Managing CAP patients at risk of clinical failure

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Respiratory Medicine (2014) xx, 1e13

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/rmed

REVIEW

Managing CAP patients at risk of clinical failure Tobias Welte* Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany Received 28 February 2014; accepted 27 October 2014

KEYWORDS ‘At risk’ patient; Community-acquired pneumonia; Comorbidity; Therapeutic management; Biomarkers; Age

Summary Community-acquired pneumonia (CAP) is a curable disease. Both the European and American clinical practice guidelines provide algorithms how to manage patients with CAP. However, as populations worldwide are ageing and bacteria are becoming multidrug resistant, it is necessary to address the major factors that put patients at risk of poor outcome. These may include age, comorbidities, the settings where pneumonia was acquired or treated, the need for hospitalisation or ICU admission, likely causative pathogen (bacteria or virus) in a certain region and their local susceptibility pattern. One complicating fact is the lack of definite causative pathogen in approximately 50% of patients making it difficult to choose the most appropriate antibiotic treatment. When risk factors are present simultaneously in patients, fewer treatment options could be rather challenging for physicians. For example, the presence of comorbidities (renal, cardiac, hepatic) may exclude certain antibiotics due to potential adverse events. Assessing the severity of the disease and monitoring biomarkers, however, could help physicians to estimate patient prognosis once diagnosis is confirmed and treatment has been initiated. This review article addresses the most important risk factors of poor outcome in CAP patients. ª 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 The ‘at risk’ patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Tel.: þ49 511 532 3531; fax: þ49 511 532 3353. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.rmed.2014.10.018 0954-6111/ª 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/). Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

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T. Welte Severity assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Presence of comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Managing the at risk patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Community-acquired pneumonia (CAP) is one of the most common infectious diseases and a major cause of morbidity and mortality worldwide [1], and is the most common infectious cause of death in the developed world [2,3] with rates as high as 48% [2,4,5]. Although CAP can occur at any age, in the past few decades, the epidemiology of CAP has undergone a marked shift and patients are now presenting at an increasingly older age [6]. For this reason, the occurrence of CAP in developed countries is likely to increase in the coming years due to the ageing populations [2,7]. While 50e80% of adult CAP patients are treated on an ambulatory basis, hospitalisations are common, particularly among the elderly [8e10] with admissions being highest among patients over the age of 65 years [2,10,11]. The high rate of hospital admission, prolonged stay in hospital and long periods of inactivity associated with CAP lead to considerable socioeconomic burden [2,3]. In addition, comorbidities are common in CAP patients and increase the risk of mortality and hospitalisation [12]. However, hospitalisation rates have fallen in recent years following recent developments in the use of biomarkers and prognostic tools to predict disease severity

Table 1 Prevalence of pathogens isolated in communityacquired pneumonia by treatment setting.

S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae S. aureus Enterobacteriaceae P. aeruginosa Legionella spp. C. burnetii Respiratory viruses Unknown

Outpatients (%)

Hospitalised patients non-ICU (%)

ICU patients (%)

38 8 13 21 1.5 0 1 0 1 17 50

27 5 6 11 3 4 3 5 4 12 41

28 2 7 4 9 9 4 12 7 3 45

ICU, intensive care unit. Reproduced with permission from Welte et al. Thorax 2012 [5].

00 00 00 00 00 00 00 00 00 00

[12e16], advances in antibiotic therapy [17e19] and inclusion of criteria for hospitalisation in current guidelines for the management of CAP patients [20]. Identification of patients at risk of poor outcomes from CAP is important since it affects both treatment and clinical outcome. Outcome is also affected by inappropriate choice of empiric treatment, since it has been found to be an independent risk factor for early treatment failure or death [21,22]. This paper will review the factors influencing the degree of risk for poor outcome in patients with CAP and look at strategies designed to optimise therapeutic management of the condition.

The ‘at risk’ patient A number of variables are associated with increased risk of poor outcome, including the aetiology [6] and severity of the disease [23], the age of the patient [12], presence of comorbid illnesses [24], and the setting [6] in which patients are treated.

Aetiology Although identifying the causative pathogen in CAP can help guide selection of the most appropriate antibiotic therapy, a microbiological diagnosis cannot be made in around 50% of patients [25], possibly due in part to difficulties associated with collecting valid sputum samples in elderly patients [26]. Nevertheless, a wide range of pathogens have been found to cause CAP, with the most common being Streptococcus pneumoniae, Chlamydophila pneumoniae, Haemophilus influenzae, Legionella spp., Staphylococcus aureus and Enterobacteriaceae [5]; similar bacteriological patterns occur in younger and older patients [26]. Of these pathogens, S. pneumoniae is the most frequently isolated, both in outpatients and hospitalised patients, including those in the intensive care unit (ICU) [5,27] (Table 1). S. pneumoniae is also reported to be common in patients with severe sepsis [28] and has been found to trigger bacteraemia and sepsis in mouse lung infection models [29]. H. influenzae is the second most frequently isolated pathogen, being found in 5e14% of elderly CAP patients [5,26,30]. Although S. aureus is a relatively uncommon cause of CAP, outcomes for patients with S. aureus CAP are poor [31]. Furthermore, methicillinresistant S. aureus (MRSA) is becoming an increasingly

Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

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Managing high-risk CAP patients Table 2

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Clinical assessment of severity using the CRB-65, CURB-65 [60] and PSI [61] indices.

CRB-65

CURB-65

PSI

 Confusion  Respiratory rate 30/min  Blood pressure (SBP <90 mmHg or DBP <60 mmHg)  Age >65 yrs

 Confusion  Respiratory rate 30/min  Urea (>7 mmol/L)

Criteria included (score)  Age (years)a

 Pleural effusion (þ10 points)

 Nursing home residency (þ10 points)

 Oxygenation parameters (10e30 points/criteria)d

 Blood pressure (SBP <90 mmHg or DBP <60 mmHg)  Age >65 yrs

 Comorbidity (10e30 points/illness)b

 Laboratory abnormalities (10e20 points/abnormality)e

Points 0

1 or 2

‡3

Mortality: low (1.2%) Treatment options: suitable for treatment outside the hospital Mortality: intermediate (8.15%) Treatment options: consider hospital referral and assessment Mortality: high (31%) Treatment options: urgent hospital admission

 Vital sign abnormalities (10e20 points/abnormality)c Risk category I

Score e

Predicted mortality rate (%) 0.1

II

70 points

0.6

III

71e90 points

0.9

IV V

91e130 >130 points

9.3 27.0

CRB-65, Confusion, Respiratory rate, low Blood pressure, age >65 years; CURB-65, Confusion, Uraemia, Respiratory rate, low Blood pressure, age >65 years; DBP, diastolic blood pressure; PSI, Pneumonia Severity Index; SBP, systolic blood pressure. a Number of years converts to points (10 points for women). b Neoplastic disease (30 points), liver disease (20 points), congestive heart failure (10 points), cerebrovascular disease (10 points), renal disease (10 points). c Disorientation (20 points), respiratory rate 30/min (20 points), systolic blood pressure <90 mmHg (20 points), temperature <35  C or 40  C (15 points), pulse 125/min (10 points). d Partial pressure of arterial oxygen <60 mmHg (10 points). e Haematocrit <30% (10 points), arterial pH < 7.35 (30 points), blood urea nitrogen 30 ng/dL (20 points), sodium <130 mmol/L (20 points), glucose 250 mg/dL (10 points).

common cause of S. aureus infections and its detection is associated with a more severe clinical presentation of CAP [27,32]. Common features associated with MRSA isolation include patient history of MRSA, nursing home admission in the previous year, close contact with someone with a skin infection, multiple infiltrates or cavities on chest X-ray and comatose state, intubation, receipt of pressors or death in the emergency department [32]. Additional risk factors for CAP due to MRSA include previous MRSA infection or exposure to antibiotics [33,34], diabetes [33], illicit drug abuse [35,36] and presence of indwelling catheters [34,37]. Legionella spp. (predominantly L. pneumophila) are frequent causative atypical pathogens in CAP and occur equally in outpatients and hospitalised patients (w4% of cases in each), though frequencies reported in the literature vary considerably (0e25%), most likely due to differences in the patient populations studied and

microbiological techniques used for detection [5,38,39]. Legionella pneumonia differs significantly in ambulatory and hospitalised patients in both clinical characteristics and outcome, with ambulatory patients tending to be younger, with less comorbidity resulting in a milder course without fatalities [38]. Legionella CAP is also associated with high rates of discordant initial antibiotic treatment, particularly in hospitalised patients, underlying the need for urinary antigen testing to exclude Legionella before discontinuation of atypical coverage [38,40]. Mycoplasma pneumoniae or C. pneumoniae are important atypical pathogens causing CAP in regions such as China [41e43], or Japan [41,44], and occasionally these may lead to outbreaks in every 3e5 years in Europe and US [45]. Macrolide resistance of M. pneumoniae is of particular concern in areas with high prevalence such as China [46,47]. Since beta-lactam antibiotics are not suitable

Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

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4 agents against atypical pathogens, broad-spectrum fluoroquinolones may be chosen when the presence of atypical is confirmed. Pneumonia caused by M. pneumoniae and C. pneumoniae in most cases is of mild-to-moderate severity; a severe course of the disease is seldom and mortality is low [48,49]. Even with inadequate antibiotic treatment the disease is self-limiting. The incidence of CAP due to Enterobacteriaceae is generally reported to be below 10%, though associated mortality is high, and may reach 20% in confirmed cases and 22% in bacteraemia cases [50,51]. This high mortality rate is likely to be due to the fact that infections with Gramnegative bacteria (GNB) are often related to comorbid illness and are more likely to occur in more vulnerable, elderly patients [22,40]. Indeed, cardiac and cerebrovascular disease, age >65 years and nursing home residency have been shown to be independent risk factors for Enterobacteriaceae [51]. It should also be noted that uncommon pathogens such as GNB and MRSA may not be susceptible to first-line empirical antibiotic treatment [27], highlighting a need for careful evaluation of risk factors for multi-drug resistant (MDR) pathogens, particularly in nursing home residents (see below). Particular attention needs to be paid to patients who are at risk of potentially being infected by Enterobacteriaceae or other drug-resistant GNB since the prevalence of MDR pathogens is increasing in Europe52 and in other areas in the world.53 Enterobacteriaceae spp. are frequently isolated in urinary tract infections, particularly in elderly people who are residents of healthcare facilities, however, these pathogens may cause pneumonia in such population and first line antibiotic treatments will not be efficacious.27 Among these MDR Enterobacteriaceae species, the increasing prevalence of ESBL-producing Klebsiella pneumoniae and carbapenemase-producing K. pneumoniae (KPC-Kp) is particularly threatening. The mortality rate associated with such cases is extremely high.54,55 Patients must be screened in some countries including Greece, Italy, The Middle East countries and in Asia Pacific. Surveillance data in these regions on these particular resistant pathogens is urgently needed. Viruses cannot be excluded when aetiology is examined. Using novel PCR technology, viral disease (e.g. influenza, parainfluenza, respiratory syncytial virus [RSV] and human metapneumovirus) could be detected in a significant number of patients [56]. Mortality due to viral pneumonia may be similar to that associated with bacterial pneumonia [56,57]. Polymicrobial infections are often recognised in such cases [58]. The interaction between viruses and bacteria is a matter of debate. Viral infection may increase the pathogenicity of bacteria mainly via stimulating the invasion process [59]. The question whether antiviral therapy in addition to antibiotic treatment is efficient has not yet been answered.

Severity assessment Assessment of severity is critical in the management of patients with CAP, since it can affect both the selection of the most appropriate therapy and outcome. The importance of this evaluation has meant that research into tools for the assessment of severity in CAP patients has attracted

T. Welte considerable interest in recent years. Such tools can be used to predict mortality and help decide the best setting in which to provide patient care. A number of tools are currently available, though the most widely used are the CURB-65 index and Pneumonia Severity Index (PSI) score [60e62]. The PSI score includes a total of 20 parameters (3 demographic, 5 comorbid conditions, 5 physical examination findings and 7 laboratory/imaging variables) assessed at the time of clinical presentation and is designed to determine the most appropriate treatment setting for each patient [61]. Conversely the CURB-65 index comprises only 5 variables, with the modified Confusion, Respiratory rate, low Blood pressure, age >65 years (CRB-65) index including only 4, withdrawing the only laboratory criterion in CURB65 (blood urea) (Table 2) [60,61]. A number of studies have reported that the CURB-65 index and the modified CRB-65 are comparable to the PSI score with regard to prediction of mortality from pneumonia (CAP) in both inpatients and outpatients [12,60e65]. Consequently, the CRB-65 may be preferred in general practice for assessment of pneumonia severity due to its simplicity and lack of laboratory parameters [20]. According to current guidelines, the decision to hospitalise should be validated against at least one objective tool of mortality risk assessment (e.g. CURB-65, CRB-65 or PSI score) (Table 3) [20,62]. In particular, hospitalisation is generally warranted in patients with a CURB-65 score greater than 2 or PSI scores of IV or above, though subjective assessment of risk should also be carried out by a physician [20,62]. Patients are defined as having severe CAP if they require ICU admission, especially if they have septic shock, or acute respiratory failure requiring intubation and mechanical ventilation [20,62]. Biomarkers are an alternative means of assessing pneumonia severity or predicting mortality from CAP and a wide range are under investigation, including C-reactive protein (CRP) [66], procalcitonin (PCT) [15,16], blood urea nitrogen [67], midregional proatrial natriuretic peptide (MR-proANP) and midregional proadrenomedullin (MR-proADM) [68], white blood cell count (WBC) [68] and copeptin [69]. Kru ¨ger and colleagues have compared the utility of a number of these new biomarkers (MR-proANP, MR-proADM, copeptin, WBC and PCT) with the CRB-65 index for the prediction of short- and long-term mortality in patients with CAP [68]. While each of these biomarkers was found to be good predictors of all-cause mortality from CAP and at least comparable to the CRB-65 index, MR-proADM was the strongest predictor. This suggests that the combination of MR-proADM with CRB-65 may be better a predictor of mortality from CAP than use of severity scores alone [68]. In another study, PCT levels on admission were shown to predict the severity and outcome of CAP with a similar prognostic accuracy to the CRB-65 score [70]. Other biomarkers which may have potential for prediction of mortality in CAP include proadrenomedullin, cortisol and blood glucose level [14,68,71,72].

Age CAP is predominantly a disease of the elderly, with incidence rising steeply over the age of 70 years [12]. The

Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

Management strategies for patients with community-acquired pneumonia recommended by current guidelines [20,62].

Diagnostic criteria

 CAP should be suspected in patients presenting with a cough and at least one of the following:  New focal chest signs  Fever lasting >4 days  Dyspnoea/tachypnoea  Diagnosis should be supported/confirmed by chest radiograph findings  The amount of microbiological work-up should be determined by the severity of pneumonia

Criteria for hospitalisation

 The decision to hospitalise should be validated against an objective tool of risk assessment (e.g. CRB-65)  Hospitalisation should be seriously considered in patients with CRB-65 scores 1  Decision making about treatment settings should be supported by clinical judgement and consideration given to non-clinical factors

Definition of severe CAP

 Patients are defined as having severe CAP if they have at least two of the following:  Systolic blood pressure <90 mmHg  Severe respiratory failure PaO2/FIO2 ratio <250  Involvement of >2 lobes in chest radiograph (multilobar involvement)  Or one of the following:  Requirement for mechanical ventilation  Requirement for vasopressors >4 h (septic shock)  Or three of the following IDSA/ATS minor criteria:  Respiratory rate 30 breaths/min  PaO2/FiO2 ratio 250  Multilobar infiltrates  Confusion/disorientation  Uraemia (BUN level 20 mg/dL)  Leukopenia (white cell count <4000 cells/mm3)  Thrombocytopenia (platelet count <100,000 cells/mm3)  Hypothermia (core temperature <36  C)  Hypotension requiring aggressive fluid resuscitation  Initial antibiotic therapy should be empirical and initiated as soon as possible  Options for non-ICU hospitalised patients include:

 CAP should be suspected in patients presenting with evidence of clinical signs and symptoms:  Cough  Fever  Sputum production  Pleuritic chest pain  Demonstrable infiltrate by chest radiograph or other imaging with/ without supporting microbiological data  Investigations for specific pathogens are advised only if it would alter the standard (empirical) treatment decision (i.e. if a specific pathogen is suspected)  Severity of illness scores (e.g. CURB-65, PSI) should be used to identify patients requiring hospital admission  Hospitalisation is usually warranted in those with CURB-65 scores 2  Objective criteria or scores should be supplemented with physician determination of subjective factors (e.g. ability to take oral medication)  Severe CAP is defined by the requirement for ICU admission plus either of the following major criteria or any three of the minor criteria:  Major criteria - Invasive mechanical ventilation - Septic shock with need for vasopressors  Minor criteria: - Respiratory rate 30 breaths/min - PaO2/FiO2 ratio 250 - Multilobar infiltrates - Confusion/disorientation - Uraemia (BUN level 20 mg/dL) 3 - Leukopenia (white cell count <4000 cells/mm ) 3 - Thrombocytopenia (platelet count <100,000 cells/mm )  - Hypothermia (core temperature <36 C) - Hypotension requiring aggressive fluid resuscitation

Recommended antibiotic therapy

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IDSA/ATS, 2007

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ERS, 2011

Managing high-risk CAP patients

 Outpatient treatment:  Previously healthy with no risk factors for DRSP infection: macrolide or doxycycline (continued on next page)

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Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

Table 3

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 Patients with comorbidities or other risks for DRSP infection: fluoroquinolone (levofloxacin or moxifloxacin), blactam þ macrolide or ceftriaxone, cefpodoxime, cefuroxime, doxycycline  Inpatient treatment:  Non-ICU: fluoroquinolone or a b-lactam þ macrolide  ICU: b-lactam þ azithromycin or fluoroquinolone  ICU with suspected Pseudomonas infection: piperacillin/tazobactam, cefepime, imipenem or meropenem þ ciprofloxacin or levofloxacin or b-lactam þ aminoglycoside þ azithromycin or blactam plus aminoglycoside þ fluoroquinolone  ICU with CA-MRSA: add vancomycin or linezolid  Penicillin G  macrolide, aminopenicillin  macrolide, aminopenicillin/b-lactamase inhibitor  macrolide, non-antipseudomonal 2nd or 3rd generation cephalosporin  macrolide, levofloxacin, moxifloxacin  For those with severe CAP (e.g. requiring ICU)  No P. aeruginosa risk factors: non-antipseudomonal 3rd generation cephalosporin þ macrolide, non-antipseudomonal 3rd generation cephalosporin þ moxifloxacin or levofloxacin  P. aeruginosa risk factors: anti-pseudomonal cephalosporin or acylureidopenicillin/b-lactamase inhibitor or carbapenem (meropenem preferred) þ ciprofloxacin þ macrolide þ aminoglycoside

ATS, American Thoracic Society; BUN, blood urea nitrogen; CA-MRSA, community acquired methicillin resistant S. aureus; CAP, community-acquired pneumonia; CRB-65, Confusion, Respiratory rate, low Blood pressure, age >65 years; CURB-65, Confusion, Uraemia, Respiratory rate, low Blood pressure, age >65 years; DRSP, drug-resistant S. pneumoniae; ICU, intensive care unit; ERS, European Respiratory Society; IDSA, Infectious Diseases Society of America; PSI, Pneumonia Severity Index; SBP, systolic blood pressure.

IDSA/ATS, 2007 ERS, 2011

T. Welte

Table 3 (continued )

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impact of CAP is also greater in older individuals since they are more likely to be hospitalised than younger patients and have a higher risk of mortality, with the mortality rate increasing with every decade until the eighth decade (Fig. 1) [12,22]. Mortality from CAP has been shown to be independently associated with age, even when comorbidity and severity of illness are taken into account [22]. Indeed, CAP appears to be a clinically distinct entity in older patients above the age of 65 years, being associated with more severe disease and presenting with fewer classical symptoms (e.g. fever and chest pain) than in younger individuals. Mortality from CAP is also higher in older patients, particularly in those with comorbidity [73]. The importance of age in patients with CAP is well recognised in current severity assessment tools, being a highly influential factor in both the PSI score and CURB-65 index [60,61]. Mortality prediction in elderly patients is still based on the same severity scoring systems (e.g. PSI classes, CRB-65 or CURB-65 scoring) as they are equally useful in older and younger patients [64]; however, such scoring systems may be reliable to predict mortality and poor outcome if a patient has healthcare-associated pneumonia (HCAP) [65]. The rationale for the much higher incidence and mortality from CAP in older individuals is not entirely clear, but is likely to be related to the high degree of comorbidity present in this population. However, changes to the immune system and lung physiology as a result of ageing are also likely to play a role [30,74].

Presence of comorbidity Comorbid illnesses are significantly more common in elderly patients with CAP and have a marked impact on outcome, with congestive heart failure, cerebrovascular disease and chronic liver disease all found to be independent risk factors for increased 30 day mortality [22,73]. In patients with defined comorbidities, mortality has been found to be highest in patients with malignant disease, though pulmonary comorbidity [excluding COPD] and dementia are also associated with high mortality (Table 4) [12]. Risk factors for developing CAP in older individuals include COPD, immunosuppression, smoking, congestive heart failure, diabetes, malignancy and previous hospitalisation for CAP [10]. Acute myocardial infarction [AMI] is common among hospitalised patients with CAP, being present in 15% of those with severe CAP, with risk of AMI increasing with higher PSI scores [75]. Furthermore, AMI is strongly associated with clinical failure and is reported to be the second-most common aetiology (after severe sepsis) associated with respiratory deterioration. This indicates that investigations to rule out AMI should form part of the initial work-up of hospitalised patients with CAP experiencing clinical failure [75]. Further incident cardiac complications, including new or worsening heart failure and new or worsening arrhythmias, are also frequent in patients with CAP and are associated with increased short-term mortality. Risk factors for such complications include older age, nursing home residence, pre-existing cardiovascular disease and severe pneumonia [76]. Immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection [77],

Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

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Managing high-risk CAP patients

7 in nursing homes, definitions for HCAP are heterogeneous and the optimal management is unclear, potentially leading to overtreatment of the condition [91]. Consequently, subdivision of CAP according to key risk factors such as age and functional status may assist in the selection of the most appropriate treatment [91]. Approaches to categorising patients with CAP should also consider their risk of developing MDR pathogens and take residence and previous antimicrobial treatment into account in the selection of appropriate antimicrobial coverage [92,93].

Managing the at risk patient

Figure 1 Distribution of in-hospital deaths of patients hospitalised with community-acquired pneumonia according to age. Data comprise patients included in the database of the Nationwide German programme for quality in healthcare between 2005 and 2006 (n Z 388,406). Reproduced with permission from Ewig et al. Thorax 2009 [12].

pregnancy [78], malignancy [79], or transplant immunosuppression [80], carry a high risk of developing CAP and altered immune function also confers a higher mortality rate than that observed in immunocompetent patients [81,82]. Furthermore, immunosuppressed patients with CAP are more likely to experience complications such as respiratory failure, acute respiratory distress syndrome or pleural effusion, and have increased susceptibility to atypical pathogens [81,83,84].

Impact of setting Residence status has a marked impact on CAP outcome, with mortality rates being around 4-fold higher among elderly nursing home residents compared with those living in the community [22,27,85]. Nursing home-acquired pneumonia (NHAP) is the largest subgroup of healthcareassociated pneumonia (HCAP) and the proportion of individuals in this category is likely to increase dramatically in the coming years due to the expected increase in the number of adults residing in nursing homes [27]. The high mortality rate associated with nursing home residency is likely to be explained by the fact that such patients are older, have greater comorbidity and more severe functional impairment than CAP patients [12]. Differences in the mortality rates of HCAP and CAP may also be due to differences in aetiology. While some studies have reported similar aetiological agents in HCAP and CAP, with S. pneumoniae being the most frequently isolated pathogen in each setting [85,86], others have reported increased incidences of GNB, MRSA and MDR microorganisms in patients with HCAP [27,33,87e90]. Although the susceptibility of the Enterobacteriaceae species isolated in these studies was not assessed, presence of these pathogens, along with MRSA or MDR microorganisms is associated with a higher mortality risk in HCAP [12,22]. Although the concept of HCAP was introduced to take account of the increasing numbers of elderly patients living

CAP associated mortality is highest within the first 5 days of hospitalisation, with risk being highest during the first day after admission, across all CRB-65 classes. Furthermore, failure of initial empiric treatment is an independent risk factor for death from CAP [21,22], highlighting the importance of early treatment with the most effective therapy, even for patients at low risk of poor outcomes [12]. A number of factors should be taken into account in the consideration of empirical therapeutic management of patients with CAP, including age, severity of disease, residency, comorbidity and functional status, as well as local resistance patterns. In particular, the increasing prevalence of b-lactam resistance among pneumococci has complicated the treatment of CAP and other respiratory tract infection, with most resistant isolates being resistant to multiple antimicrobial classes [94,95]. The high prevalence of resistance to macrolides in many countries also limits the efficacy of this drug class in the treatment of pneumococcal infections [96]. In contrast, the prevalence of fluoroquinolone resistance among S. pneumoniae isolates remains low, with the most active agents being moxifloxacin, gatifloxacin and gemifloxacin [97e100]. Of note, gatifloxacin for systemic use is withdrawn from the market due to toxicity [101]. As the aetiology of CAP is often unknown [25], recommended antibiotic treatment for CAP is usually empirical, with appropriate agents being selected according to disease severity and initiated as soon as possible (Table 3) [20,62,102]. Although coverage of atypical pathogens is not currently recommended for non-severe CAP patients [20,62], broader antibiotic therapy compensates for unusual circumstances, particularly for patients with increased risk factors. Indeed use of antimicrobial regimens with atypical coverage has been shown to be associated with better outcomes, suggesting that consideration should be given to empiric use of such regimens for all hospitalised patients [103]. The increasing incidence of GNB, MRSA and MDR pathogens among individuals with higher severity scores supports this view, since such infections may not be susceptible to regular first-line CAP treatment [27,33,87e90]. Furthermore, it suggests a need for careful evaluation of risk factors for MDR pathogens (e.g. previous antibiotic treatment, recent hospitalisation, chronic respiratory disease and functional status) for all CAP patients, particularly those presenting from nursing homes [27]. For outpatients with no modifying risk factors (e.g. drugresistant S. pneumoniae infection, Gram-negative or Pseudomonas aeruginosa infection), guidelines recommend standard therapy with a macrolide or a tetracycline (Table

Please cite this article in press as: Welte T, Managing CAP patients at risk of clinical failure, Respiratory Medicine (2014), http:// dx.doi.org/10.1016/j.rmed.2014.10.018

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8

T. Welte Table 4 Patient mortality from community-acquired pneumonia according to comorbidity. Comorbidity

2005 deaths (%)

2006 deaths (%)

Total (%)

Malignancy (other than bronchial) Lung cancer Pulmonary diseases (other than COPD) Dementia Renal diseases CNS disorders Cardiac comorbidity Diabetes mellitus Liver diseases COPD Total No comorbidity

27.65

28.66

28.2

25.07 24.03

25.33 24.82

25.21 24.45

21.93 20.2 19.27 17.06 13.41 12.26 9.85 17.08 12.5

22.76 21.3 19.54 17.63 13.88 13.6 10.37 17.75 13.35

22.36 20.79 19.41 17.35 13.66 12.93 10.12 17.43 12.95

COPD, chronic obstructive pulmonary disease. Reproduced with permission from Ewig et al. Thorax 2009 [12].

3) [20,62]. Evidence suggests that macrolide/b-lactam combination therapy is more effective than b-lactam monotherapy in hospitalised patients and is associated with lower risk of treatment failure [104]. For this reason, guidelines recommend combination therapy (e.g. macrolide/b-lactam) as an option for initial empirical treatment for hospitalised patients with CAP [20,62]. Data indicate that fluoroquinolones (moxifloxacin, gemifloxacin and levofloxacin) are also effective as monotherapy for hospitalised CAP patients [105,106], though ciprofloxacin is contraindicated due to its absence of pneumococcal coverage. Studies investigating the efficacy of fluoroquinolones (moxifloxacin, and levofloxacin) in the treatment of CAP have generally reported faster resolution of symptoms when compared with b-lactam monotherapy or macrolide/b-lactam combination therapy with comparable adverse events [107e111]. Levofloxacin (500 mg) has been shown to be at least as effective as amoxicillin/ clavulanate plus clarithromycin in hospitalised CAP patients [110], and cefotaxime plus ofloxacin in CAP patients requiring intensive care admission [111]. Similarly, moxifloxacin was as effective as amoxicillin, with or without clarithromycin, in patients with CAP [95] and was also as effective as amoxicillin-clavulanate plus roxithromycin in CAP patients with risk factors (i.e. older age, alcoholism and comorbidities, including COPD and diabetes mellitus) [112]. Moxifloxacin monotherapy was also shown to be noninferior to levofloxacin plus ceftriaxone in patients hospitalised with CAP in the MOTIV (MOxifloxacin Treatment IV) study, with clinical cure rates being comparable across PSI severity risk classes, including those with PSI IV and V [113]. Meta-analysis of trials comparing treatment with fluoroquinolones and macrolides in patients with mild-tomoderate CAP shows an advantage for fluoroquinolones with regard to treatment failure (relative risk [RR] 0.78) and microbiological failure (RR 0.63), with adverse events requiring discontinuation also being more frequent with macrolides [114].

For severe CAP cases requiring ICU admission, combination therapy involving a b-lactam plus a macrolide or a fluoroquinolone is recommended to extend the antimicrobial coverage and improve survival [20,62]. Use of macrolides was associated with decreased mortality in patients with severe sepsis due to pneumonia [28]. However, fluoroquinolones may be used as monotherapy in patients with severe pneumonia without septic shock [20]. The beneficial effect of macrolides in severe CAP may be due to the immunomodulatory properties of these agents [115]. This is supported by mouse models that suggest that use of macrolides to attenuate the inflammatory response in secondary pneumonia following influenza is associated with better outcomes [116]. Nevertheless, additional data are required in order to clarify the mechanism underlying the benefit of macrolides in this setting. Selection of appropriate empirical antimicrobial therapy for the treatment of CAP should also take into account the need for rapid bactericidal action and penetration into the site of infection. Ceftaroline has been shown to provide potent antimicrobial activity against common CAP pathogens, displaying lower minimum inhibitory concentrations for S. pneumoniae and S. aureus in vitro when compared with ceftriaxone and other cephalosporins [117]. With regard to macrolide antibiotics, the pharmacodynamics of azithromycin provides a number of advantages over erythromycin and newer macrolides, including its long half-life and good tissue penetration, allowing for once-daily dosing and shorter courses of therapy [118]. The fluoroquinolones moxifloxacin, levofloxacin and sparfloxacin are bactericidal against S. pneumoniae, with moxifloxacin providing the fastest kill rate along with effective penetration in respiratory tissues [119,120]. Patient factors are important parameters to be taken into consideration in the selection of empirical antibiotics for the treatment of CAP, since they can have a marked impact on outcome. CAP is primarily a disease of elderly patients, with incidence rising steeply over the age of 70 years. This vulnerable population requires prompt, effective treatment to avoid respiratory deterioration, yet few studies have evaluated antibiotics in the treatment of CAP in the elderly. Nevertheless, the efficacy of sequential IV/ oral moxifloxacin in the treatment of CAP has been compared with IV/oral levofloxacin in hospitalised elderly (65 years) patients [121]. Overall cure rates at the test-ofcure visit (5e12 days post therapy) in this study were similar between groups (moxifloxacin 92.9%, levofloxacin 87.9%), with comparable cure rates also being demonstrated for patients 75 years old (94.5% vs 90%, respectively). Moxifloxacin was also associated with faster clinical recovery than levofloxacin therapy (97.9% at 3e5 days after the start of therapy vs 90% for levofloxacin; P Z 0.01), with a comparable safety profile. A further aspect to be considered is that elderly patients frequently have comorbid conditions, particularly cardiac conditions, requiring a need for multiple medications [122]; it thus is important to review the cardiac risk of the agents themselves. Review of the short-term cardiac effects of selected antibiotics (azithromycin, amoxicillin, ciprofloxacin and levofloxacin) revealed a small absolute increase in cardiovascular deaths for patients receiving azithromycin, which was most pronounced among patients at higher risk

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Managing high-risk CAP patients of cardiovascular disease [123]. Furthermore, risk of cardiovascular death was found to be significantly greater with azithromycin than with either amoxicillin or ciprofloxacin, though the risk did not differ significantly from that with levofloxacin. In addition, risk of QTc prolongation has been associated with both macrolides and fluoroquinolones, with cardiac arrhythmias being reported with the fluoroquinolones sparfloxacin and grepafloxacin [124e127]. However, moxifloxacin and levofloxacin were found to have comparable cardiac rhythm safety profiles in hospitalised elderly CAP patients [122]. Furthermore, the frequency of new arrhythmias in this high-risk elderly population treated with these two fluoroquinolones did not exceed that expected in healthy elderly subjects, or those with cardiac disease. The safety profile of moxifloxacin has also been shown to be comparable to that of comparator antibiotics (b-lactams  macrolides, macrolides and fluoroquinolones) in a recent review of clinical studies across all indications, with no increase in cardiac events being reported. [128]

Conclusions Therapeutic management of patients with bacterial CAP involves the need to cover a broad spectrum of pathogens including S. pneumoniae, atypicals and Enterobacteriaceae. Coverage of atypical pathogens appears to be particularly important, since use of antimicrobials with activity against such pathogens has been shown to be associated with better outcomes. As mortality from CAP usually occurs within the first five days, antibiotic agents must also be rapidly bactericidal with a fast clinical efficacy and show excellent penetration into the bronchopulmonary compartment. Moreover, agents need to demonstrate a good safety profile, as patients often are elderly with a variety of comorbidities (most likely cardiovascular) and receiving multiple co-medications. A range of antibiotic agents are available for the treatment of outpatients and inpatients with CAP. While macrolides and b-lactam antibiotics are effective in the treatment of CAP, the increasing prevalence of resistance to these agents raises concerns about their continued effectiveness. Fluoroquinolones display excellent activity against common and atypical respiratory pathogens responsible, with data particularly supporting their use in high-risk patients. Of these agents, moxifloxacin appears to be the most potent, demonstrating equivalent efficacy to a variety of combination treatments when used as monotherapy, with good tolerability in a range of patients, including the elderly and those with comorbid conditions. It should be noted, however, that selection of an appropriate antibiotic must take into account the associated risks, since there are warnings and precautions on the labels of all agents (macrolides, b-lactams and fluoroquinolones). Therefore, careful assessment of the benefit/risk ratio should be made on an individual basis before prescription of any antibiotic agent, particularly for vulnerable patients.

Funding This manuscript was based on a presentation (Lower respiratory tract infections, Managing patients at risk of poor

9 outcomes) given by Tobias Welte, Hannover, Germany at the ERS Congress, September 2012, sponsored by Bayer HealthCare, Germany.

Conflict of interest Tobias Welte is a member of the advisory board of Bayer Healthcare, Forest Laboratories, Gilead and Novartis. He received lecture fees from Astellas, Bayer Healthcare, Forest Laboratories, Gilead, Novartis and Pfizer as well as basic research grants from Bayer Healthcare and Novartis.

Acknowledgements Highfield Communication, Oxford, UK, funded by Bayer HealthCare, Germany, assisted in preparation of this manuscript.

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