.

J Infect Chemother xxx (2015) 1e8

Mycoplasma pneumoniae, Staphylococcus aureus[6e9]and others.

In order to identify high-risk patients with pneumonia caused by

Pseudomonas aeruginosa or other multidrug-resistant organisms

(MDROs), the concept of health-care associated pneumonia (HCAP)

was developed, and antipseudomonal antimicrobial agents are

currently recommended for patients with HCAP [10], especially

those with high risks[8] However, the prognostic advantages for

initial Pseudomonas coverage are unclear with respect to

over-treatment, and the necessity of carbapenem administration has not

been investigated in either CAP or HCAP

At our facility, the frequent use of carbapenems was significant

problem until June 2011, during which time antipseudomonal

beta-lactams were commonly prescribed for pneumonia, especially

in patients with HCAP We therefore implemented new regulations

regarding our carbapenem policy[11], and since July 2011,

carba-penems have been rarely used for the treatment of CAP or HCAP In

this study, we investigated the need for carbapenems to treat CAP

and/or HCAP among newly hospitalized adult patients

2 Patients and methods

This study was performed at Tsukuba Medical Center Hospital

(TMCH, 413 beds), which is located next to the University of

Tsukuba Hospital and plays a role as a tertiary emergency

medical center in the Tsukuba district of Japan The intervention

was performed as a part of infection control, and carbapenem

use was restricted to the treatment of bacterial meningitis, febrile

neutropenia, rapidly progressive sepsis, nosocomial onset

intra-abdominal infection and infections with highly drug-resistant

Gram-negative bacteria The use of carbapenems in patients

without these conditions was not recommended, and the

pre-scribing physicians were individually instructed with daily

moni-toring by an Infectious Disease (ID) physician An alternative

increase in the rate of tazobactam/piperacillin (TAZ/PIPC)

admin-istration was anticipated; thus, all individual prescriptions of TAZ/

PIPC were also monitored daily, and the use of these drugs in

pa-tients without life-threatening conditions, hospital-acquired

in-fections or highly drug-resistant Gram-negative inin-fections was not

recommended during the intervention period

The clinical evaluation was performed by comparing the

out-comes in the pre-intervention period (July 2010 to June 2011) with

those obtained during the two-year intervention period (July 2011

to June 2013) The two-year intervention period was divided into

two categories, (i) phase I (July 2011 to June 2012) and (ii) phase II

(July 2012 to June 2013), as most of the physicians at TMCH agreed

to comply with our carbapenem policy in the phase II intervention

period after being informed of the results of the phase I

interven-tion period[11] This study was approved by the ethics committee

2.1 Patients with pneumonia and definitions of CAP and HCAP

At TMCH, almost all adult pneumonia patients (18 years of age

or older) who required inpatient care are admitted to the

Depart-ment of Respiratory Medicine (RM) or DepartDepart-ment of General

Medicine and Primary Care (GM) Therefore, we reviewed the

re-cords of all patients discharged from RM or GM between July 2010

and June 2013 The initial chart review was performed by an ID

physician (H.S.), and cases suspicious for a diagnosis of pneumonia

were further reviewed by a pulmonologist (K.K) and radiologist

(S.S) individually; only patients diagnosed with pneumonia by

both physicians were included in this study Patients with lung

abscesses[12]or empyema[13,14]and/or those diagnosed with an

active infection of tuberculosis, non-tuberculous mycobacteria or

fungi were excluded from this study

Following the identification of adult patients clinically diag-nosed with pneumonia, we reviewed their clinical information and excluded patients who did not fulfill the study criteria for

use was not avoided in life-threatening cases and we thus excluded patients with pneumonia who required initial intensive care unit (ICU) management or treatment with vasopressor agents or me-chanical ventilation in this study The requirement of ICU man-agement was determined by each physician

HCAP was considered in cases of pneumonia in which the pa-tient met the pneumonia-specific criteria for HCAP[10], including: hospitalization for2 days during the previous 90 days, antibiotic use during the previous 90 days, a non-ambulatory status, tube feeding, an immunocompromised status or the use of gastric acid suppressive agents

2.2 Clinical assessment and outcome measurements

We compared the baseline characteristics, comorbidities, severity of pneumonia, laboratoryfindings on admission, causative pathogens, concurrent infections, treatment and prognosis The severity of pneumonia was assessed according to the Pneumonia Severity Index (PSI) and A-DROP scale (age, dehydration, respira-tory failure, orientation disturbance and low blood pressure)

[15,16] Causative pathogens were considered if (i) the bacteria were isolated from good quality sputum (Geckler class 4 or more)

bacteria, (ii) blood cultures were positive and the same bacteria were isolated from a sputum culture or (iii) urine antigen and/or antibody testing was positive for the target pathogens Treatment was evaluated based on the use of carbapenems, antipseudomonal agents and the frequency of combination therapy Dose adequacy was assessed according to the defined daily dose[17]adjusted for the renal function in each case

The primary outcome was in-hospital mortality, and the sec-ondary outcomes were 30-day mortality, deterioration of activities

of daily living (new onset of a bed-ridden status), new re-quirements for tube feeding or parental nutrition (PN) and/or the new introduction of home oxygen therapy (HOT)

2.3 Statistical analysis

We compared the patients with pneumonia among three periods (pre-intervention period, intervention period phase I, intervention period phase II) The comparisons were made sepa-rately between the cases of CAP and those of HCAP Categorical variables were analyzed using thec2test, and continuous variables were assessed using a one-way analysis of variance (ANOVA) Variables found to be significantly different (p < 0.05) were further evaluated using Bonferroni-corrected P values In all patients with pneumonia in each of the three periods, independent factors associated with in-hospital mortality were assessed using a multivariable adjusted logistic regression analysis to evaluate the clinical significance of HCAP Variables with a significant associa-tion (p< 0.05) in the univariate analysis were included in the multivariate analysis after adjusting for confounding factors The SPSS version 20 software package (IBM, Armonk, NY, USA) was used for all analyses

3 Results The hospital environment did not differ during the study period (July 2010 to June 2013) (Table 1) A total of 4313 admissions were recorded at RM or GM and assessed for eligibility (Fig 1)

fulfilled the study criteria (221 patients with CAP and 370 patients

with HCAP) The subjects were divided into three categories based

on the period (pre-intervention period: 182 cases, intervention

period phase I: 224 cases, intervention period phase II: 185 cases)

Each period included multiple episodes of pneumonia admissions,

with 18 patients in the pre-intervention period, 31 patients in

intervention period phase I and 15 patients in intervention period

phase II

The baseline characteristics of the patients with pneumonia

(CAP and HCAP) in each period are described inTable 2 Among the

three periods, age was slightly higher and females were more

predominant in intervention phase II The characteristics were not

different between the cases of CAP and HCAP, except for age,

gender, recent antibiotic use, chronic pulmonary disease and liver

disease The severity of disease was not different in each group

and the etiology of pneumonia was similar among the periods (Table 3) S pneumoniae was the most frequent pathogen Mean-while, P aeruginosa was the second most frequent pathogen in the cases of HCAP, and most pneumonia cases with P aeruginosa were classified as HCAP (21/24: 88%)

The details of treatment are summarized inTable 4 In the pre-intervention period, carbapenems were frequently used, with the

pre-intervention period, the rate of initial carbapenem use was signif-icantly reduced in the intervention period (P< 0.001), with only two cases (one of CAP, one of HCAP) initially treated with carba-penems in intervention period phase II In addition, the rate of initial use of TAZ/PIPC did not increase in the intervention period,

Table 1

Details of the clinical workload of TMCH and GM/RM during the study period (July 2010eJune 2013).

Pre-intervention period Intervention period Intervention period

Phase I Phase II (July 2010eJune 2011) (July 2011eJune 2012) (July 2012eJune 2013)

Number of deaths during hospitalization at TMCH 722 706 605

Proportion of carbapenem agents among total antibiotics in TMCH a 10.8% 5.8% 3.8%

TMCH Tsukuba Medical Center Hospital, GM Department of General Medicine and Primary Care, RM Department of Respiratory Medicine.

a The dose of antimicrobial agents was evaluated using the ATC/defined daily dose (DDD) system [17]

Fig 1 Flowchart of the case selection process TMCH Tsukuba Medical Center Hospital, COPD chronic obstructive pulmonary disease, IP interstitial pneumonia, NTM non-tuberculous mycobacteria, ICU intensive care unit.

K Kamata et al / J Infect Chemother xxx (2015) 1e8 3

and antipseudomonal beta-lactams were selected in only 8%

(9/109) of cases of HCAP during intervention period phase II

Car-bapenems were used in approximately one-fourth of the patients

with HCAP (23%: 26/115), while antipseudomonal beta-lactams

were used in approximately half of the patients with HCAP (43%:

49/115) in the pre-intervention period during hospitalization In

contrast, the rate of use was reduced to 4% (4/109: p< 0.001) for

carbapenems and 17% (18/109: p < 0.001) for antipseudomonal

beta-lactams during intervention period phase II

During the intervention periods, there were 39 cases

(inter-vention period phase I: 21 cases, inter(inter-vention period phase II: 18

cases) who were initially treated with antimicrobial therapy other

than antipseudomonal beta-lactams and were administered

anti-pseudomonal beta-lactams during the hospitalizations Of the 39

cases, antipseudomonal beta-lactams were administered in 22

16 cases (41%) for suspected or confirmed hospital acquired

in-fections, such as pneumonia, and one case (3%) for suspected

side effect of the initial antimicrobial therapy Of the 39 cases,

transferred to the ICU on day 6 This case was initially treated with

ampicillin-sulbactam and a clinical improvement was achieved, however, he had rapidly deteriorating respiratory failure soon after meal recommencement

The in-hospital mortality did not differ among the cases of CAP

in each period Among the patients with HCAP, the mortality rate was lower in intervention period phase II than in the pre-intervention period [5% (5 cases) vs 15% (17 cases): P¼ 0.013] Of thefive patients, three died of aspiration following improvements

in the pneumonia, one died of underlying disease (vasculitis) and one died of heart failure The 30-day mortality and rates of the new onset of a bed-ridden status or new requirements for HOT and/

or tube feeding or PN were not different between the cases of CAP and HCAP in each period

For all cases in the three periods, a multivariable adjusted lo-gistic regression analysis showed a lower serum albumin level (P< 0.001), higher PSI class (P ¼ 0.021) and the initial use of

inde-pendently related to mortality, although it was identified to be a significant factor in the univariate analysis (Table 5) Among the cases initially treated with carbapenems, an adequate dose was

Table 2

Baseline characteristics of the 591 cases of pneumonia.

Pre-intervention

Intervention phase I

Intervention phase II

Pre-intervention

Intervention phase I

Intervention phase II

n ¼ 67 n ¼ 78 n ¼ 76 n ¼ 115 n ¼ 146 n ¼ 109 Age 77 (64.5e85) 79.5 (68e85) 73 (53e84.5) 0.374 80 (73e85) 80.5 (75e87) 83 (78e89) 0.03 Female 16 (24) 33 (42) 24 (32) 0.06 32 (28) 49 (34) 50 (46) 0.016 Nursing home or LTCF 1 (2) 2 (3) 3 (4) 0.663 23 (20) 28 (19) 27 (25) 0.525

Tube feeding or PN 0 (0) 0 (0) 0 (0) N/A 20 (17) 19 (13) 15 (14) 0.584 Home oxygen therapy 1 (2) 3 (4) 0 (0) 0.196 7 (6) 13 (9) 6 (6) 0.514 History of aspiration 10 (15) 12 (16) 13 (17) 0.92 58 (50) 71 (49) 53 (50) 0.973 Recent hospitalization 0 (0) 0 (0) 0 (0) N/A 38 (33) 34 (23) 32 (29) 0.207 Antibiotics in the past 3 mo 0 (0) 0 (0) 0 (0) N/A 49 (43) 50 (34) 29 (27) 0.042 Antacid drugs 0 (0) 0 (0) 0 (0) N/A 63 (55) 94 (64) 71 (65) 0.191

[Quinolones] 9 (13) 11 (14) 10 (13) 11 (10) 16 (11) 17 (16)

Charlson comorbidity index 1 (0e1) 1 (0e1) 1 (0e1) 0.736 2 (1e2.5) 2 (1e2) 1 (1e2) 0.328 Chronic pulmonary diseases 22 (33) 26 (33) 23 (30) 0.91 35 (30) 58 (40) 26 (24) 0.024 Cerebrovascular diseases 9 (13) 14 (18) 16 (21) 0.489 43 (37) 49 (34) 36 (33) 0.747 Heart failure 10 (15) 15 (19) 8 (11) 0.317 17 (15) 35 (24) 24 (22) 0.171 Diabetes mellitus 18 (27) 11 (14) 16 (21) 0.161 20 (17) 40 (27) 25 (23) 0.162

Renal diseases 2 (3) 3 (4) 4 (5) 0.783 10 (9) 9 (6) 4 (4) 0.297

Immunosuppression 0 (0) 0 (0) 0 (0) N/A 15 (13) 19 (13) 9 (8) 0.427

Grades 1e3 34 (51) 28 (36) 39 (51) 21 (18) 28 (19) 18 (17)

Bilateral pneumonia 23 (34) 19 (24) 22 (29) 0.419 42 (37) 33 (23) 35 (32) 0.041 Albumin (g/dL) 3.5 (3e3.7) 3.6 (3.2e3.9) 3.5 (3.1e3.8) 0.432 3.2 (2.7e3.6) 3.2 (2.9e3.7) 3.3 (2.9e3.6) 0.266 eGFR (mL・min 1 ・1.73 m -2 ) 43 (33e60) 42 (30e66) 42 (24e65) 0.824 36 (25e56) 37 (25e49) 33 (23e45) 0.387 C-reactive protein (mg/dL) 11 (4e21) 9 (4e15) 11 (4e20) 0.12 8 (3e13) 8 (3e15) 6 (2e11) 0.12 All categorical data are presented as number (proportion, %) Continuous data are presented as median (interquartile range).

CAP community-acquired pneumonia, HCAP healthcare-associated pneumonia, LTCF long-term care facility, PN parenteral nutrition, PSI Pneumonia Severity Index, A-DROP Japan Respiratory Society community associated-pneumonia severity index, eGFR estimated glomerular filtration rate, N/A not applicable.

a In the PSI, elderly patients who are nursing home residents were often classified into a higher grade due to its scoring system (e.g., a 91-year-old nursing home resident is classified into Grade 5 if he has a history of one comorbidity and dehydration).

b In our study, the cases with A-DROP grade 5 had an initial low blood pressure (SBP < 90) without the requirement of continuous vasopressor agent use Some dehydrated patients with pneumonia had transient hypotension with an improvement of hydration after being admitted to the emergency department.

administered in 40% (12/30) of the cases, which was significantly

lower than that of the other antimicrobial agents (88%, P< 0.001)

Most of P aeruginosa associated pneumonia occurred among the

patients with dysphagia (79%: 19/24), especially the patients who

required enteral feeding (89%: 17/19), and multiple pathogenic organisms were detected in most of the patients (67%, 16/24) The absence of initial antipseudomonal coverage was not associated with an increase in mortality in this study

Table 3

Etiology and concurrent infections in the 591 cases of pneumonia.

value

value

Pre-intervention

Intervention phase I

Intervention phase II

Pre-intervention

Intervention phase I

Intervention phase II

n ¼ 67 n ¼ 78 n ¼ 76 n ¼ 115 n ¼ 146 n ¼ 109 Detection rate of causative

pathogens

24 (36) 31 (40) 23 (30) 0.466 41 (36) 41 (28) 42 (39) 0.183

Causative pathogens

Mixed infections 4 (6) 4 (5) 0 (0) 0.109 14 (12) 12 (8) 11 (10) 0.571 Streptococcus pneumoniae 14 (21) 15 (19) 14 (18) 0.931 18 (16) 24 (16) 19 (17) 0.938 Klebsiellla pneumoniae 1 (2) 0 (0) 0 (0) 0.315 6 (5) 6 (4) 5 (5) 0.914 Haemophilus influenzae 2 (3) 4 (5) 2 (3) 0.671 3 (3) 3 (2) 5 (5) 0.481 Moraxella catarrhalis 1 (2) 0 (0) 1 (1) 0.573 5 (4) 1 (1) 1 (1) 0.066 Legionella pneumophila 1 (2) 0 (0) 2 (3) 0.367 0 (0) 0 (0) 0 (0) N/A Mycoplasma pneumoniae 3 (5) 10 (13) 3 (4) 0.061 3 (3) 1 (1) 3 (3) 0.387

(Pseudomonas aeruginosa) 1 (2) 2 (3) 0 (0) 0.386 9 (8) 5 (3) 7 (6) 0.288

Concurrent bacterial infections a 1 (2) 1 (1) 2 (3) 0.799 2 (2) 2 (1) 4 (4) 0.427

All categorical data are presented as number (proportion, %).

CAP community-acquired pneumonia, HCAP healthcare-associated pneumonia, MSSA methicillin-sensitive Staphylococcus aureus, MRSA methicillin-resistant Staphylococcus aureus, SPACE Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter spp., Citrobacter spp and Enterobacter spp., N/A not applicable.

a Concurrent bacterial infections were defined if cases with pneumonia had other infection sites or bacteremia, which were considered have different etiology.

Table 4

Treatment and prognosis of the 591 cases of pneumonia.

value

Pre-intervention

Intervention phase I

Intervention phase II

Pre-intervention

Intervention phase I

Intervention phase II

n ¼ 67 n ¼ 78 n ¼ 76 n ¼ 115 n ¼ 146 n ¼ 109 Initial therapy

Antipseudomonal beta-lactam 13 (19) 4 (5) 6 (8) 0.013 38 (33) 20 (14) 9 (8) <0.001 [Carbapenems] 8 (12) 1 (1) 1 (1) 0.002 15 (13) 4 (3) 1 (1) <0.001 [Tazobactam/Piperacillin] 1 (2) 2 (3) 1 (1) 0.822 4 (4) 5 (3) 3 (3) 0.942 [Other antipseudomonal beta-lactam] 4 (6) 1 (1) 4 (5) 0.294 19 (17) 11 (8) 5 (5) 0.006 Non antipseudomonal beta lactam 47 (70) 67 (86) 61 (80) 0.064 75 (65) 123 (84) 92 (84) <0.001 [Third cephems] 15 (22) 14 (18) 17 (22) 0.741 16 (14) 31 (21) 26 (24) 0.147 [Ampicillin/Sulbactam] 28 (42) 51 (65) 42 (55) 0.017 56 (49) 88 (60) 57 (52) 0.155

Anti-MRSA antimicrobials 0 (0) 0 (0) 0 (0) N/A 0 (0) 0 (0) 0 (0) N/A

Combination therapy 6 (9) 11 (14) 15 (20) 0.187 13 (11) 24 (16) 9 (8) 0.133 [Beta-lactam þ Quinolones ] 1 (2) 6 (8) 5 (7) 0.224 1 (1) 8 (6) 2 (2) 0.066 [Beta-lactam þ Macrolides] 4 (6) 3 (4) 7 (9) 0.389 11 (10) 12 (8) 5 (5) 0.345 Adequate dose of antibiotics 56 (84) 72 (92) 67 (88) 0.267 87 (76) 132 (90) 93 (85) 0.007 Carbapenem use during hospitalization 14 (21) 4 (5) 5 (7) 0.003 26 (23) 15 (10) 4 (4) <0.001 Antipseudomonal beta-lactam use during

hospitalization

20 (30) 10 (13) 15 (20) 0.039 49 (43) 35 (24) 18 (17) <0.001 Anti-MRSA antimicrobial use during

hospitalization

0 (0) 0 (0) 1 (1) 0.384 2 (2) 1 (1) 0 (0) 0.341

New incidence of becoming bed ridden 6 (9) 5 (7) 7 (10) 0.765 7 (7) 8 (6) 4 (4) 0.592 New requirement for HOT 0 (0) 2 (3) 1 (1) 0.412 2 (2) 5 (4) 2 (2) 0.6 New requirement for TF or PN 2 (3) 2 (3) 5 (7) 0.374 11 (11) 18 (14) 10 (10) 0.611 30-day mortality 0 (0) 2 (3) 3 (4) 0.278 6 (5) 8 (6) 2 (2) 0.313

In hospital mortality 2 (3) 3 (4) 4 (5) 0.783 17 (15) 15 (10) 5 (5) a 0.039 All categorical data are presented as number (proportion, %).

CAP community-acquired pneumonia, HCAP healthcare-associated pneumonia, MRSA methicillin-resistant Staphylococcus aureus, HOT home oxygen therapy, TF tube feeding,

PN parental nutrition.

a 3 died of aspiration after pneumonia improved, 1 died of underlying vasculitis and 1 died of heart failure.

K Kamata et al / J Infect Chemother xxx (2015) 1e8 5

4 Discussion

In the clinical evaluation of the 591 hospitalized pneumonia

patients who did not require ICU management or the use of

me-chanical ventilation or vasopressor agents, refraining from

admin-istering carbapenems did not worsen the prognosis of the

hospitalized patients with CAP and HCAP The pneumonia-specific

pneumonia; however, a majority of the cases of pneumonia were

caused by non-MDROs In intervention period phase II, only one

patient was initially administered carbapenem, and less than 10%

of the patients were treated with antipseudomonal beta-lactams

for HCAP, although the cause of death was not directly related to

pneumonia

In previous studies, the therapeutic utility of carbapenems was

primarily analyzed in cases of nosocomial or ventilator-associated

pneumonia [18e20] With respect to CAP, Bartoloni et al

per-formed a multicenter study of the treatment of CAP using

imipenem-cilastatin (IPM/CS) or MEPM, with a reported cure rate of 57 of 64 patients (89%) for IPM/CS and 60 of 66 patients (91%) for MEPM[21] Regarding HCAP, Yamamoto et al investigated the efficacy of MEPM and TAZ/PIPC and reported that both anti-microbials achieved a high cure rate (TAZ/PIPC: 88% and MEPM: 74%) and that the use of these drugs as initial empiric therapy for

in the treatment of nursing and healthcare-associated pneumonia (NHCAP) and concluded that TAZ/PIPC and BIPM were associated

These previous studies compared other carbapenems or TAZ/ PIPC, for which the spectrum is almost equivalent to that of carbapenems

The rapid spread of carbapenem-resistant Gram-negative bacilli is a growing problem [24,25], and carbapenem-resistant

P aeruginosa is commonly identified after treatment for

Table 5

Analysis of the relationship between variables and in-hospital mortality among the 591 cases with pneumonia.

Survivors (n ¼ 545)

Non-survivors (n ¼ 46)

P value Adjusted

P value a

Nursing home or LTCF 71 (13) 13 (28) 0.004

History of aspiration or dysphagia 192 (35) 25 (54) 0.01

Immunosuppressive drugs 34 (6) 4 (9) 0.526

Charlson's comorbidity index scale 1 (1e2) 1 (1e3) 0.01

Chronic pulmonary diseases 174 (32) 16 (35) 0.69

Serum albumin concentration (g/dL) 3.3 (2.9

e3.7)

2.9 (2.3e3.3) <0.001 <0.001 eGFR (mL・min-1・1.73 m-2) 38 (26e55) 37 (26e52) 0.894

Causative pathogens

Pseudomonas aeruginosa b 22 (4) 2 (4) 0.71 (Initial antipseudomonal beta-lactam therapy) 6 (27) 1 (50)

(Other initial antimicrobial agents therapy c ) 16 (73) 1 (50)

Initial therapy

Antipseudomonal beta-lactam 79 (15) 11 (24) 0.091

All categorical data are presented as number (proportion, %) Continuous data are presented as median (interquartile range).

HACP healthcare-associated pneumonia, LTCF long-term care facility, PN parenteral nutrition, PSI Pneumonia Severity Index, A-DROP

Japan Respiratory Society community-associated pneumonia severity index, eGFR estimated glomerular filtration rate, MRSA

methicillin-resistant Staphylococcus aureus.

a Multivariate analysis was performed to assess the relationship between HCAP and in-hospital mortality The analysis was adjusted

to take into account PSI and serum albumin concentration.

b Of the 24 cases, 19 cases (79%) had a history of aspiration and most (17/19; 89%) required enteral feeding Mix infections were

common and other pathogenic organisms were detected in 16 cases (67%).

c Of the 17 cases, 10 cases were not administered antipseudomonal beta-lactams during the hospitalizations None of the 10 cases

died during the hospitalization Of the other 7 cases, one case died on day 93; he was administered tazobactam/piperacillin for

recurrence of pneumonia, which occurred after the initiation of enteral feeding.

d Most of the carbapenem use (23/30) was performed during the pre-intervention period An adequate dose was administered in

40% (12/30) of the cases, which was significantly lower than that of the other antimicrobial agents (88%, P < 0.001).

reported decreased susceptibility of P aeruginosa isolates in repeat

cultures in patients with ventilator-associated pneumonia, with

a rate of 36% in the DRPM treatment group and 53% in the

imipe-nem treatment group[18] In addition, Luyt et al reported a rate

of 57% in the carbapenem treatment group, which did not differ

Carba-penems are currently the only reliable antimicrobials for central

nervous system infections caused by drug-resistant

Gram-negative bacteria[26,27] Therefore, the clinical use of

carbape-nems should be restricted to cases of infections without alternative

treatment

Ourfindings indicate that the administration of carbapenems is

not mandatory for the treatment of patients with CAP or HCAP who

do not require ICU management or equivalent therapies Notably,

a reduction in the rate of carbapenems use is achievable without

increasing TAZ/PIPC use Although carbapenems are recommended

for the treatment of HCAP and NHCAP in patients with additional

MDRO risk factors[28,29], this recommendation might need to be

reconsidered in further investigations

The application of antipseudomonal coverage for HCAP has been

under debate for a long time Most of cases with HCAP continue to

be caused by non-MDROs [30], and Attridge et al reported the

possible worse prognosis for antipseudomonal coverage against

HCAP[31] Furthermore, the results of a meta-analysis suggested

that the universal application of antipseudomonal antimicrobials

may not have a benefit for the prognosis of HCAP [32] Recent

concern has focused on how to effectively identify cases of

pneu-monia caused by MDROs among patients with HCAP The presence

of multiple risk factors for MDROs is considered to be effective for

identifying patients with MDRO-related pneumonia among those

with HCAP or NHCAP[8,29]

On the other hand, while P aeruginosa can cause invasive

pneumonia, especially in immunosuppressive patients [33], and

inappropriate treatment may be associated with a poor prognosis

in cases of MDR Gram-negative bacteremia[34], the main cause of

HCAP is not necessarily the invasiveness of the pathogen, but rather

host factors Chalmers et al reported that the mortality of HCAP is

due to underlying patient-related factors rather than the presence

of antibiotic-resistant pathogens [30] In the current study, the

univariate analysis showed that HCAP is associated with in-hospital

mortality, but not overall mortality, according to the multivariable

model adjusted for patient-related factors, including the serum

albumin level and PSI score

The presence of dysphagia and/or a history of aspiration are

known risk factors for pneumonia [35e38], and a recent trial

indicated that the incidence of this disease can be reduced with

approximately half of the patients with HCAP had a history of

aspiration, and the frequency of this history increased in

associa-tion with the risk of MDRO For example, most of the patients with

P aeruginosa associated pneumonia had dysphagia Moreover, the

absence of initial antipseudomonal coverage was not found to be

related to an increased rate of adverse outcomes among the

pa-tients with HCAP Therefore, if aspiration is highly suspected based

on the patient's history and/or radiologicalfindings[40], the use of

initial antipseudomonal coverage might be less important in cases

of HCAP without shock or respiratory failure requiring mechanical

ventilation Meanwhile, we did not restrict the application of

antipseudomonal antimicrobial agents, except carbapenems and

TAZ/PIPC, and the use of other antipseudomonal antimicrobial

agents was determined by each individual hospital physician

Hence, this allowance may have an impact on the outcomes in the

intervention periods and additional research should be performed

to identify patients who require antipseudomonal coverage based

on the clinical outcome

There are other limitations associated with this study First, this study was performed in a single institution as an assessment of daily interventions for infection control, and the data were collected at the end of the study period Therefore, the results may not be the same as those obtained in other hospitals, and our findings may not have been reported if the current data had shown negative results for the restriction of carbapenem use Second, revised Clinical and Laboratory Standards Institute (CLSI) suscep-tibility criteria for Gram-negative bacteria have been in place since

2012 in our facility, and we did not compare the possible number of ESBL- or Amp C-producing microbes and/or carbapenem-resistant

P aeruginosa in this study Third, while the prognosis of the pa-tients with HCAP was better in the intervention phase II period than

in the pre-intervention period and the overuse of antipseudomonal beta-lactams may be associated with adverse outcomes, the pre-sent results reflect the effects of infection control and availability of

ID consultations during the intervention period, which indicates the adequacy of the dose of antimicrobials during this period Moreover, most patients with pneumonia are treated in the hos-pital without a pulmonologist or ID physician, and it is necessary to clarity whether our current practice is applicable in such environ-ments with a developing network

In conclusion, the current results showed that treatment with carbapenems can be avoided as an antimicrobial treatment option in cases of CAP or HCAP among patients without a critical condition The prognosis of HCAP is influenced by the patient's comorbidities, rather than presence of MDROs, and the frequent use of antipseudomonal beta-lactams does not improve the clinical outcomes

Conflicts of interest This study wasfinancially supported by TMCH for publication H.S received honoraria for an educational lecture regarding infec-tion control sponsored by Pfizer, Inc

Acknowledgements For their significant contributions to this work, we are very grateful to the doctors in the Department of Respiratory Medicine and the Department of General Medicine and Primary Care References

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