University of Groningen
Community-acquired pneumonia requiring hospitalization
Postma, Douwe F.; van Werkhoven, Cornelis H.; Oosterheert, Jan Jelrik
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Current Opinion in Pulmonary Medicine
DOI:
10.1097/MCP.0000000000000371
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Postma, D. F., van Werkhoven, C. H., & Oosterheert, J. J. (2017). Community-acquired pneumonia requiring hospitalization: rational decision making and interpretation of guidelines. Current Opinion in Pulmonary Medicine, 23(3), 204-210. https://doi.org/10.1097/MCP.0000000000000371
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C
URRENTO
PINIONCommunity-acquired pneumonia requiring
hospitalization: rational decision making and
interpretation of guidelines
Douwe F. Postma
a, Cornelis H. van Werkhoven
b, and Jan Jelrik Oosterheert
aPurpose of review
This review focuses on the evidence base for guideline recommendations on the diagnosis, the optimal choice, timing and duration of empirical antibiotic therapy, and the use of microbiological tests for patients hospitalized with community-acquired pneumonia (CAP): issues for which guidelines are frequently used as a quick reference. Furthermore, we will discuss possibilities for future research in these topics.
Recent findings
Many national and international guideline recommendations, even on critical elements of CAP management, are based on low-to-moderate quality evidence.
Summary
The diagnosis and management of CAP has hardly changed for decades. The recommendation to cover atypical pathogens in all hospitalized CAP patients is based on observational studies only and is challenged by two recent trials. The following years, improved diagnostic testing, radiologically by low-dose Computed Tomography or ultrasound and/or microbiologically by point-of-care multiplex PCR, has the potential to largely influence the choice and start of antibiotic therapy in hospitalized CAP patients. Rapid microbiological testing will hopefully improve antibiotic de-escalation or early pathogen-directed therapy, both potent ways of reducing broad-spectrum antibiotic use. Current guideline recommendations on the timing and duration of antibiotic therapy are based on limited evidence, but will be hard to improve.
Keywords
antibiotic de-escalation, community-acquired pneumonia, empirical antibiotic therapy, microbiological testing
INTRODUCTION
Community-acquired pneumonia (CAP) is one of the most common infectious diseases requiring hos-pitalization worldwide [1,2]. The mainstay of treat-ment relies on antibiotic therapy and supportive care, with the latter ranging from oxygen therapy to vasoactive medication and/or mechanical venti-lation. The appropriate use of antibiotic therapy is dependent upon an adequate clinical and micro-biological diagnosis of CAP. Different aspects of the management of CAP are addressed in national and international guidelines.
This review focuses on the diagnosis, the choice, optimal timing and duration of antibiotic therapy, and rational use of microbiological tests in the management of hospitalized CAP: issues for which guidelines are frequently used as a quick reference.
DIAGNOSIS OF COMMUNITY-ACQUIRED
PNEUMONIA
Essentially, CAP must be considered a clinical nosis. This is reflected in the lack of specific diag-nostic criteria in international guidelines on CAP [3–7]. Patients with CAP classically present with a (productive) cough, fever and dyspnea; they appear ill and focal crepitations or rales can be heard by
a
Department of Internal Medicine and Infectious Diseases andbJulius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, GA Utrecht, The Netherlands
Correspondence to Douwe F. Postma, Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Room F.02.126, PO Box 85500/3508 GA Utrecht, The Netherlands. Tel: +31 887555555; e-mail: d.f.postma@umcutrecht.nl
Curr Opin Pulm Med2017, 23:204–210
chest auscultation. However, there is no specific set of clinical signs, symptoms or tests which includes or excludes a diagnosis of pneumonia [8]. In clinical settings, a chest radiograph is often performed to confirm a diagnosis of CAP. The sensitivity of a chest radiograph is estimated to be 60–70% in cohorts of patients with a clinical diagnosis of CAP [9,10]. According to Infectious Diseases Society of America (IDSA) guidelines, in patients who are hospitalized for suspected CAP, but without obvious infiltrates on chest radiograph, it may be reasonable to start treatment with antibiotics. Chest imaging is there-fore considered to be at best supportive for the diagnosis of CAP or advised to be used to differen-tiate CAP from other diseases [3,4]. Recent studies have shown that low-dose Computed Tomography (CT) (with equivalent radiation exposure as com-pared with traditional X-ray) and chest ultrasound are promising alternatives for chest radiographs in CAP. Low-dose CT can alter the diagnosis of 58.6% (95% confidence interval, 53.2–64.0%) of CAP patients, either ruling CAP in or out in X-ray ‘positive’ or ‘negative’ patients. This led to the optimization of patient management in 25% of patients [11]. Chest ultrasound showed a high sen-sitivity and specificity to recognize CAP, and had excellent correlation with CT results [12&
,13–16]. Even though both methods need further validation in real-world clinical settings, their results are prom-ising. Potentially, imaging results could be used to guide or withhold antibiotic treatment in patients with obvious other causes than bacterial CAP.
These results directly influence the discussion on which CAP patients should be included in studies
of CAP. So far, studies have used several definitions for CAP, and often a chest infiltrate on X-ray is regarded as a mandatory sign in CAP research, and thus X-ray negative CAP patients are hardly ever studied. Because of the fact that X-ray ‘negative’ CAP seems very similar to X-ray ‘positive’ CAP [10], and the aforementioned sensitivity of chest X-rays, we argue that, until we are able to improve our diagnostic protocols for CAP, it is important that clinical studies include all patients who are diag-nosed and treated as CAP. This will reflect the whole range of CAP patients and guarantee generalizability of study results to daily clinical practice.
When CAP cannot be ignored in your differen-tial diagnosis, it seems reasonable to treat CAP. In the near future, more sensitive diagnostic tests such as low-dose CT and chest ultrasound will have to prove their additive value in clinical trials, by reduc-ing inappropriate antibiotic treatment and/or by improving patient outcome.
CHOICE OF EMPIRICAL ANTIBIOTIC
THERAPY
As the microbiological cause of CAP cannot be pre-dicted reliably on clinical symptoms, international guidelines recommend basing initial treatment choices on the severity of disease presentation [3,6,17]. When patients are admitted to an ICU ward, guidelines uniformly advise to use either combi-nation therapy of a b-lactam and a macrolide or ciprofloxacin, or monotherapy with moxifloxacin or levofloxacin. There is only observational evidence underlying this recommendation to include em-pirical coverage of pneumococci as well as atypical pathogens; however, the consensus is that the risk of inappropriate empirical treatment cannot be ac-cepted in patients with a severe disease presentation. For patients admitted to non-ICU wards, there is even less supporting evidence for such a strategy. Hypothetically, improved results with b-lactam/mac-rolide combination and fluoroquinolone mono-therapy might result from coverage of atypical pathogens, synergy between b-lactams and macro-lides, and anti-inflammatory effects if macrolides are used [18,19]. Yet, both of these antibiotic classes have also been associated with increased resistance devel-opment, whereas the narrower spectrum of b-lactam antibiotics has less of an impact in this respect [20,21]. Moreover, guideline recommendations for combination treatment with macrolides are based on observational studies, which are inherently biased by confounding by indication [22]. Fluoroquinolones have been compared in randomized trials, but these have not demonstrated superiority as compared with b-lactams with or without macrolides, except for
KEY POINTS
Improvements in diagnostic imaging in CAP may lead
to more prudent selection of which patients to treat with antibiotics.
Routine atypical coverage in patients with CAP
admitted to non-ICU wards does not seem necessary.
Optimal diagnostic strategies might also lead to earlier
therapy in CAP patients, although shorter times to the first antibiotic dose are not unequivocally associated with improved outcomes.
There is no evident added value of procalcitonin for
shortening the duration of antibiotic treatment in CAP patients.
Novel molecular methods for microbiological testing
might further improve the possibility for targeted treatment, discontinuation of antibiotics or further antibiotic de-escalation.
patients with proven Legionnaires disease for whom fluoroquinolones are superior [23]. These trials were also affected by strict eligibility criteria and possible prerandomization antibiotic use, which hampers the generalization of their results to routine clinical prac-tice.
As a result, until recently, the relative effective-ness of empirical treatment of CAP with b-lactam monotherapy, combination therapy with a b-lactam and macrolide or fluoroquinolone monotherapy was unknown. This was addressed in two separate randomized trials in Europe [24,25].
The first one was an open-label individually randomized controlled trial, comparing with cef-triaxone with azithromycin, including 580 patients with radiologically confirmed CAP in six Swiss hos-pitals. The study failed to demonstrate noninferior-ity of b-lactam monotherapy for clinical stabilnoninferior-ity on day 7 of admission, and did not show the superiority of combination therapy either. There was no differ-ence in all-cause mortality between the treatment groups.
The second study was a cluster randomized cross-over study of 2283 patients hospitalized to non-ICU wards with a clinical diagnosis of CAP. The study demonstrated noninferiority of a strategy of b-lactam monotherapy to combination therapy with a macro-lide or fluoroquinolone monotherapy in terms of 90-day all-cause mortality. In addition, no differences were found for 30-day all-cause mortality, length of stay, length of intravenous treatment, occurrence of complications and in a sensitivity analysis of radio-logically proven CAP [25].
Although the studies might seem contradictory at first glance, both study results could also be seen as random differences around a null-effect. Further-more, the Swiss Randomised Controlled Trial (RCT) was rather rigorous in its antibiotic protocol adher-ence, only allowing switching of therapy by strict criteria, which is not representative of clinical prac-tice and could have only negatively affected the b-lactam monotherapy arm.
Lack of generalization of these results to regions with different causes might be the most important study limitations, although the incidence of atypical pathogens is probably not that much different in European hospitals [26,27]. Yet, these atypical pathogens, if present, apparently did not affect the outcome after starting empirical treatment with b-lactams only, as also suggested by two meta-analyses of this topic in which outcome was only affected in Legionella-related pneumonia [23,28]. Obviously, only future randomized comparisons of b-lactam monotherapy versus atypical coverage in other regions can further elucidate this question [29&
]. To our knowledge, there are no randomised
trials comparing narrow-spectrum with broad-spec-trum b-lactam monotherapy in hospitalized CAP patients.
Summarizing, the current evidence base does not warrant routine atypical coverage in patients with CAP admitted to non-ICU wards.
TIMING OF EMPIRICAL ANTIBIOTIC
THERAPY
International guidelines advise to administer anti-biotics when the diagnosis of CAP has been com-pleted and to start therapy in the emergency room to save time from delay in transfer to the ward. This ‘time to first antibiotic dose’ (TFAD) has received a lot of attention, since many government quality control services have been evaluating antibiotic administration time in the last decade. In many countries, including the Netherlands, the timing of starting antibiotics in CAP patients was part of a set of quality control parameters. Initially, policies supporting short TFADs were based on a number of observational studies that demonstrated a beneficial effect of early antibiotic therapy in CAP [30–33]. Many of these studies were from large administra-tive databases, in which small effects were found; only significant because of the large numbers of patients. A number of studies that adjusted more elaborately for confounders were not able to confirm positive results [34–36]. In addition, an interesting before-after study from San Francisco questioned the quality of care delivered by targeting a short TAFD, evaluating groups of CAP patients before and after their target TFAD was set to less than 4 h. The reduction in required TFAD from less than 8 to less than 4 h led to less diagnostic accuracy of the emergency room’s physician’s admitting diagnosis [37]. These studies led to the current con-sensus of administering antibiotics in the emer-gency room as soon as a diagnosis of CAP has been made. Naturally, this advice precludes pneu-monia patients fulfilling (new) sepsis criteria for which therapy should be started according to the international ‘Surviving Sepsis Campaign’ [38,39&
]. It will probably be hard to improve the TFAD for patients with an established diagnosis of CAP. Recent work demonstrated that older patients with multiple comorbidities in septic shock from pneu-monia had a delay in their receipt of antibiotics, although community-acquired infection led to a shorter time to antibiotic therapy [40&
]. Another trial showed that early goal-directed therapy in sep-tic patients did not improve mortality in ICUs in New Zealand and Australia [41].
In conclusion, improving diagnostic tools (radio-logically and microbio(radio-logically) and optimizing the
diagnostic process are more likely to improve (the timing) of antibiotic therapy than a vigorously short TFAD by itself.
DURATION OF ANTIBIOTIC THERAPY
There is limited evidence on the optimal duration of antibiotic therapy in CAP patients. This is also com-plicated by the available antimicrobial drugs for which, at least in theory, different durations of treatment could be optimal depending on for example microbial cause or pharmacokinetics. Generally, international guidelines advise to treat CAP of undocumented microbial cause for 5 days. This is based on two RCTs which demonstrated that treatment with 5 or 7 days (with a fluoroquinolone or with a macrolide) had comparable clinical effi-cacies [42,43]. In another study of CAP patients who had significantly improved after 3 days of treat-ment, outcome was comparable for those who were randomized to discontinuation of antibiotic therapy after day 3 and those who continued for 5 more days [44]. Recently, this result was confirmed in a randomized trial from Spain in which clinically stable patients were randomized after 5 days of antibiotic therapy to stop treatment or leave anti-biotics at the discretion of the treating physician. Stopping treatment after 5 days led to equiva-lent outcomes and a large reduction antibiotic exposure [45&].
Furthermore, patients can safely switch from intravenous to oral antibiotics as soon as clinical improvement occurs (e.g. decrease in fever and respiratory rate and hemodynamic stability). Procal-citonin (PCT) measurement seemed promising to further reduce antibiotic use, yet in four clinical studies of PCT measurement in CAP, the mean duration of therapy was only reduced to 5–6 days [46–49]. This reduction could already be safely achieved without PCT measurements in the afore-mentioned trials, based on the assessment of clinical stability. A recent study of presumed bacterial infec-tions in ICU patients demonstrated a similar reduction in duration of therapy [50&
]. These results do not yet warrant routine use of PCT-guided treat-ment for patients with CAP. Whether the duration of antibiotic treatment of CAP can be further reduced remains to be determined.
MICROBIOLOGY-BASED ANTIBIOTIC
DE-ESCALATION
When empirical antibiotic treatment with broad-spectrum antibiotics is started, microbiological tests should be used to enable de-escalation to narrow-spectrum antibiotics. The general consensus is that
pathogen-directed treatment is preferred, as shorter exposure to broad-spectrum antibiotics will reduce the risk of Clostridium difficile infection and lead to less antibiotic selective pressure, and hence less antibiotic-resistance development. However, there is a lack of strong epidemiological data to support or reject a microbiology-based de-escalation approach. Although observational studies suggest that de-esca-lation is associated with better outcome [51&
,52], these studies failed to adequately adjust for clinical improvement prior to de-escalation [53&
]. Therefore, guideline recommendations are mainly based on expert opinions and antibiotic susceptibility data.
Theoretically, microbiology-based de-escalation could be established in either of two ways: detection of the causative agent allowing for pathogen-directed treatment or exclusion of certain (mainly atypical) pathogens that allows narrowing of the antibiotic spectrum. The latter is challenging because multiple pathogens may have to be excluded, some tests have a limited sensitivity and the consequences of nontreatment of these patho-gens are uncertain. Therefore, most guidelines do not make explicit recommendations regarding de-escalation based on negative test results.
All guidelines recommend collecting blood cul-tures before initiation of antibiotic treatment because antibiotics rapidly decrease the sensitivity of blood cultures. However, although most Euro-pean guidelines recommend collection of blood cultures in all hospitalized CAP patients [4,7], the US guideline only recommends blood cultures for patients ‘whenever the result is likely to change individual antibiotic management’ or ‘in whom the diagnostic yield is thought to be greatest’ and provides a list of clinical criteria for microbiological testing [3]. This represents a different weighting of the individual and population benefits of collecting blood cultures against the costs. Pathogen-directed treatment based on blood cultures is recommended in all guidelines. However, blood cultures are positive in only 6–16% of the cases (excluding contamination) and results are delayed by 24– 48 h, reducing the overall utility of the test [54–58]. The pathogen most frequently detected in blood cultures is Streptococcus pneumoniae, accounting for over 50% of pathogens identified in blood cultures. This would enable de-escalation to penicillin mono-therapy, as recommended by the guidelines. How-ever, this opportunity is often not taken in clinical practice [59]. The American Thoracic Society/IDSA guideline states that ‘the possibility of polymicro-bial CAP and the potential benefit of combination therapy for bacteremic pneumococcal pneumonia have complicated the decision to narrow antibiotic therapy.’ Multiple pathogens are indeed found in a
low proportion of CAP patients. However, the clinical relevance of the copathogens is not well understood. The superiority of combination therapy compared with monotherapy in patients with pneu-mococcal bacteraemia is based on observational studies only. Moreover, to our knowledge, there is no epidemiological evidence that penicillin is inferior to broader spectrum antibiotics in patients with polymicrobial CAP.
The pneumococcal urinary antigen test decreases the time to results and increases the yield substan-tially compared with blood cultures. However, con-cerns are that in patients with chronic pulmonary disease, due to colonization with S. pneumoniae, the test may be false-positive [60]. Several observational studies show that, in clinical practice, de-escalation based on the pneumococcal urinary antigen test is performed in only a small proportion of the patients [61,62&
,63]. Unfortunately, there are no well-designed studies investigating the impact of Pneumo-coccal Urinary Antigen Test (PUAT)-based de-escala-tion on clinical outcome. Hopefully, an antibiotic stewardship trial, currently performed in the Nether-lands, in which PUAT-based de-escalation is one of the stewardship interventions, will shed more light on this question (ClinicalTrials.gov NCT02604628). Novel molecular methods, such as multiplex PCR of respiratory samples, enable rapid identifi-cation of bacteria and viruses (e.g. [64&
]). PCR may allow early targeted treatment for bacterial patho-gens or rapid discontinuation of antibiotics if a viral pathogen without bacterial copathogens is ident-ified and the patient is clinically stable. This would reduce antibiotic selective pressure and other anti-biotic-induced adverse effects and might improve patient outcome by more pathogen-directed treat-ment. Although promising, at present, the impact of PCR testing on antibiotic consumption and patient outcome has not been established. An important determinant for the utility of diagnostic tests is the rapid availability of the result. As previous studies were hampered by diagnostic delays, this might have resulted in their failure to change antibiotic treatment [65]. Recently, easy-to-use devices for point-of-care multiplex PCR testing have become available, with results being available in approxi-mately 1 h [66]. The benefits and safety of point-of-care PCR testing in CAP patients should be tested in well-designed pragmatic trials.
CONCLUSION
Although CAP is one of the most common and oldest adversaries in infectious diseases, it is also one of the most heterogeneous. This might explain why there is only low-to-moderate quality evidence
for most of the aspects that we have discussed in this review. Prudent selection of empirical therapy and proactive antibiotic de-escalation will be important to reduce broad-spectrum antibiotic use. In the end, the optimal treatment of CAP is a balance between the safety of the individual patient and a reduction of antibiotic selection pressure and eventually anti-biotic resistance. Improved diagnostic testing, radiologically by low-dose CT or ultrasound or microbiologically by improved rapid testing with antigen tests or multiplex PCR, will aid the choice, start and streamlining of antibiotic therapy.
Acknowledgements None.
Financial support and sponsorship
C.H.v.W. has received a research grant from The Nether-lands Organization for Health Research and Develop-ment (ZonMw).
Conflicts of interest
D.F.P. and J.J.O. have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
& of special interest && of outstanding interest
1. Welte T, Torres A, Nathwani D. Clinical and economic burden of
community-acquired pneumonia among adults in Europe. Thorax 2012; 67:71– 79.
2. Fry AM, Shay DK, Holman RC, et al. Trends in hospitalizations for pneumonia
among persons aged 65 years or older in the United States. JAMA 2005; 294:2712–2719.
3. Mandell La, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of
America/American Thoracic Society consensus guidelines on the manage-ment of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(Suppl 2):S27–S72.
4. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management
of community acquired pneumonia in adults: update 2009. Thorax 2009; 64:iii1–iii55.
5. Spindler C, Stra˚lin K, Eriksson L, et al. Swedish guidelines on the
manage-ment of community-acquired pneumonia in immunocompetent adults: Swedish Society of Infectious Diseases. Scand J Infect Dis 2012; 44: 885–902.
6. Wiersinga WJ, Bonten MJ, Boersma WG, et al. SWAB/NVALT (Dutch
Working Party on Antibiotic Policy and Dutch Association of Chest Physi-cians) guidelines on the management of community-acquired pneumonia in adults. Neth J Med 2012; 70:90–101.
7. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult
lower respiratory tract infections: full version. Clin Microbiol Infect 2011; 17: E1–E59.
8. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired
pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278:1440 –1445.
9. Syrja¨la¨ H, Broas M, Suramo I, et al. High-resolution computed tomography for
the diagnosis of community-acquired pneumonia. Clin Infect Dis 1998; 27: 358–363.
10. Hagaman JT, Rouan GW, Shipley RT, Panos RJ. Admission chest radiograph
lacks sensitivity in the diagnosis of community-acquired pneumonia. Am J Med Sci 2009; 337:236–240.
11. Claessens Y-E, Debray M-P, Tubach F, et al. Early chest computed
tomo-graphy scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med 2015; 192: 974–982.
12.
&
Bourcier J-E, Braga S, Garnier D. Lung ultrasound will soon replace chest radiography in the diagnosis of acute community-acquired pneumonia. Curr Infect Dis Rep 2016; 18:43.
Narrative review discussing current state of evidence for using chest ultrasound as a diagnostic tool in patients with CAP.
13. Bourcier J-E, Paquet J, Seinger M, et al. Performance comparison of lung
ultrasound and chest x-ray for the diagnosis of pneumonia in the ED. Am J Emerg Med 2014; 32:115–118.
14. Reissig A, Copetti R, Mathis G, et al. Lung ultrasound in the diagnosis
and follow-up of community-acquired pneumonia. Chest 2012; 142: 965–972.
15. Nazerian P, Volpicelli G, Vanni S, et al. Accuracy of lung ultrasound for the
diagnosis of consolidations when compared to chest computed tomography. Am J Emerg Med 2015; 33:620–625.
16. Ye X, Xiao H, Chen B, Zhang S. Accuracy of lung ultrasonography versus
chest radiography for the diagnosis of adult community-acquired pneumonia: review of the literature and meta-analysis. PLoS One 2015; 10:e0130066.
17. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management
of community acquired pneumonia in adults: update. Thorax 2009; 64 (Suppl 3): iii1–i55.
18. Kovaleva A, Remmelts HHF, Rijkers GT, et al. Immunomodulatory effects of
macrolides during community-acquired pneumonia: a literature review. J Antimicrob Chemother 2012; 67:530–540.
19. File TM, Marrie TJ. Does empiric therapy for atypical pathogens improve
outcomes for patients with CAP? Infect Dis Clin North Am 2013; 27:99–114.
20. Fuller JD, Low DE. A review of Streptococcus pneumoniae infection treatment
failures associated with fluoroquinolone resistance. Clin Infect Dis 2005; 41:118–121.
21. Malhotra-Kumar S, Lammens C, Coenen S, et al. Effect of azithromycin and
clarithromycin therapy on pharyngeal carriage of macrolide-resistant strepto-cocci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 2007; 369:482–490.
22. Grobbee DE, Hoes AW. Confounding and indication for treatment in
evalua-tion of drug treatment for hypertension. Br Med J 1997; 315:1151–1154.
23. Eliakim-Raz N, Robenshtok E, Shefet D, et al. Empiric antibiotic coverage of
atypical pathogens for community-acquired pneumonia in hospitalized adults. Cochrane database Syst Rev 2012; 9:CD004418.
24. Garin N, Genne´ D, Carballo S, et al. b-Lactam monotherapy vs
b-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med 2014; 174: 1894–1901.
25. Postma DF, van Werkhoven CH, van Elden LJR, et al. Antibiotic treatment
strategies for community-acquired pneumonia in adults. N Engl J Med 2015; 372:1312–1323.
26. Van Gageldonk-Lafeber AB, Wever PC, van der Lubben IM, et al. The
aetiology of community-acquired pneumonia and implications for patient management. Neth J Med 2013; 71:418–425.
27. Postma D, Van Werkhoven C. New trends in the prevention and management
of community-acquired pneumonia. Netherlands J 2012; 70:337–348.
28. Mills GD, Oehley MR, Arrol B. Effectiveness of beta lactam antibiotics
compared with antibiotics active against atypical pathogens in nonsevere community acquired pneumonia: meta-analysis. BMJ 2005; 330:456. 29.
&
Van Werkhoven CH, Oosterheert JJ, Bonten MJM. Management of commu-nity-acquired pneumonia. JAMA 2016; 316:221.
Our interpretation of the current evidence base for antibiotic treatment in patient with CAP admitted to non-ICU wards.
30. Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and
outcomes in elderly patients with pneumonia. JAMA 1997; 278:2080–2084.
31. Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and
outcomes for medicare patients hospitalized with community-acquired pneu-monia. Arch Intern Med 2004; 164:637.
32. Battleman DS, Callahan M, Thaler HT. Rapid antibiotic delivery and
appro-priate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization. Arch Intern Med 2002; 162:682–688.
33. Benenson R, Magalski A, Cavanaugh S, Williams E. Effects of a pneumonia
clinical pathway on time to antibiotic treatment, length of stay, and mortality. Acad Emerg Med 1999; 6:1243–1248.
34. Bruns AHW, Oosterheert JJ, Hustinx WNM, et al. Time for first antibiotic dose
is not predictive for the early clinical failure of moderate–severe community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 2009; 28:913–919.
35. Marrie TJ, Wu L. Factors influencing in-hospital mortality in
community-acquired pneumonia: a prospective study of patients not initially admitted to the ICU. Chest 2005; 127:1260–1270.
36. Pines JM, Isserman JA, Hinfey PB. The measurement of time to first antibiotic
dose for pneumonia in the emergency department: a white paper and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med 2009; 37:335–340.
37. Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing
pneumonia. Arch Intern Med 2008; 168:351–356.
38. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
inter-national guidelines for management of severe sepsis and septic shock – 2008. Crit Care Med 2008; 36:296–327.
39.
&
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–810.
New sepsis definitions and their application. 40.
&
Amaral ACKB, Fowler RA, Pinto R, et al. Patient and organizational factors associated with delays in antimicrobial therapy for septic shock. Crit Care Med 2016; 44:2145–2153.
Explorative article looking into factors that are associated with delays in antibiotic therapy.
41. ARISE Investigators, ANZICS Clinical Trials Group. Peake SL, Delaney A,
Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496–1506.
42. File TM Jr, Mandell LA, Tillotson G, et al. Gemifloxacin once daily for 5 days
versus 7 days for the treatment of community-acquired pneumonia: a rando-mized, multicentre, double-blind study. J Antimicrob Chemother 2007; 60: 112–120.
43. Tellier G, Niederman MS, Nusrat R, et al. Clinical and bacteriological efficacy
and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Chemother 2004; 54:515–523.
44. El Moussaoui R, de Borgie C, van den Broek P, et al. Effectiveness of
discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. Br Med J 2006; 332:1355–1358.
45.
&
Uranga A, Espan˜a PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia. JAMA Intern Med 2016; 176:1257. Most recent study demonstrating that most patients with CAP can be safely treated for 5 days.
46. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of
procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363:600–607.
47. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic
therapy in community-acquired pneumonia. Am J Respir Crit Care Med 2006; 174:84–93.
48. Kristoffersen KB, Sogaard OS, Wejse C, et al. Antibiotic treatment
interrup-tion of suspected lower respiratory tract infecinterrup-tions based on a single pro-calcitonin measurement at hospital admission: a randomized trial. Clin Microbiol Infect 2009; 15:481–487.
49. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based
guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302: 1059–1066.
50.
&
De Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalci-tonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis 2016; 16:819–827.
Randomized study comparing procalcitonin versus usual care in an effort to reduce antibiotic exposure in ICU patients.
51.
&
Yamana H, Matsui H, Tagami T, et al. De-escalation versus continuation of empirical antimicrobial therapy in community-acquired pneumonia. J Infect 2016; 73:314–325.
Recent observational study on antibiotic de-escalation in CAP patients with or without a detected pathogen.
52. Carugati M, Franzetti F, Wiemken T, et al. De-escalation therapy among
bacteraemic patients with community-acquired pneumonia. Clin Microbiol Infect 2015; 21:936.e11–936.e18.
53.
&
Paul M, Dickstein Y, Raz-Pasteur A. Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis. Clin Micro-biol Infect 2016; 22:960–967.
Meta-analysis of studies on antibiotic de-escalation.
54. Corbo J, Friedman B, Bijur P, Gallagher EJ. Limited usefulness of initial blood
cultures in community acquired pneumonia. Emerg Med J 2004; 21:446– 448.
55. Marrie TJ, Durant H, Yates L, et al. Community-acquired pneumonia requiring
hospitalization: 5-year prospective study. Rev Infect Dis 1989; 11:586–599.
56. Falguera M, Trujillano J, Caro S, et al. A prediction rule for estimating the risk of
bacteremia in patients with community-acquired pneumonia. Clin Infect Dis 2009; 49:409–416.
57. Campbell SG, Marrie TJ, Anstey R, et al. The contribution of blood cultures to
the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study. Chest 2003; 123:1142–1150.
58. Van Werkhoven CH, Huijts SM, Postma DF, et al. Predictors of bacteraemia in
patients with suspected community-acquired pneumonia. PLoS One 2015; 10:e0143817.
59. Afshar N, Tabas J, Afshar K, Silbergleit R. Blood cultures for
community-acquired pneumonia: are they worthy of two quality measures? A systematic review. J Hosp Med 2009; 4:112–123.
60. Andreo F, Ruiz-Manzano J, Prat C, et al. Utility of pneumococcal urinary
antigen detection in diagnosing exacerbations in COPD patients. Respir Med 2010; 104:397–403.
61. Sorde R, Falco V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with com-munity-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med 2011; 171:166–172.
62.
&
Mothes A, Le´otard S, Nicolle I, et al. Community-acquired pneumonia and positive urinary antigen tests: factors associated with targeted antibiotic therapy. Med Mal Infect 2016; 46:365–371.
Observational study of CAP patients with positive urinarty antigen tests and the influence on switching to targeted therapy.
63. Blanc V, Mothes A, Smetz A, et al. Severe community-acquired pneumonia and
positive urinary antigen test for S. pneumoniae: amoxicillin is associated with a favourable outcome. Eur J Clin Microbiol Infect Dis 2015; 34:2455–2461.
64.
&
Gadsby NJ, Russell CD, McHugh MP, et al. Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia. Clin Infect Dis 2016; 62:817–823.
Recent observational study on the yield of novel molecur microbiological testing in patients with CAP.
65. Oosterheert JJ, van Loon AM, Schuurman R, et al. Impact of rapid detection of
viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection. Clin Infect Dis 2005; 41:1438–1444.
66. Andersson ME, Olofsson S, Lindh M. Comparison of the FilmArray assay and
in-house real-time PCR for detection of respiratory infection. Scand J Infect Dis 2014; 46:897–901.
