Procalcitoninandcap PDF
Procalcitoninandcap PDF
Procalcitoninandcap PDF
Community-acquired Pneumonia
A Randomized Trial
Mirjam Christ-Crain, Daiana Stolz, Roland Bingisser, Christian Mu
ller, David Miedinger, Peter R. Huber,
ller
Werner Zimmerli, Stephan Harbarth, Michael Tamm, and Beat Mu
Departments of Internal Medicine, Endocrinology, Pneumology, Emergency Medicine, and Clinical Chemistry, University Hospital, Basel;
Medical University Clinic, Kantonsspital, Liestal; and Division of Hospital Epidemiology, University Hospital, Geneva, Switzerland
Rationale: In patients with community-acquired pneumonia, guidelines recommend antibiotic treatment for 7 to 21 d. Procalcitonin
is elevated in bacterial infections, and its dynamics have prognostic
implications.
Objective: To assess procalcitonin guidance for the initiation and
duration of antibiotic therapy in community-acquired pneumonia.
Methods: In a randomized intervention trial, 302 consecutive patients with suspected community-acquired pneumonia were included. Data were assessed at baseline, after 4, 6, and 8 d, and
after 6 wk.
The control group (n 151) received antibiotics according to usual
practice. In the procalcitonin group (n 151), antibiotic treatment
was based on serum procalcitonin concentrations as follows:
strongly discouraged, less than 0.1 g/L; discouraged, less than
0.25 g/L; encouraged, greater than 0.25 g/L; strongly encouraged, greater than 0.5 g/L. The primary endpoint was antibiotic
use; secondary endpoints were measures of clinical, laboratory, and
radiographic outcome.
Results: At baseline, both groups were similar regarding clinical,
laboratory, and microbiology characteristics, and Pneumonia Severity Index. Procalcitonin guidance reduced total antibiotic exposure
(relative risk, 0.52; 95% confidence interval, 0.480.55; p 0.001),
antibiotic prescriptions on admission (85 vs. 99%; p 0.001), and
antibiotic treatment duration (median, 5 vs. 12 d; p 0.001) compared with patients treated according to guidelines. After adjustment for Pneumonia Severity Index, the hazard ratio of antibiotic
discontinuation was higher in the procalcitonin group than in the
control group (3.2; 95% confidence interval, 2.5 to 4.2). Outcome
was similar in both groups, with an overall success rate of 83%.
Conclusions: Procalcitonin guidance substantially reduces antibiotic
use in community-acquired pneumonia. These findings may have
important clinical and public health implications.
Keywords: antibiotic therapy; community-acquired pneumonia;
procalcitonin
(Received in original form December 17, 2005; accepted in final form April 4, 2006 )
Funding obtained from Brahms (Hennigsdorf, Germany), Pfizer (Schweiz AG),
and Mepha (Schweiz AG) was used for assay material and salaries of technical
personnel involved in laboratory work and for shipping and handling of data and
specimens and presentation of data at scientific meetings. Additional support,
which provided more than two-thirds of the total study costs, was granted by funds
from the Departments of Internal Medicine and Emergency Medicine, the Stiftung
Forschung Infektionskrankheiten (SFI), and, mainly, from the Departments of Endocrinology and Pulmonary Medicine, University Hospital Basel, Switzerland.
Correspondence and requests for reprints should be addressed to Mirjam
Christ-Crain, M.D., University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
E-mail: christmj@bluewin.ch
This article has an online supplement, which is accessible from this issues table
of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 174. pp 8493, 2006
Originally Published in Press as DOI: 10.1164/rccm.200512-1922OC on April 7, 2006
Internet address: www.atsjournals.org
Community-acquired pneumonia (CAP) is the major infectionrelated cause of death in developed countries (1, 2). Approximately 10 to 20% of hospitalized patients with CAP must be
admitted to the intensive care unit, where 20 to 50% of them
will ultimately die (3, 4).
CAP is characterized by recently acquired respiratory symptoms and by an inltrate on chest radiograph, signs that are
unspecic. In CAP, respiratory symptoms can be ambiguous,
and especially elderly patients may present without fever (5).
The differential diagnosis of clinically suspected CAP includes
infectious (bacterial and nonbacterial) and noninfectious causes.
In bacterial CAP, prompt initiation of antibiotic therapy is
pivotal, as a delay of more than 4 h can be associated with
increased mortality (6). The optimal duration of antibiotic therapy in CAP is unknown (7). Most likely, it varies from patient
to patient. Current guidelines recommend antibiotic courses of
7 to 21 d, depending on illness severity and type of pathogen
(2, 8, 9). However, adherence to guidelines is variable (10, 11)
and physicians tend to treat longer, especially in elderly patients
with comorbidities and patients with severe CAP (12, 13). Duration of antibiotic therapy can be guided by clinical signs such as
defervescence, decrease in sputum production and coughing, or
improvement of general condition. However, interpretation of
the clinical response lacks standardization and validation and is
prone to interobserver variability (14).
A novel approach to estimate the presence of an infection
and its treatment response is the use of biomarkers (15, 16).
Circulating levels of calcitonin precursors, including procalcitonin, are elevated in bacterial infections (17, 18). As a prototype
of a hormokine mediator, procalcitonin can follow either a
classical hormonal expression pathway or, alternatively, in the
presence of an infection, a cytokine-like expression pathway (18,
19). The ubiquitous release of procalcitonin during infections is
induced either directly by microbial toxins (e.g., endotoxin) and/
or indirectly by humoral factors (e.g., interleukin-1, tumor necrosis factor-, and interleukin-6) or the cell-mediated host response (19). This induction can be attenuated by cytokines
released during viral infections (e.g., interferon-) (16, 19). Importantly, procalcitonin is a pivotal mediator in systemic infections and immunoneutralization of hyperprocalcitoninemia improves survival in several animal models of sepsis (1823).
As a diagnostic marker, procalcitonin guidance markedly and
safely reduced antibiotic prescriptions in a mixed population
with lower respiratory tract infections, using a sensitive assay
(13). The dynamics of procalcitonin levels have prognostic implications, as persistently elevated levels are associated with adverse
outcome (24). Conversely, decreasing procalcitonin levels suggest
a favorable outcome, usually showing a log-linear drop-off and a
half-life of 20 to 24 h (18). In this randomized intervention trial,
we assessed the capability of procalcitonin guidance to shorten
antibiotic duration in patients with all severity levels of CAP
admitted to the emergency department. We hypothesized that
procalcitonin guidance could signicantly shorten antibiotic duration with a similar clinical and laboratory outcome (25, 26).
METHODS
Setting and Study Population
This is a randomized, controlled, open intervention trial involving patients with all severities of CAP admitted to the emergency department
(27). We compared antibiotic therapy in patients treated according to
usual practice (control group) with patients in whom antibiotic treatment was guided by serum procalcitonin levels (procalcitonin group).
The study was approved by the institutional review board and registered
in the Current Controlled Trials Database as Procalcitonin-guided Reduction of the Duration of Antibiotic Therapy in Community-acquired
Pneumonia (the ProCAP-Study; ISRCTN04176397). Written, informed
consent was obtained from all included patients or their legal representatives. All data were held and analyzed by the authors.
All patients with suspicion of CAP admitted from November 2003
through February 2005 to the University Hospital (Basel, Switzerland),
a 950-bed tertiary care hospital, were assessed for eligibility (Figure 1).
Included were adult patients (older than 18 yr of age) with CAP as
principal diagnosis on admission, dened by a new inltrate on chest
radiograph and the presence of one or several of the following acute
respiratory signs or symptoms: cough, sputum production, dyspnea, core
body temperature exceeding 38.0C, auscultatory ndings of abnormal
breath sounds and rales, and leukocyte count greater than 10 109 or
less than 4 109 cells L1 (2). Excluded were patients with cystic brosis
or active pulmonary tuberculosis, patients with hospital-acquired pneumonia, and severely immunocompromised patients.
Patients were examined on presentation to the emergency department by a resident supervised by a board-certied specialist in internal
85
Antibiotic Treatment
On admission, patients were randomly assigned to one of the two groups
by sealed, opaque envelopes. In the control group, antibiotic therapy
was chosen on the basis of usual practice guidelines (2, 8, 9). The
treating physician was unaware of serum procalcitonin levels (9, 30).
In the procalcitonin group, the antibiotic treatment was guided by
serum procalcitonin levels. Thereafter, the physician in charge was
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 174 2006
advised to classify the patients into four groups, according to the probability of bacterial infection. This classication and the cutoffs used were
derived by calculating multilevel likelihood ratios and validated in a
previous study (13). A procalcitonin level of less than 0.1 g/L suggested
the absence of bacterial infection and the initiation or continuation of
antibiotics was strongly discouraged. A procalcitonin level between 0.1
and 0.25 g/L indicated that bacterial infection was unlikely, and the
initiation or continuation of antibiotics was discouraged. A procalcitonin level from 0.25 to 0.5 g/L was considered to indicate a possible
bacterial infection and the initiation or continuation of antibiotic therapy was encouraged. A procalcitonin level greater than 0.5 g/L strongly
suggested the presence of bacterial infection and antibiotic treatment
and continuation was strongly encouraged. Reevaluation of the clinical
status and measurement of serum procalcitonin levels was recommended after 624 h in all patients from whom antibiotics were withheld. Procalcitonin levels were reassessed after 4, 6, and 8 d. Antibiotics
were discontinued on the basis of the procalcitonin cutoffs dened
above. In patients with very high procalcitonin values on admission (e.g.,
greater than 10 g/L), discontinuation of antibiotics was encouraged if
levels decreased to levels less than 10% of the initial value (e.g., 1 g /L,
instead of less than 0.25 g/L).
Outcome Measures
Age, yr
Male sex, no. (%)
Smoking status
Current smoker, no. (%)
Pack-years, current and ex-smokers
Antibiotic pretreatment, no. (%)
Coexisting illnesses, no. (%)
Coronary artery disease
Hypertensive heart disease
Congestive heart failure
Peripheral vascular disease
Cerebrovascular disease
Renal dysfunction
Liver disease
Diabetes mellitus
Chronic obstructive pulmonary disease
Neoplastic disease
History, no. (%)
Cough
Sputum
Dyspnea
Examination
Rales, no. (%)
Body temperature, C
Oxygen saturation, %
Respiratory rate, breaths/min
Heart rate, beats/min
Systolic blood pressure, mm Hg
Laboratory findings
Procalcitonin (g/L), median (IQ range)
C-reactive protein (mg/L),
median (IQR)
Leukocyte count ( 109/L)
Quality-of-Life score, points
Visual Analog Scale, %
Imaging, no. (%)
Pleural effusion
Multilobar pneumonia
PSI, points
PSI class, no. (%)
I, II, and III
IV
V
The primary endpoint was total antibiotic use (i.e., antibiotic prescription [percentage] and duration [patient days]). The incidence density
ratio of antibiotic exposure was calculated as total antibiotic exposure
time divided by total follow-up time, until Week 6 (expressed as relative
risk). Appropriateness of initial antibiotic therapy was dened as previously described (31). Secondary endpoints were measures of laboratory and clinical outcome.
Primary and secondary endpoints were recorded on Days 4, 6, and
8 and at follow-up after 6 wk, respectively. At the follow-up visit after
6 wk, the outcome was evaluated by clinical, laboratory, radiographic,
and microbiological criteria. Cure was dened as resolution of clinical,
laboratory, and radiographic signs of CAP. Improvement was dened
as reduction of clinical signs and symptoms, improvement of laboratory
ndings, and reduction of the number or intensity of radiographic signs
of CAP. Treatment success represented the sum of the rates for cure and
improvement. Treatment failure included death, recurrence, relapse, or
persistence of clinical, laboratory, and radiologic signs of CAP, and
patients lost to follow-up.
Statistical Analysis
Discrete variables are expressed as counts (percentage) and continuous
variables as means SD. Endpoints were predened and analyzed on
the basis of intention to treat. A study sample of 150 patients in each
group gave the study a power of 95% to detect a 30% reduction in
antibiotic exposure from 10 to 7 d per patient assuming a two-tailed
test, a 1% level of signicance, and a SD of 6 d in both groups. This
sample size gave the study a power of 74% to detect a 10% increase
in the combined treatment failure and complication rate (from 10 to
20%), using the procalcitonin algorithm with a one-sided value of
0.05. Comparability of the control group and the procalcitonin group
was analyzed by 2 test and nonparametric Mann-Whitney U test. The
time to discontinuation of antibiotic treatment was compared between
the two study groups by use of the log-rank test. Using Cox proportional
hazards regression analysis, we estimated the rate of antibiotic treatment discontinuation, after adjustment for the PSI class. We performed
crude cost and sensitivity analyses to estimate direct costs associated
with changes of repeated measurements of procalcitonin and antibiotic
therapy. Indirect costs (e.g., adverse events, emergence of antibiotic
resistance, and need for high-priced second-line antibiotics for future
treatment) were not considered. The economic analysis was conducted
in Swiss francs and then converted to U.S. dollars, using the average
actual currency conversion rate during the trial period.
RESULTS
Baseline Characteristics of Patients
70 17
93 (62)
34 (23)
42 27
27 (18)
39 (26)
38 20
34 (23)
49
42
7
11
8
36
12
32
44
25
48
36
9
9
8
45
19
29
32
23
(33)
(28)
(5)
(7)
(5)
(24)
(8)
(21)
(29)
(17)
(32)
(24)
(6)
(6)
(5)
(30)
(13)
(19)
(21)
(15)
134 (89)
108 (72)
118 (78)
136 (90)
113 (75)
111 (74)
137 (91)
38.4 1.1
92 5
24 7
96 20
130 26
134 (89)
38.4 1.1
91 6
23 7
97 19
130 24
0.57 (0.22.5)
0.44 (0.21.9)
111 (57204)
13.7 6.7
40 13
43 20
152 (72212)
13.4 6.6
39 13
39 21
17 (11)
24 (16)
99.7 36.1
20 (13)
29 (19)
99.2 34.5
54 (36)
68 (45)
29 (19)
66 (44)
62 (41)
23 (15)
The Visual Analog Scale ranged from 0 (feeling extremely ill) to 100 (feeling
completely healthy).
87
Microbiology
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Figure 3. Antibiotic duration. The duration of antibiotic courses in the procalcitonin group and in the
control group is given overall (top), in patients classified according to Pneumonia Severity Index risk class
(middle), and blood culture result (bottom). Squares
denote mean values, boxes the SEM, and whiskers
1.96 SEM. Results of the procalcitonin group are
shown in the solid boxes, and results of the control
group are in the hatched boxes.
89
Procalcitonin Group
(n 151)
Control Group
(n 151)
p Value
0.03 (0.020.08)
0.2 (0.10.3)
0.04 (0.020.07)
0.2 (0.10.5)
0.62
0.98
128 (85)
124 (97)
40 (31)
5.8 5.3
6.8 5.1
13.0 8.9
136 (126146)
29,428
100 (33186)
149 (99)
144 (97)
55 (37)
12.9 6.5
13.1 6.4
13.9 4.9
323 (309338)
59,535
190 (133337)
0.001
0.83
0.32
0.001
0.001
0.29
0.001
0.001
0.001
146 (97)
12.0 9.1
146 (97)
13.0 9.0
1.0
0.35
20
1
1
4
1
4
1
18
10
(13)
(1)
(1)
(3)
(1)
(3)
(1)
(12)
(56)
5 (211)
26 (1378)
10.4 3.8
10.2 3.7
36.8 0.4
37.2 0.6
96 3
17 2
77 12
76 13
129 14
132 19
10 10
79 18
149 (99)
127
108
19
24
(84)
(85)
(15)
(16)
21
0
0
4
3
7
1
20
10
(14)
(0)
(0)
(3)
(2)
(5)
(1)
(13)
(50)
4 (212)
47 (1796)
10.2 4.7
10.6 5.6
36.7 0.5
37.3 0.6
95 3
18 3
80 13
79 13
129 14
131 20
11 10
74 20
151 (100)
124
105
19
27
(82)
(85)
(15)
(18)
0.87
0.32
0.32
1.0
0.31
0.36
1.0
0.73
0.73
0.86
0.1
0.73
0.44
0.93
0.36
0.22
0.24
0.09
0.41
0.42
0.84
0.14
0.29
0.16
0.65
0.65
Definition of abbreviations: CI confidence interval; ICU intensive care unit; IQR interquartile range.
* Plus-minus values represent means SD. The conversion factor for procalcitonin is as follows: g/L 0.161 nmol/L.
if prescribed means that mean duration was calculated when only patients were considered in whom antibiotics were
prescribed on admission.
Values are given from Day 8 of hospital stay. All other follow-up measurements were done after 4 to 6 wk.
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TABLE 3. SENSITIVITY ANALYSES: EFFECT OF CHANGES IN TOTAL COSTS OF ANTIBIOTIC
THERAPY AND PROCALCITONIN*
Procalcitonin Group
(n 151)
Control Group
(n 151)
p Value
100 (33186)
200 (150200)
290 (212378)
190 (133337)
0
190 (133337)
0.001
NA
0.001
383 (241544)
432 (250630)
481 (250716)
379 (266673)
474 (332842)
569 (3991010)
0.14
0.007
0.001
212
192
173
154
190
190
190
190
(133337)
(133337)
(133337)
(133337)
0.83
0.14
0.007
0.001
190 (133337)
190 (133337)
190 (133337)
0.001
0.60
0.001
As in this trial
Costs for antibiotic therapy
Costs for procalcitonin measurement
Sum of costs for antibiotics and procalcitonin
Sum assuming higher antibiotic costs
2-fold
2.5-fold
3-fold
Sum assuming lower procalcitonin costs
$30 per measurement
$25 per measurement
$20 per measurement
$15 per measurement
Sum assuming less procalcitonin measurements
per patient
Three measurements
Two measurements
One measurement
(136292)
(121272)
(100252)
(78232)
250 (183338)
200 (133288)
150 (83238)
Considering 3.5 procalcitonin measurements per patient during the course of CAP and the prize of procalcitonin ($50 per
measurement) and antibiotic therapy currently reimbursed by health insurances in Switzerland, respectively.
DISCUSSION
This is the rst randomized trial investigating guidance of antibiotic treatment duration in CAP by a laboratory test. Procalcitonin stewardship markedly reduced antibiotic exposure in patients with CAP, mainly by individually reducing the duration of
antibiotic courses from a median of 12 to 5 d. In the procalcitonin
group antibiotic courses were markedly shorter as suggested by
current guidelines. Measures of clinical and laboratory outcome
were similar in both groups.
The use of procalcitonin improves the accuracy of the clinical
diagnosis of sepsis (16, 24). For this purpose it is more helpful
than CRP and other laboratory markers (17, 32). Circulating
procalcitonin levels correlate with the clinical course of a sys-
91
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References
1. Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor
WN, Fine MJ. Causes of death for patients with community-acquired
pneumonia: results from the Pneumonia Patient Outcomes Research
Team cohort study. Arch Intern Med 2002;162:10591064.
2. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA,
Campbell GD, Dean N, File T, Fine MJ, Gross PA, et al. Guidelines
for the management of adults with community-acquired pneumonia:
diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:17301754.
3. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA,
Kapoor WN. Prognosis and outcomes of patients with communityacquired pneumonia: a meta-analysis. JAMA 1996;275:134141.
4. Kaplan V, Angus DC, Grifn MF, Clermont G, Scott Watson R, LindeZwirble WT. Hospitalized community-acquired pneumonia in the elderly: age- and sex-related patterns of care and outcome in the United
States. Am J Respir Crit Care Med 2002;165:766772.
5. Janssens JP, Krause KH. Pneumonia in the very old. Lancet Infect Dis
2004;4:112124.
6. Meehan TP, Fine MJ, Krumholz HM, Scinto JD, Galusha DH, Mockalis
JT, Weber GF, Petrillo MK, Houck PM, Fine JM. Quality of care,
process, and outcomes in elderly patients with pneumonia. JAMA
1997;278:20802084.
7. File TM Jr, Mandell LA. What is optimal antimicrobial therapy for
bacteremic pneumococcal pneumonia? Clin Infect Dis 2003;36:396
398.
8. Mandell LA, Bartlett JG, Dowell SF, File TM Jr, Musher DM, Whitney C.
Update of practice guidelines for the management of communityacquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;
37:14051433.
9. File TM Jr. Clinical efcacy of newer agents in short-duration therapy for
community-acquired pneumonia. Clin Infect Dis 2004;39:S159S164.
10. Menendez R, Torres A, Zalacain R, Aspa J, Martin-Villasclaras JJ,
Borderias L, Benitez-Moya JM, Ruiz-Manzano J, de Castro FR,
Blanquer J, et al. Guidelines for the treatment of community-acquired
pneumonia: predictors of adherence and outcome. Am J Respir Crit
Care Med 2005;172:757762.
11. Aujesky D, Fine MJ. Does guideline adherence for empiric antibiotic
therapy reduce mortality in community-acquired pneumonia? Am J
Respir Crit Care Med 2005;172:655656.
12. Mandell LA, File TM Jr. Short-course treatment of community-acquired
pneumonia. Clin Infect Dis 2003;37:761763.
13. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR,
Tamm M, Muller B. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: clusterrandomised, single-blinded intervention trial. Lancet 2004;363:600
607.
14. Wipf JE, Lipsky BA, Hirschmann JV, Boyko EJ, Takasugi J, Peugeot RL,
Davis CL. Diagnosing pneumonia by physical examination: relevant or
relic? Arch Intern Med 1999;159:10821087.
15. Muller B. Procalcitonin and ventilator-associated pneumonia: yet another
breath of fresh air. Am J Respir Crit Care Med 2005;171:23.
16. Christ-Crain M, Muller B. Procalcitonin in bacterial infections: hype,
hope, more or less? Swiss Med Wkly 2005;135:451460.
17. Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR,
Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of
sepsis in a medical intensive care unit. Crit Care Med 2000;28:977983.
18. Becker KL, Nylen ES, White JC, Muller B, Snider RH Jr. Procalcitonin
and the calcitonin gene family of peptides in inammation, infection,
and sepsis: a journey from calcitonin back to its precursors [Clinical
Review 167]. J Clin Endocrinol Metab 2004;89:15121525.
93
47.
48.
49.
50.
51.
52.
53.