respiratory investigation 52 (2014) 107–113
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Procalcitonin-guided antibiotic therapy in aspiration pneumonia and an assessment of the continuation of oral intake Takashi Ogasawaraa,n, Hiroki Umezawaa,b, Yusuke Naitoa,b, Takao Takeuchia,b, Shinpei Katoa, Toshiaki Yanoa, Norio Kasamatsua, Ikko Hashizumea a
Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu, Shizuoka 432-8580, Japan b Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Procalcitonin-guided antibiotic therapy for community-acquired pneumonia is
Received 8 May 2013
effective and safe. However, the usefulness of procalcitonin for aspiration pneumonia and
Received in revised form
its nutrition-related outcomes are unknown.
15 July 2013
Methods: We conducted a noninferiority randomized controlled study in patients with
Accepted 1 August 2013
aspiration pneumonia who were admitted to our hospital between September 2010 and
Available online 26 September 2013
January 2012. We randomly assigned 105 patients to groups with different durations of
Keywords: Procalcitonin Aspiration pneumonia Body mass index Oral intake
antibiotic therapy based on the procalcitonin levels upon admission (procalcitonin group) or according to the standard guidelines (control group). The primary endpoints were relapse of aspiration pneumonia and death within 30 days, with a predefined noninferiority boundary of 10%. Secondary endpoints included duration of antibiotic exposure. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined continuation of oral nutritional intake, relapse of pneumonia, and in-hospital death. Results: The rate of relapse and death within 30 days were similar in the procalcitonin and control groups (25% versus 37.5%; difference, 12.5%; 95% confidence interval, 30.9% to 5.9%). Procalcitonin-guided antibiotic therapy significantly shortened the median duration of antibiotic exposure (5 versus 8 days; po0.0001); however, the continuation of oral intake was not increased (56% versus 50%; p¼0.54). A multivariable analysis showed a significant association between the continuation of oral nutritional intake and the body mass index upon admission. Conclusions: Procalcitonin-guided antibiotic therapy for aspiration pneumonia can shorten the duration of antibiotic exposure, but it does not increase the continuation of oral intake (UMIN000004800). & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Abbreviations: PCT, procalcitinin; NHCAP, nursing and healthcare-associated pneumonia; JRS, the Japan Respiratory Society; PEG, percutaneous endoscopic gastrostomy; CRP, C-reactive protein; CI, confidence interval; IQR, interquartile range; BMI, body mass index; A-DROP, age, dehydration, respiration, orientation, pressure; PNI, prognostic nutritional index; MWST, modified water-swallowing test n Corresponding author. Tel.: þ81 53 432 7111; fax: þ81 53 452 9217. E-mail address: [email protected] (T. Ogasawara). 2212-5345/$ - see front matter & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2013.08.002
108
1.
respiratory investigation 52 (2014) 107 –113
Introduction
Aspiration pneumonia is a major cause of death among elderly or debilitated patients. Difficulty in swallowing (which may result from stroke, dementia, etc.) is not uncommon in this group of patients, and dysphagia with aspiration is considered the most important factor contributing to the risk of pneumonia in patients with stroke [1]. Aspiration is defined as the misdirection of oropharyngeal or gastric contents into the larynx and lower respiratory tract [2]. Among elderly patients, aspiration pneumonia often relapses and sometimes develops into refractory or fatal pneumonia because of repeated silent aspiration, which is a more important cause of pneumonia than the aspiration of gastric contents. Elderly people frequently receive poor oral care, which can lead to oropharyngeal colonization by potential respiratory tract pathogens, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. A nursing and healthcare-associated pneumonia (NHCAP) guideline has been proposed by the Japanese Respiratory Society (JRS) [3]. Patients with NHCAP are at an increased risk of developing antibiotic-resistant bacteria, especially after exposure to broad-spectrum antibiotics for 42 days during the previous 90 days or after receiving tube feedings [4]. In the treatment of aspiration pneumonia which is the major pathogenic mechanism of NHCAP, both decreasing antibiotic exposure and continuing oral nutritional intake are important for preventing the development of antibiotic-resistant bacteria. To date, procalcitonin (PCT) has been used as a diagnostic marker of severe bacterial infection and sepsis. Measurement of the serum PCT concentration is useful for both the diagnosis of a bacterial infection and estimating the severity of systemic inflammatory reactions. If the PCT level is 40.5 ng/mL, there is always a suspicion of sepsis or a severe bacterial infection. In such cases, aggressive antibiotic use is recommended for patients with airway infections [5–7]. PCTguided antibiotic therapy leads to an important reduction in antibiotic use in patients with lower respiratory tract infections without increasing the risk for serious adverse outcomes [5,7]. However, the usefulness of PCT-guided antibiotic use in patients with aspiration pneumonia is unclear. We initiated a study to estimate the efficacy and safety of PCT-guided antibiotic therapy for decreasing antibiotic exposure in patients with aspiration pneumonia. Another aim of this study was to investigate whether PCT-guided antibiotic therapy contributes to the continuation of oral nutritional intake.
2.
Methods
A prospective, randomized, open-label, noninferiority trial was conducted between September 2010 and January 2012. This study was approved by the institutional review board at our hospital (Approved date: July 20, 2010; Approved #: 8/2010) and registered at the university hospital medical information network (Registration date: December 27, 2010; Registration #: UMIN000004800). Eligible patients and their families provided written informed consent. Patients at risk for aspiration, who had been hospitalized after developing pneumonia, were enrolled. Aspiration
pneumonia was clinically diagnosed on the basis of the findings on computed tomography (CT) (for example, bronchopneumonia in the dorsal lower lobes), combined with a history of aspiration pneumonia, stroke or dementia, poor systemic condition, or any combination of these (for example, bedridden patients or patients fed by a nasogastric tube or percutaneous endoscopic gastrostomy [PEG]). We also referred to clinical symptoms such as choking or coughing while eating as suspected dysphagia [8]. Selection criteria included the following: at least 1 month had elapsed since the last treatment for relapsed pneumonia and ventilator use was not scheduled for the pneumonia treatment. Exclusion criteria included patients with a known severe allergy to any drugs; patients with sepsis or a severe infectious disease; patients with severe underlying diseases (for example, malignancy, chronic obstructive pulmonary disease [COPD], heart failure) that affected the prognosis; and patients who could not safely have cessation of oral intake or hydration as a treatment for aspiration pneumonia because of dementia. Following enrollment, the patients were randomly allocated in a 1:1 ratio to groups assigned different durations of antibiotic therapy based on PCT levels upon admission (PCT group) or according to the standard guideline (control group). PCT levels were measured via outsourcing to SRL (Tokyo, Japan), and the results were obtained 2 or 3 days after admission. In the PCT group, if the PCT levels upon admission were o0.5 ng/mL, 0.5–1.0 ng/mL, or 41.0 ng/mL, the duration of antibiotic therapy was determined to be 3, 5, or 7 days, respectively [5]. If the PCT level upon admission was 45.0 ng/mL, we continued antibiotic treatment until it was less than 10% of the peak PCT level reached. In the control group, antibiotic therapy followed the recommendations of the JRS guideline for management of community-acquired pneumonia in adults [8]. Antibiotic therapy was discontinued if 3 of the following 4 criteria were met: fever declined (body temperature o37.0 1C), normalization of leukocyte count, decrease in the C-reactive protein (CRP) level to 30% of the maximum, and an obvious improvement as observed by chest radiography. In both groups, the choice of antibiotic regimen was left to the discretion of the treating physician. The primary noninferiority endpoint was a composite of a relapse of aspiration pneumonia and death from any cause occurring within 30 days of admission. Predefined secondary endpoints were antibiotic exposure and adverse events from antibiotic therapy (the incidence of pseudomembranous enterocolitis). In this study, we assessed the fasting duration, length of hospital stay, and rate of the continuation of oral nutritional intake. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined the continuation of oral nutritional intake, a relapse of pneumonia, and an in-hospital death, using multivariate logistic regression.
2.1.
Statistical analysis
According to prior patient data from our hospital, the risk for a relapse of aspiration pneumonia and an in-hospital death was estimated to be 40%. As the efficacy of PCT-guided antibiotic therapy in patients with aspiration pneumonia was unclear, we estimated it to be 45%. As a tolerable upper limit, a noninferiority margin of 10% was chosen on the basis of guidelines issued by the Center for Drug Evaluation and Research and the Committee
respiratory investigation 52 (2014) 107 –113
for Proprietary Medicinal Product [9]. Based on this noninferiority boundary, 49 patients were necessary in each treatment arm to establish the noninferiority of the PCT group with an 80% power and a 2-sided 95% confidence interval (CI). As for the background factors and baseline laboratory data, continuous variables are indicated as the median value and interquartile range (IQR). The χ2 test was used for analyzing discrete variables, with the Mann– Whitney U test for continuous variables. Differences were considered significant with a po0.05. We examined the important prognostic factors that determined a continuation of oral intake, a relapse of aspiration pneumonia, or an in-hospital death by using a multivariate logistic regression analysis. Variables included age, sex, body weight, body mass index (BMI), state of consciousness with or without confusion, coexisting illness (dementia, cerebrovascular disease, heart failure, hypertension, coronary heart disease, chronic kidney disease, diabetes, malignancy, and COPD), performance status, A-DROP (age, dehydration, respiration, orientation and pressure) score, serum albumin, blood urea nitrogen, lymphocyte count, CRP, PCT, prognostic nutritional index (PNI) [10], duration of antibiotic therapy, and fasting duration. STAT VIEW Version 5.0 (SAS Institute, Cary, NC, USA) was used for the statistical calculations.
3.
Results
3.1.
Patient characteristics
The study enrolled 105 patients; 2 patients withdrew their informed consent, 5 patients were excluded because of other final diagnoses, and 1 patient was excluded because of a defect in the PCT data (Fig. 1). Thus, the intention-to-treat population comprised 96 patients: 48 in the PCT group and 48 in the control group. The baseline characteristics were well balanced between the 2 treatment arms (Table 1). The control group included
more patients with coronary heart disease than the PCT group, but this was not significant. As determined by the laboratory findings, the nutritional and inflammatory statuses were also similar between the 2 groups.
3.2.
Primary endpoint
The incidence of both relapse of aspiration pneumonia and death from any cause within 30 days was not higher in the PCT group (25%) than in the control group (37.5%) (Fig. 2). The 95% CI for the risk difference was from 30.9% to 5.9%, and the upper boundary of the 95% CI was within the predefined noninferiority margin of 10% (Table 2). There were no significant differences in the number of relapses or deaths during hospitalization between both groups. Among the 15 deceased patients, the causes of death were pneumonia in 10 patients and senility in 2 patients. Other causes included dehydration, chronic renal failure, and septic shock.
3.3.
Secondary endpoints
The median duration for antibiotic exposure was significantly lower in the PCT group (5 versus 8 days; po0.0001). The incidence of pseudomembranous enterocolitis was lower in the PCT group than in the control group, although the difference was not significant (2% versus 10%; p ¼0.20) (Table 2). Greater than 95% of the initial treatment regimen was antibiotics, such as sulbactum/ampicillin or ceftriaxone, and classified as category B in the NHCAP guideline [3]. The detection rate of a drug-resistant bacterium in a sputum culture was also similar in both groups (13% versus 15%; p¼ 0.77). The duration of antibiotic treatment was shorter in the PCT group than in the control group; however, the fasting duration and the length of hospital stay were similar in both
105 patients were randomly assigned to a treatment group
1 1 1 1
52 were assigned to the control group
53 were assigned to the procalcitonin group
Relapse case Nonaspiration pneumonia Heart failure Defect in procalcitonin data
2 Withdrew informed consent 1 Sepsis 1 Pneumonia caused by S. pneumonia 1 Cellulitis
48 included in the primary analysis
109
48 included in the primary analysis
Fig. 1 – CONSORT diagram of the study.
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respiratory investigation 52 (2014) 107 –113
Table 1 – Baseline characteristics. Control group n ¼ 48
Characteristics Demographics Age, median (IQR), y Male sex, No. (%)
86.5 (85–89) 26 (54)
Systemic condition, median (IQR) Weight, kg BMI Performance status A-DROP
40.4 16.7 3 3
Coexisting illness, No. (%) Dementia Cerebrovascular disease Heart failure Hypertension Coronary heart disease Chronic kidney disease Diabetes Malignancy COPD
40 13 13 23 8 6 8 9 9
Laboratory findings, median (IQR) Albumin, g/dl PCT, ng/ml C-reactive protein, mg/dl Leukocyte count, /μl Lymphocyte count, /μl
3.3 0.66 8.2 11750 850
PCT group n ¼ 48
85 (81–92) 22 (45)
(33.4–48.8) (14.9–19.8) (2–4) (2–3)
39 17.1 3 3
(83) (27) (27) (48) (17) (13) (17) (19) (19)
38 17 11 22 2 6 6 7 12
(3.0–3.6) (0.17–2.61) (4.5–15.9) (7800–14150) (550–1280)
3.2 0.53 11.0 11400 825
p Value
0.92 0.41
(33–42.6) (14.9–19) (2–4) (2–4)
0.16 0.44 0.92 0.55
(79) (35) (23) (46) (4) (13) (13) (15) (25)
0.79 0.38 0.64 0.84 0.09 0.76 0.77 0.78 0.62
(2.9–3.5) (0.15–2.23) (3.4–16.8) (9075–15400) (595–1135)
0.38 0.60 0.47 0.45 0.64
Abbreviations: IQR, interquartile range; A-DROP, severity scoring system of community-acquired pneumonia (age, dehydration, respiration, orientation, pressure); COPD, chronic obstructive pulmonary disease; PCT, procalcitonin.
admission was associated with oral intake (Table 4). In a similar manner, a logistic analysis showed significant associations between the BMI upon admission and the relapse of aspiration pneumonia and between the serum albumin level upon admission and an in-hospital death. There was no association between the duration of antibiotic therapy and these outcomes.
Probabilityof relapse-free survival
1.0 0.8
0.6 0.4
4.
Discussion
0.2 0 0
10
20
30
Number of days after randomization Fig. 2 – A Kaplan–Meier plot of the primary endpoint. The black line refers to the PCT group, and the gray line refers to the control group.
groups (5 versus 6 days; p ¼0.77; 28 versus 30 days; p¼ 0.45, respectively) (Table 3). The rate for the continuation of oral nutritional intake was also similar in both groups. Univariate analysis showed that BMI (p¼ 0.0016), A-DROP (p¼ 0.0005), confusion (p¼0.0016), and fasting duration (p¼ 0.0004) were significant (po0.001) prognostic factors that determined the continuation of oral intake. A multivariate logistic regression analysis revealed that the BMI upon
In this first randomized noninferior trial for aspiration pneumonia, compared to the standard guideline, PCT-guided antibiotic therapy reduced antibiotic exposure without increasing the risk of relapse for aspiration pneumonia or an in-hospital death. However, the shortened PCT-guided antibiotic therapy did not reduce the number of patients who received tube feedings that was considered a risk factor for the development of antibiotic-resistant bacteria. The multivariate analysis showed that the continuation of oral intake was associated with the nutritional status upon admission, but not with the duration of antibiotic therapy. In our hospital, patients who are admitted because of aspiration pneumonia are generally required to refrain from eating and drinking for a few days. By having an inadequate oral intake because of dysphagia, these patients are often malnourished, and prolonged fasting will worsen their nutritional status. In the PCT group, oral intake was restarted (median, 5 days) concurrently with the discontinuation of antibiotic therapy (median, 5 days), whereas in the control
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Table 2 – Outcomes of the study groups, control versus PCT-guided. Control group n ¼48 Primary endpoint Relapse of pneumonia and Death within 30 days, n (%) Risk difference, % (95% CI) Relapse of pneumonia, n (%) In-hospital death, n (%)
18 (37.5) 11 (23) 10 (21)
Secondary endpoint Duration of antibiotics exposure, median (IQR), day Pseudomembranous enterocolitis, n (%) Initial antibiotic treatment Sulbactam/Ampicillin, n (%) Ceftriaxone (7 Clindamycin), n (%) Sputum culture Drug-resistant bacteriuma, n (%)
PCT group n¼ 48
12 (25) 12.5 (30.9 to 5.9) 10 (21) 5 (10)
p Value
0.19 0.80 0.26
o 0.0001
8 (6–10)
5 (4–7)
5 (10)
1 (2)
0.20
41 (85) 5 (10)
44 (92) 3 (6)
0.52
7 (15)
6 (13)
0.77
Abbreviations: IQR, interquartile range. Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia or extendedspectrum β-lactamase (ESBL)-producing bacterium.
a
Table 3 – Fasting duration, length of hospital stay, and nutritional outcomes of the study groups. Control group n ¼ 48
PCT group n ¼48
p Value
Fasting duration, median (IQR) [day] Length of hospital stay, median (IQR) [day]
6 (3–10) 30 (17–39)
5 (2.75–8) 28 (19–43)
0.77 0.45
Nutrition-related outcome Oral intake, n (%) Parenteral nutrition, n (PPN/TPN) Tube feeding, n NG/PEG
24 (50) 15 (11/ 3) 9 (4/5)
27 (56) 9 (6/3) 12 (5/7)
0.54
Abbreviations: IQR, interquartile range; PPN, peripheral parenteral nutrition; TPN, total parenteral nutrition; NG, nasogastric tube feeding; PEG, percutaneous endoscopic gastrostomy.
group, fasting was stopped (median, 6 days) before the discontinuation of antibiotic therapy (median, 8 days). The present study showed that a shortened duration of antibiotic therapy by 3 days did not influence whether patients could continue their oral nutritional intake. In our hospital, a restart of oral intake is generally determined by using a modified water-swallowing test (MWST) [11], based on an improvement in respiratory failure or a decrease in the amount of sputum. If patients are thought to be unable to eat orally according to the MWST result, a final diagnosis of dysphagia is made by a videofluoroscopic or videoendoscopic examination of their swallowing. In this study, only 53% patients with aspiration pneumonia were able to continue oral intake after antibiotic therapy. This may suggest that the development of aspiration pneumonia requiring hospitalization might itself be a poor prognostic factor for oral nutritional intake. Although the logistic regression analysis showed an association between a fasting duration of o7 days and the continuation of oral intake, patients with an adequate oral intake obviously did not need prolonged fasting. A prospective study is necessary to examine whether a shortened fasting duration and an intentional early restart of oral intake increase the number of patients with continuous oral intake.
In addition to oral intake, a relapse of aspiration pneumonia was also associated with the BMI upon admission. This result implies that patients with a low BMI who have inadequate oral intake frequently have a risk of relapse for aspiration pneumonia. As defined by the BMI, obesity and being overweight are associated with serious morbidity; however, the obesity paradox, which suggests that high BMI patients have a lower mortality than normal BMI patients, has recently been reported in several studies [12–14]. Our results are consistent with Park's report that underweight nursing home residents are at risk for developing dysphagia [15]. In this study, only 2 patients were obese (BMI425), and the mean BMI for all patients was very low (17.4 kg/m2). Therefore, whether the obesity paradox plays a role in aspiration pneumonia or dysphagia remains unclear and warrants further examination. Our analysis showed an association between male gender and an in-hospital death. The higher laryngeal elevation found in males, as compared to that of females, is considered to be one of the risk factors for the development of dysphagia [15]. Pneumonia is also the leading cause of death among elderly men in Japan. As a result of these facts, it could be predicted that hospitalization for aspiration pneumonia in elderly men with dysphagia would lead to a high in-hospital mortality rate. Furthermore, a low serum albumin level (r3.0 g/dL), indicating
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Table 4 – Multivariate analysis of oral intake, relapse of pneumonia, and in-hospital deaths. Variable
Referent
Odds ratio
95% CI
p Value
Continuance of oral intakea BMI A-DROP Confusion Fasting duration
Z3 Yes Z7
1.311 0.486 0.430 0.334
1.099–1.564 0.154–1.529 0.137–1.352 0.117–0.954
0.0026 0.2173 0.1487 0.0406
Yes Z7
1.035 0.702 0.364 2.801
0.929–1.152 0.500–0.985 0.120–1.105 0.936–8.377
0.5368 0.0405 0.0745 0.0654
5.161 4.691 7.258 1.728 1.018 1.138
1.089–24.467 0.756–29.083 1.679–31.383 0.352–8.488 0.978–1.060 0.947–1.366
0.0387 0.0968 0.0080 0.5007 0.3830 0.1677
Relapse of pneumonian Body weight BMI Hypertension Fasting duration In-hospital deathn Male A-DROP Albumin, g/dl CRP, mg/dl BUN, mg/dl Duration of antibiotic use
Z3 r3.0 Z20
Abbreviations: CI, confidence interval; BMI, body mass index; A-DROP, severity scoring system of community-acquired pneumonia (age, dehydration, respiration, orientation, pressure); CRP, C-reactive protein. a Significant variables (po0.001, on univariate analysis) were assessed. n Significant variables (po0.05, on univariate analysis) were assessed.
malnutrition, and a low BMI were also associated with inhospital death. Viasus found that the serum albumin level upon admission was a good prognostic marker for communityacquired pneumonia [16]. Hypoalbuminemia and pneumonia were positively associated with mortality in patients with advanced dementia [17]. Therefore, we consider the prognosis of patients with aspiration pneumonia to be entirely dependent on the nutritional status upon admission. Our study had several limitations. First, this study was a single institution trial with a small number of patients. The sample size was determined upon the basis of a hypothesis that the efficacy within the PCT group was 45%. We might have underestimated the real effect of PCT-guided antibiotic therapy. Second, we did not exclude in-hospital deaths by cause of death, except for aspiration pneumonia. Our patients with aspiration pneumonia had many complications, and it can often be difficult to distinguish a death from natural causes (for example, senility) from that due to pneumonia. Third, the PCT levels could not be obtained real time, so we used a protocol adopted as a treatment for outpatients in a reported trial [5]. The duration of antibiotic exposure might have been even shorter in the PCT group, if the PCT levels had been measured at the central laboratory in our hospital and were available within hours. Although the patients were treated with antibiotics for a period of at least 3 days in the present study, further validation is required to determine the safety of patients if antibiotic therapy is not administered. Fourth, the analysis of the prognostic factors associated with oral intake was retrospective. A prospectively planned decrease in the fasting duration might lead to different results. In conclusion, PCT-guided antibiotic therapy for patients with aspiration pneumonia has the same safety and efficacy as that of a treatment based on the standard guideline. Although PCT-guided therapy decreased unnecessary antibiotic exposure, it did not lead to an increase in the
continuation of oral intake. The oral intake and prognosis of patients with aspiration pneumonia might be more closely related to the nutritional status upon admission than that of the therapeutic process.
Conflict of interest The authors have no conflicts of interest.
r e f e r e n c e s
[1] Horner J, Massey EW, Riski JE, et al. Aspiration following stroke: clinical correlates and outcome. Neurology 1998;38:1359–62. [2] Marik PE. Aspiration pneumonitis and pneumonia. N Engl J Med 2001;344:665–71. [3] The Japanese Respiratory Society. Guidelines for the management of nursing and healthcare-associated pneumonia. Tokyo: The Japanese Respiratory Society; 2011 ([in Japanese]). [4] Shindo Y, Sato S, Maruyama E, et al. Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital. Chest 2009;135:633–40. [5] Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guideline on antibiotics use in lower respiratory tract infections: the ProHOSP randomized controlled trial. J Am Med Assoc 2009;302:1059–66. [6] Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006;174:84–93. [7] Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotics use and outcome in lower respiratory tract infections: cluster-randomised, singleblinded intervention trial. Lancet 2004;363:600–7.
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[8] The JRS Guidelines for the management of communityacquired pneumonia in Adults. The Japanese Respiratory Society. Tokyo 2007; [in Japanese]. [9] Röhmel J. Statistical considerations of FDA and CPMP rules for the investigation of new anti-bacterial products. Stat Med 2001;20:2561–71. [10] Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nihon Geka Gakkai Zasshi 1984;85:1001–5 [in Japanese]. [11] Osawa A, Maeshima S, Tanahashi N. Water-swallowing test: screening for aspiration in stroke patients. Cerebrovasc Dis 2013;35:276–81. [12] Dhoot J, Tariq S, Erande A, et al. Effect of morbid obesity on in-hospital mortality and coronary revascularization outcomes after acute myocardial infarction in the United States. Am J Cardiol 2013;111:1104–10.
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[13] Corrales-Medina VF, Valayam J, Serpa JA, et al. The obesity paradox in community-acquired bacterial pneumonia. Int J Infect Dis 2011;15:e54–7. [14] Blum A, Simsolo C, Sirchan R, et al. Obesity paradox in chronic obstructive pulmonary disease. Isr Med Assoc J 2011;13:672–5. [15] Park YH, Han HR, Oh BM, et al. Prevalence and associated factors of dysphagia in nursing home residents. Geriatr Nurs 2013;34:212–7. [16] Viasus D, Garcia-Vidal C, Simonetti A, et al. Prognostic value of serum albumin levels in hospitalized adults with community-acquired pneumonia. J Infect 2013;66:415–23. [17] Alvarez-Fernández B, García-Ordoñez MA, MartínezManzanares C, et al. Survival of a cohort of elderly patients with advanced dementia: nasogastric tube feeding as a risk factor for mortality. Int J Geriatr Psychiatry 2005;20:363–70.
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Procalcitonin-guided antibiotic therapy in aspiration pneumonia and an assessment of the continuation of oral intake Takashi Ogasawaraa,n, Hiroki Umezawaa,b, Yusuke Naitoa,b, Takao Takeuchia,b, Shinpei Katoa, Toshiaki Yanoa, Norio Kasamatsua, Ikko Hashizumea a
Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu, Shizuoka 432-8580, Japan b Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Procalcitonin-guided antibiotic therapy for community-acquired pneumonia is
Received 8 May 2013
effective and safe. However, the usefulness of procalcitonin for aspiration pneumonia and
Received in revised form
its nutrition-related outcomes are unknown.
15 July 2013
Methods: We conducted a noninferiority randomized controlled study in patients with
Accepted 1 August 2013
aspiration pneumonia who were admitted to our hospital between September 2010 and
Available online 26 September 2013
January 2012. We randomly assigned 105 patients to groups with different durations of
Keywords: Procalcitonin Aspiration pneumonia Body mass index Oral intake
antibiotic therapy based on the procalcitonin levels upon admission (procalcitonin group) or according to the standard guidelines (control group). The primary endpoints were relapse of aspiration pneumonia and death within 30 days, with a predefined noninferiority boundary of 10%. Secondary endpoints included duration of antibiotic exposure. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined continuation of oral nutritional intake, relapse of pneumonia, and in-hospital death. Results: The rate of relapse and death within 30 days were similar in the procalcitonin and control groups (25% versus 37.5%; difference, 12.5%; 95% confidence interval, 30.9% to 5.9%). Procalcitonin-guided antibiotic therapy significantly shortened the median duration of antibiotic exposure (5 versus 8 days; po0.0001); however, the continuation of oral intake was not increased (56% versus 50%; p¼0.54). A multivariable analysis showed a significant association between the continuation of oral nutritional intake and the body mass index upon admission. Conclusions: Procalcitonin-guided antibiotic therapy for aspiration pneumonia can shorten the duration of antibiotic exposure, but it does not increase the continuation of oral intake (UMIN000004800). & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Abbreviations: PCT, procalcitinin; NHCAP, nursing and healthcare-associated pneumonia; JRS, the Japan Respiratory Society; PEG, percutaneous endoscopic gastrostomy; CRP, C-reactive protein; CI, confidence interval; IQR, interquartile range; BMI, body mass index; A-DROP, age, dehydration, respiration, orientation, pressure; PNI, prognostic nutritional index; MWST, modified water-swallowing test n Corresponding author. Tel.: þ81 53 432 7111; fax: þ81 53 452 9217. E-mail address: [email protected] (T. Ogasawara). 2212-5345/$ - see front matter & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2013.08.002
108
1.
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Introduction
Aspiration pneumonia is a major cause of death among elderly or debilitated patients. Difficulty in swallowing (which may result from stroke, dementia, etc.) is not uncommon in this group of patients, and dysphagia with aspiration is considered the most important factor contributing to the risk of pneumonia in patients with stroke [1]. Aspiration is defined as the misdirection of oropharyngeal or gastric contents into the larynx and lower respiratory tract [2]. Among elderly patients, aspiration pneumonia often relapses and sometimes develops into refractory or fatal pneumonia because of repeated silent aspiration, which is a more important cause of pneumonia than the aspiration of gastric contents. Elderly people frequently receive poor oral care, which can lead to oropharyngeal colonization by potential respiratory tract pathogens, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. A nursing and healthcare-associated pneumonia (NHCAP) guideline has been proposed by the Japanese Respiratory Society (JRS) [3]. Patients with NHCAP are at an increased risk of developing antibiotic-resistant bacteria, especially after exposure to broad-spectrum antibiotics for 42 days during the previous 90 days or after receiving tube feedings [4]. In the treatment of aspiration pneumonia which is the major pathogenic mechanism of NHCAP, both decreasing antibiotic exposure and continuing oral nutritional intake are important for preventing the development of antibiotic-resistant bacteria. To date, procalcitonin (PCT) has been used as a diagnostic marker of severe bacterial infection and sepsis. Measurement of the serum PCT concentration is useful for both the diagnosis of a bacterial infection and estimating the severity of systemic inflammatory reactions. If the PCT level is 40.5 ng/mL, there is always a suspicion of sepsis or a severe bacterial infection. In such cases, aggressive antibiotic use is recommended for patients with airway infections [5–7]. PCTguided antibiotic therapy leads to an important reduction in antibiotic use in patients with lower respiratory tract infections without increasing the risk for serious adverse outcomes [5,7]. However, the usefulness of PCT-guided antibiotic use in patients with aspiration pneumonia is unclear. We initiated a study to estimate the efficacy and safety of PCT-guided antibiotic therapy for decreasing antibiotic exposure in patients with aspiration pneumonia. Another aim of this study was to investigate whether PCT-guided antibiotic therapy contributes to the continuation of oral nutritional intake.
2.
Methods
A prospective, randomized, open-label, noninferiority trial was conducted between September 2010 and January 2012. This study was approved by the institutional review board at our hospital (Approved date: July 20, 2010; Approved #: 8/2010) and registered at the university hospital medical information network (Registration date: December 27, 2010; Registration #: UMIN000004800). Eligible patients and their families provided written informed consent. Patients at risk for aspiration, who had been hospitalized after developing pneumonia, were enrolled. Aspiration
pneumonia was clinically diagnosed on the basis of the findings on computed tomography (CT) (for example, bronchopneumonia in the dorsal lower lobes), combined with a history of aspiration pneumonia, stroke or dementia, poor systemic condition, or any combination of these (for example, bedridden patients or patients fed by a nasogastric tube or percutaneous endoscopic gastrostomy [PEG]). We also referred to clinical symptoms such as choking or coughing while eating as suspected dysphagia [8]. Selection criteria included the following: at least 1 month had elapsed since the last treatment for relapsed pneumonia and ventilator use was not scheduled for the pneumonia treatment. Exclusion criteria included patients with a known severe allergy to any drugs; patients with sepsis or a severe infectious disease; patients with severe underlying diseases (for example, malignancy, chronic obstructive pulmonary disease [COPD], heart failure) that affected the prognosis; and patients who could not safely have cessation of oral intake or hydration as a treatment for aspiration pneumonia because of dementia. Following enrollment, the patients were randomly allocated in a 1:1 ratio to groups assigned different durations of antibiotic therapy based on PCT levels upon admission (PCT group) or according to the standard guideline (control group). PCT levels were measured via outsourcing to SRL (Tokyo, Japan), and the results were obtained 2 or 3 days after admission. In the PCT group, if the PCT levels upon admission were o0.5 ng/mL, 0.5–1.0 ng/mL, or 41.0 ng/mL, the duration of antibiotic therapy was determined to be 3, 5, or 7 days, respectively [5]. If the PCT level upon admission was 45.0 ng/mL, we continued antibiotic treatment until it was less than 10% of the peak PCT level reached. In the control group, antibiotic therapy followed the recommendations of the JRS guideline for management of community-acquired pneumonia in adults [8]. Antibiotic therapy was discontinued if 3 of the following 4 criteria were met: fever declined (body temperature o37.0 1C), normalization of leukocyte count, decrease in the C-reactive protein (CRP) level to 30% of the maximum, and an obvious improvement as observed by chest radiography. In both groups, the choice of antibiotic regimen was left to the discretion of the treating physician. The primary noninferiority endpoint was a composite of a relapse of aspiration pneumonia and death from any cause occurring within 30 days of admission. Predefined secondary endpoints were antibiotic exposure and adverse events from antibiotic therapy (the incidence of pseudomembranous enterocolitis). In this study, we assessed the fasting duration, length of hospital stay, and rate of the continuation of oral nutritional intake. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined the continuation of oral nutritional intake, a relapse of pneumonia, and an in-hospital death, using multivariate logistic regression.
2.1.
Statistical analysis
According to prior patient data from our hospital, the risk for a relapse of aspiration pneumonia and an in-hospital death was estimated to be 40%. As the efficacy of PCT-guided antibiotic therapy in patients with aspiration pneumonia was unclear, we estimated it to be 45%. As a tolerable upper limit, a noninferiority margin of 10% was chosen on the basis of guidelines issued by the Center for Drug Evaluation and Research and the Committee
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for Proprietary Medicinal Product [9]. Based on this noninferiority boundary, 49 patients were necessary in each treatment arm to establish the noninferiority of the PCT group with an 80% power and a 2-sided 95% confidence interval (CI). As for the background factors and baseline laboratory data, continuous variables are indicated as the median value and interquartile range (IQR). The χ2 test was used for analyzing discrete variables, with the Mann– Whitney U test for continuous variables. Differences were considered significant with a po0.05. We examined the important prognostic factors that determined a continuation of oral intake, a relapse of aspiration pneumonia, or an in-hospital death by using a multivariate logistic regression analysis. Variables included age, sex, body weight, body mass index (BMI), state of consciousness with or without confusion, coexisting illness (dementia, cerebrovascular disease, heart failure, hypertension, coronary heart disease, chronic kidney disease, diabetes, malignancy, and COPD), performance status, A-DROP (age, dehydration, respiration, orientation and pressure) score, serum albumin, blood urea nitrogen, lymphocyte count, CRP, PCT, prognostic nutritional index (PNI) [10], duration of antibiotic therapy, and fasting duration. STAT VIEW Version 5.0 (SAS Institute, Cary, NC, USA) was used for the statistical calculations.
3.
Results
3.1.
Patient characteristics
The study enrolled 105 patients; 2 patients withdrew their informed consent, 5 patients were excluded because of other final diagnoses, and 1 patient was excluded because of a defect in the PCT data (Fig. 1). Thus, the intention-to-treat population comprised 96 patients: 48 in the PCT group and 48 in the control group. The baseline characteristics were well balanced between the 2 treatment arms (Table 1). The control group included
more patients with coronary heart disease than the PCT group, but this was not significant. As determined by the laboratory findings, the nutritional and inflammatory statuses were also similar between the 2 groups.
3.2.
Primary endpoint
The incidence of both relapse of aspiration pneumonia and death from any cause within 30 days was not higher in the PCT group (25%) than in the control group (37.5%) (Fig. 2). The 95% CI for the risk difference was from 30.9% to 5.9%, and the upper boundary of the 95% CI was within the predefined noninferiority margin of 10% (Table 2). There were no significant differences in the number of relapses or deaths during hospitalization between both groups. Among the 15 deceased patients, the causes of death were pneumonia in 10 patients and senility in 2 patients. Other causes included dehydration, chronic renal failure, and septic shock.
3.3.
Secondary endpoints
The median duration for antibiotic exposure was significantly lower in the PCT group (5 versus 8 days; po0.0001). The incidence of pseudomembranous enterocolitis was lower in the PCT group than in the control group, although the difference was not significant (2% versus 10%; p ¼0.20) (Table 2). Greater than 95% of the initial treatment regimen was antibiotics, such as sulbactum/ampicillin or ceftriaxone, and classified as category B in the NHCAP guideline [3]. The detection rate of a drug-resistant bacterium in a sputum culture was also similar in both groups (13% versus 15%; p¼ 0.77). The duration of antibiotic treatment was shorter in the PCT group than in the control group; however, the fasting duration and the length of hospital stay were similar in both
105 patients were randomly assigned to a treatment group
1 1 1 1
52 were assigned to the control group
53 were assigned to the procalcitonin group
Relapse case Nonaspiration pneumonia Heart failure Defect in procalcitonin data
2 Withdrew informed consent 1 Sepsis 1 Pneumonia caused by S. pneumonia 1 Cellulitis
48 included in the primary analysis
109
48 included in the primary analysis
Fig. 1 – CONSORT diagram of the study.
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Table 1 – Baseline characteristics. Control group n ¼ 48
Characteristics Demographics Age, median (IQR), y Male sex, No. (%)
86.5 (85–89) 26 (54)
Systemic condition, median (IQR) Weight, kg BMI Performance status A-DROP
40.4 16.7 3 3
Coexisting illness, No. (%) Dementia Cerebrovascular disease Heart failure Hypertension Coronary heart disease Chronic kidney disease Diabetes Malignancy COPD
40 13 13 23 8 6 8 9 9
Laboratory findings, median (IQR) Albumin, g/dl PCT, ng/ml C-reactive protein, mg/dl Leukocyte count, /μl Lymphocyte count, /μl
3.3 0.66 8.2 11750 850
PCT group n ¼ 48
85 (81–92) 22 (45)
(33.4–48.8) (14.9–19.8) (2–4) (2–3)
39 17.1 3 3
(83) (27) (27) (48) (17) (13) (17) (19) (19)
38 17 11 22 2 6 6 7 12
(3.0–3.6) (0.17–2.61) (4.5–15.9) (7800–14150) (550–1280)
3.2 0.53 11.0 11400 825
p Value
0.92 0.41
(33–42.6) (14.9–19) (2–4) (2–4)
0.16 0.44 0.92 0.55
(79) (35) (23) (46) (4) (13) (13) (15) (25)
0.79 0.38 0.64 0.84 0.09 0.76 0.77 0.78 0.62
(2.9–3.5) (0.15–2.23) (3.4–16.8) (9075–15400) (595–1135)
0.38 0.60 0.47 0.45 0.64
Abbreviations: IQR, interquartile range; A-DROP, severity scoring system of community-acquired pneumonia (age, dehydration, respiration, orientation, pressure); COPD, chronic obstructive pulmonary disease; PCT, procalcitonin.
admission was associated with oral intake (Table 4). In a similar manner, a logistic analysis showed significant associations between the BMI upon admission and the relapse of aspiration pneumonia and between the serum albumin level upon admission and an in-hospital death. There was no association between the duration of antibiotic therapy and these outcomes.
Probabilityof relapse-free survival
1.0 0.8
0.6 0.4
4.
Discussion
0.2 0 0
10
20
30
Number of days after randomization Fig. 2 – A Kaplan–Meier plot of the primary endpoint. The black line refers to the PCT group, and the gray line refers to the control group.
groups (5 versus 6 days; p ¼0.77; 28 versus 30 days; p¼ 0.45, respectively) (Table 3). The rate for the continuation of oral nutritional intake was also similar in both groups. Univariate analysis showed that BMI (p¼ 0.0016), A-DROP (p¼ 0.0005), confusion (p¼0.0016), and fasting duration (p¼ 0.0004) were significant (po0.001) prognostic factors that determined the continuation of oral intake. A multivariate logistic regression analysis revealed that the BMI upon
In this first randomized noninferior trial for aspiration pneumonia, compared to the standard guideline, PCT-guided antibiotic therapy reduced antibiotic exposure without increasing the risk of relapse for aspiration pneumonia or an in-hospital death. However, the shortened PCT-guided antibiotic therapy did not reduce the number of patients who received tube feedings that was considered a risk factor for the development of antibiotic-resistant bacteria. The multivariate analysis showed that the continuation of oral intake was associated with the nutritional status upon admission, but not with the duration of antibiotic therapy. In our hospital, patients who are admitted because of aspiration pneumonia are generally required to refrain from eating and drinking for a few days. By having an inadequate oral intake because of dysphagia, these patients are often malnourished, and prolonged fasting will worsen their nutritional status. In the PCT group, oral intake was restarted (median, 5 days) concurrently with the discontinuation of antibiotic therapy (median, 5 days), whereas in the control
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Table 2 – Outcomes of the study groups, control versus PCT-guided. Control group n ¼48 Primary endpoint Relapse of pneumonia and Death within 30 days, n (%) Risk difference, % (95% CI) Relapse of pneumonia, n (%) In-hospital death, n (%)
18 (37.5) 11 (23) 10 (21)
Secondary endpoint Duration of antibiotics exposure, median (IQR), day Pseudomembranous enterocolitis, n (%) Initial antibiotic treatment Sulbactam/Ampicillin, n (%) Ceftriaxone (7 Clindamycin), n (%) Sputum culture Drug-resistant bacteriuma, n (%)
PCT group n¼ 48
12 (25) 12.5 (30.9 to 5.9) 10 (21) 5 (10)
p Value
0.19 0.80 0.26
o 0.0001
8 (6–10)
5 (4–7)
5 (10)
1 (2)
0.20
41 (85) 5 (10)
44 (92) 3 (6)
0.52
7 (15)
6 (13)
0.77
Abbreviations: IQR, interquartile range. Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia or extendedspectrum β-lactamase (ESBL)-producing bacterium.
a
Table 3 – Fasting duration, length of hospital stay, and nutritional outcomes of the study groups. Control group n ¼ 48
PCT group n ¼48
p Value
Fasting duration, median (IQR) [day] Length of hospital stay, median (IQR) [day]
6 (3–10) 30 (17–39)
5 (2.75–8) 28 (19–43)
0.77 0.45
Nutrition-related outcome Oral intake, n (%) Parenteral nutrition, n (PPN/TPN) Tube feeding, n NG/PEG
24 (50) 15 (11/ 3) 9 (4/5)
27 (56) 9 (6/3) 12 (5/7)
0.54
Abbreviations: IQR, interquartile range; PPN, peripheral parenteral nutrition; TPN, total parenteral nutrition; NG, nasogastric tube feeding; PEG, percutaneous endoscopic gastrostomy.
group, fasting was stopped (median, 6 days) before the discontinuation of antibiotic therapy (median, 8 days). The present study showed that a shortened duration of antibiotic therapy by 3 days did not influence whether patients could continue their oral nutritional intake. In our hospital, a restart of oral intake is generally determined by using a modified water-swallowing test (MWST) [11], based on an improvement in respiratory failure or a decrease in the amount of sputum. If patients are thought to be unable to eat orally according to the MWST result, a final diagnosis of dysphagia is made by a videofluoroscopic or videoendoscopic examination of their swallowing. In this study, only 53% patients with aspiration pneumonia were able to continue oral intake after antibiotic therapy. This may suggest that the development of aspiration pneumonia requiring hospitalization might itself be a poor prognostic factor for oral nutritional intake. Although the logistic regression analysis showed an association between a fasting duration of o7 days and the continuation of oral intake, patients with an adequate oral intake obviously did not need prolonged fasting. A prospective study is necessary to examine whether a shortened fasting duration and an intentional early restart of oral intake increase the number of patients with continuous oral intake.
In addition to oral intake, a relapse of aspiration pneumonia was also associated with the BMI upon admission. This result implies that patients with a low BMI who have inadequate oral intake frequently have a risk of relapse for aspiration pneumonia. As defined by the BMI, obesity and being overweight are associated with serious morbidity; however, the obesity paradox, which suggests that high BMI patients have a lower mortality than normal BMI patients, has recently been reported in several studies [12–14]. Our results are consistent with Park's report that underweight nursing home residents are at risk for developing dysphagia [15]. In this study, only 2 patients were obese (BMI425), and the mean BMI for all patients was very low (17.4 kg/m2). Therefore, whether the obesity paradox plays a role in aspiration pneumonia or dysphagia remains unclear and warrants further examination. Our analysis showed an association between male gender and an in-hospital death. The higher laryngeal elevation found in males, as compared to that of females, is considered to be one of the risk factors for the development of dysphagia [15]. Pneumonia is also the leading cause of death among elderly men in Japan. As a result of these facts, it could be predicted that hospitalization for aspiration pneumonia in elderly men with dysphagia would lead to a high in-hospital mortality rate. Furthermore, a low serum albumin level (r3.0 g/dL), indicating
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Table 4 – Multivariate analysis of oral intake, relapse of pneumonia, and in-hospital deaths. Variable
Referent
Odds ratio
95% CI
p Value
Continuance of oral intakea BMI A-DROP Confusion Fasting duration
Z3 Yes Z7
1.311 0.486 0.430 0.334
1.099–1.564 0.154–1.529 0.137–1.352 0.117–0.954
0.0026 0.2173 0.1487 0.0406
Yes Z7
1.035 0.702 0.364 2.801
0.929–1.152 0.500–0.985 0.120–1.105 0.936–8.377
0.5368 0.0405 0.0745 0.0654
5.161 4.691 7.258 1.728 1.018 1.138
1.089–24.467 0.756–29.083 1.679–31.383 0.352–8.488 0.978–1.060 0.947–1.366
0.0387 0.0968 0.0080 0.5007 0.3830 0.1677
Relapse of pneumonian Body weight BMI Hypertension Fasting duration In-hospital deathn Male A-DROP Albumin, g/dl CRP, mg/dl BUN, mg/dl Duration of antibiotic use
Z3 r3.0 Z20
Abbreviations: CI, confidence interval; BMI, body mass index; A-DROP, severity scoring system of community-acquired pneumonia (age, dehydration, respiration, orientation, pressure); CRP, C-reactive protein. a Significant variables (po0.001, on univariate analysis) were assessed. n Significant variables (po0.05, on univariate analysis) were assessed.
malnutrition, and a low BMI were also associated with inhospital death. Viasus found that the serum albumin level upon admission was a good prognostic marker for communityacquired pneumonia [16]. Hypoalbuminemia and pneumonia were positively associated with mortality in patients with advanced dementia [17]. Therefore, we consider the prognosis of patients with aspiration pneumonia to be entirely dependent on the nutritional status upon admission. Our study had several limitations. First, this study was a single institution trial with a small number of patients. The sample size was determined upon the basis of a hypothesis that the efficacy within the PCT group was 45%. We might have underestimated the real effect of PCT-guided antibiotic therapy. Second, we did not exclude in-hospital deaths by cause of death, except for aspiration pneumonia. Our patients with aspiration pneumonia had many complications, and it can often be difficult to distinguish a death from natural causes (for example, senility) from that due to pneumonia. Third, the PCT levels could not be obtained real time, so we used a protocol adopted as a treatment for outpatients in a reported trial [5]. The duration of antibiotic exposure might have been even shorter in the PCT group, if the PCT levels had been measured at the central laboratory in our hospital and were available within hours. Although the patients were treated with antibiotics for a period of at least 3 days in the present study, further validation is required to determine the safety of patients if antibiotic therapy is not administered. Fourth, the analysis of the prognostic factors associated with oral intake was retrospective. A prospectively planned decrease in the fasting duration might lead to different results. In conclusion, PCT-guided antibiotic therapy for patients with aspiration pneumonia has the same safety and efficacy as that of a treatment based on the standard guideline. Although PCT-guided therapy decreased unnecessary antibiotic exposure, it did not lead to an increase in the
continuation of oral intake. The oral intake and prognosis of patients with aspiration pneumonia might be more closely related to the nutritional status upon admission than that of the therapeutic process.
Conflict of interest The authors have no conflicts of interest.
r e f e r e n c e s
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