Lower respiratory tract infections and pneumonia are common infectious diseases worldwide that still cause substantial morbidity and mortality. The WHO reported lower respiratory tract infections to be the third leading cause of death worldwide in 2004.[1] Some population-based studies in the US[2] and Europe[3,4] have estimated a yearly incidence of community-acquired pneumonia of between 5 and 11 cases per 1000 adults. The mortality reported varies from <1% to >30%, depending on the sample of patients investigated.[5,6]

In this article, we review treatment strategies for the management of community-acquired pneumonia in elderly people. We compile recommendations of current guidelines[5–12] and discuss issues relevant to elderly care. For the purpose of this review, we define ‘elderly’ patients as those aged ≥65 years, and ‘old’ patients as those aged ≥80 years. These age categories have been recently confirmed as prognostically important,[13] as is age in general.[14,15]

1. Literature Search Methodology

The authors performed a review of current national and international guidelines on community-acquired pneumonia. Eligible guidelines were identified by searching the Trip database (http://www.tripdatabase.com); guideline web portals such as that of the US National Guideline Clearinghouse (http://www.guidelines.gov) and the German Association of Scientific Medical Societies (http://www.uni-duesseldorf.de/awmf); websites of important medical societies, such as the American Thoracic Society (http://www.thoracic.org), the British Thoracic Society (http://www.brit-thoracic.org.uk) and the European Respiratory Society (http://www.ersnet.org); and further comparable national and international organizations and institutions. Guidelines were also retrieved by a MEDLINE search via PubMed (http://pubmed.gov), using ‘pneumonia’ as a medical subject heading (MeSH) and the publication type ‘practice guideline’ as a limit. Further primary literature on several topics was identified by additional searches in MEDLINE, again using ‘pneumonia’ as a MeSH term, but excluding respective entries for Pneumocystis and ventilator-associated pneumonia. Further entries, such as ‘anti-bacterial agents’, were combined in searches usually limited to adults and humans (limits for ages and species: ‘all adult’ and ‘humans’). Further articles were identified by examining references cited in relevant publications and in the authors’ reference lists.

2. Clinical Features and Definition of Community-Acquired Pneumonia

Pneumonia is an acute infectious lower respiratory tract disease that causes inflammation of the lung parenchyma. Clinical signs and symptoms typically include fever (temperature ≥38.0°C), sweating, cough, purulent sputum, dyspnoea, tachypnoea and pleural pain. On chest examination, various signs such as percussion dullness, diminished or bronchial breath sounds, egophony and crackles can be found. In terms of prognosis, the most ominous finding is hypotension, i.e. systolic blood pressure <90 mmHg.[16]

Although collecting information on signs and symptoms is a necessary part of clinical practice in patients with possible pneumonia, interpreting their meaning should be undertaken with caution for a variety of reasons. First, the clinical presentation of patients may not be typical. Especially in the elderly, nonspecific complaints such as discomfort, fatigue, mobility impairment, falls or worsened cognitive impairment may be predominant clinically.[17–20] Second, findings on examination have only relatively low reliability in patients with suspected pneumonia.[17–19,21] Thus, diagnostic variation in different settings is likely increased further by observer variability. Finally, epidemiological studies and clinical trials usually apply extended criteria for diagnosing pneumonia, typically including the absence of other infectious diseases as an explanation for the illness and the radiological verification of chest infiltrates.[22–25]

Pneumonia is considered to be community acquired when the disease evolves in the normal community setting in a patient who has had no contact with the healthcare system. By contrast, community-onset healthcare-associated pneumonia is defined as a pneumonia in any patient hospitalized for at least 2 days within the previous 3 months, residing in a nursing home or long-term care facility, or receiving recent antibacterial therapy, chemotherapy, dialysis or wound care within the previous 30 days.[26] The distinction is important, as the spectrum of causal pathogens and, hence, management and prognosis differ.[27–29]

Other pneumonia entities not reviewed in this article are hospital-acquired pneumonia, which develops during hospitalization, usually beyond the first 48–72 hours after admission; aspiration pneumonia, caused by the entrance of gastric or oral content into the bronchial system, often resulting in a pneumonia involving anaerobic bacteria; pneumonia in immunocompromised patients, including those with HIV infection or overt AIDS; pneumonia in patients with cystic fibrosis, bronchiectasia or lung cancer with bronchial stenosis; influenza-related or other viral pneumonia; severe acute respiratory syndrome; and tuberculosis. Also, although important in the elderly, pneumonia in nursing home residents is not reviewed in this article as this has been done recently.[30,31]

3. Aetiological Factors and Pathogens

Several factors are related to the risk of developing community-acquired pneumonia. Among them, smoking, chronic obstructive pulmonary disease,[32,33] diabetes mellitus[34] and chronic heart failure[18,35] are the most prominent. Age is also associated with community-acquired pneumonia, although it is not fully established whether age independently affects risk or merely reflects concomitant risk factors, such as co-morbidity or a higher rate of previous treatment with antibacterials.[34,36,37]

The spectrum of aetiological pathogens is diverse and shows substantial variation between studies. This variation is due to geographic and seasonal characteristics, differences in study design and the population investigated, and most importantly, differences in methods and the extent of efforts to define a causal pathogen.[5,7,8,38–40] In this context, it should be noted that for several pathogens, sufficiently specific, non-invasive, rapid, readily available and inexpensive diagnostic tests are lacking, which may contribute to further biases.

Despite these shortcomings, it is generally agreed that Streptococcus pneumoniae is still the most important pathogen worldwide, accounting for an estimated 25–50% of pneumonia cases and approximately two-thirds of bacteraemic pneumonia.[38–40] Other important pathogens include Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella species, Gram-negative Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, C. psittaci, Coxiella burnetii, anaerobes and respiratory viruses such as adenovirus, respiratory syncytial virus, parainfluenza and influenza virus.[38–40] Other pathogens may also play a causal role in community-acquired pneumonia. Some studies indicate that the spectrum of pathogens involved is different in elderly patients, with M. pneumoniae being less frequent and Gram-negative bacteria being more frequent as causative pathogens in this age group.[36,37,41–43]

Some of the problems in defining the causal pathogen will probably be solved in the near future with some promising advances in laboratory techniques. For example, improvements in polymerase chain reaction (PCR) methods have been reported for a variety of pathogens.[44–47] PCR not only allows the identification of pathogens, but also provides insight into antimicrobial resistance patterns.[47] Improved quantitative real-time PCR, urinary antigen detection and serological surface adhesin A testing have been proposed for the detection of S. pneumoniae.[48] Another interesting technique is matrix-assisted laser desorption ionization-time to flight mass spectrometry, which identifies organisms on the basis of bacterial protein analysis. This method appears to be reliable, inexpensive and fast, possibly leading to a more timely diagnosis of pathogens.[49,50]

4. Antimicrobial Resistance

The widespread use of antibacterials for infectious diseases has contributed to an increasing prevalence of resistance of pathogens, thereby increasing the risk of treatment failure, complications and death from community-acquired pneumonia. It is, therefore, essential to consider current patterns of antimicrobial resistance when making treatment decisions.[5–8]

Resistance to penicillin by S. pneumoniae currently does not appear to be a prevalent problem in most countries. Since the Clinical and Laboratory Standards Institute raised the cut-off values for the minimum inhibitory concentration for penicillin to levels considered clinically meaningful,[51] the prevalence of S. pneumoniae strains resistant to penicillin dropped to 10% or below in most reports.[52–59] Macrolide resistance by S. pneumoniae has been of greater concern as, up until 2006, reports on isolates from the US, Germany and other European and Asian countries showed macrolide resistance rates of between 18% and >75% of cases.[60–63] However, more recent data have revealed significantly lower or declining non-susceptibility rates, with pneumococcal vaccination efforts being one of the possible explanations.[52,57,64–66] The most important risk factor for macrolide resistance is previous treatment with a macrolide. Macrolide resistance increases the risk for treatment failure when pneumonia is accompanied by Streptococcus bacteraemia.[67] It is generally assumed that macrolide resistance is clinically important, although the evidence linking resistance to macrolides with worse clinical outcomes is still conflicting.[68–70]

The emergence of S. pneumoniae resistance against fluoroquinolones has also been a matter of debate, although most recent studies report only a very low rate of resistance. In German surveillance data up to 2006, no fluoroquinolone-resistant isolates were detected.[71] The US Centers for Disease Control and Prevention identified levofloxacin resistance in only 0.4% of cases in 2009.[72,73] Further studies support these findings.[57,58,74] Pretreatment with a quinolone is the major risk factor for fluoroquinolone resistance.[5–8] Clinical relevance is likely, although not fully established.[70]

Data on tetracycline resistance reveal considerable prevalences of between 10% and 25% for S. pneumoniae.[75] Multidrug resistance (MDR), usually defined as a resistance to three or more antimicrobial classes, is found with increasing frequency, especially in Asian isolates.[70,76,77] Up to 40% of S. pneumoniae isolates exhibit MDR, limiting options for empirical antibacterial treatment.[76,77]

In addition to the examples discussed earlier in this section, antimicrobial resistance by some other pathogens should be kept in mind. β-Lactamase-producing strains of H. influenzae are reported with prevalences of about 10–15%.[78,79] Resistance has only infrequently been reported to cefuroxime and ciprofloxacin, and not at all to levofloxacin and moxifloxacin. β-Lactamase production is frequent in Moraxella catarrhalis, in up to 90% of isolates worldwide.[78–80] Resistance to cefuroxime, erythromycin or fluoroquinolones has not been observed. S. aureus is widely resistant to penicillin.[70] When methicillin (meticillin)-resistant S. aureus (MRSA) is the causal pathogen in community-acquired pneumonia, it is usually the result of pretreatment with antibacterials, previous hospitalization or nursing home residency.[6–8]

5. Assessment of Disease Severity

Over the last decade, the importance of assessing the severity of pneumonia has been recognized for both management decisions and outcomes. Fine and colleagues[81] developed the Pneumonia Severity Index (PSI), a score consisting of 20 weighted items that are summed to place the patient in one of five possible risk categories. Other prognostic scoring systems are the CURB-65 or its variant, CRB-65. The CURB-65 consists of six items (see table I), namely the presence of confusion, elevated serum urea level on admission, increased respiratory rate, low systolic or diastolic blood pressure and age ≥65 years.[82] The score sum ranges between 0 and 6 points. A score of 0 or 1 point indicates low-risk pneumonia, which may be managed in the ambulatory care setting. A score of 2–3 points identifies intermediate risk and a score of ≥4 defines severe community-acquired pneumonia with a high risk for complications and mortality (see table I for more information on pneumonia severity assessment using CURB-65 and CRB-65).

Table I
figure Tab1

Assessment of the severity of pneumonia in the elderly using the CURB-65 and CRB-65 clinical prediction rules[6–8,82,83] a

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The assessment of confusion can be challenging in patients with known cognitive impairment. In clinical practice, the information of an experienced proxy on the cognitive abilities of the patient and any changes in these abilities during the acute phase of pneumonia is used. It should be noted, however, that risk assessment on the basis of this information should be interpreted with caution. For the CRB-65, the serum urea criterion is omitted, resulting in a score easily obtainable in ambulatory care on the basis of clinical findings and without the need for other tests.[83]

Both CURB-65 and CRB-65 have been validated in different settings including elderly populations. A recent meta-analysis showed comparable prognostic performance for all three scores, i.e. PSI, CURB-65 and CRB-65, for the prediction of mortality.[84] Several international guidelines prefer and recommend CURB-65 or CRB-65 for the initial severity assessment.[6–8,10,11]

The risk tools mentioned were initially developed to assist and guide the decision on hospital admission. Despite their overall satisfying test performance with regard to mortality, at least two general limitations of the scores should be acknowledged. First, management decisions should not be based solely on a score result, as misclassification in either direction may occur. Other factors not included in the scores should also be taken into account. For example, in addition to being in a low-risk group according to one of the risk tool scores, a patient for whom ambulatory care is considered should be able to take oral medication, be sufficiently compliant and have adequate social support. Second, neither of the scores is fully satisfactory in guiding the decision for in-patient admission to an intensive care unit (ICU). The main reason for this is that general rules and indications for ICU admission vary markedly between healthcare systems and different settings. For example, in hospitals with intermediate-care units, only patients who require invasive mechanical ventilation may be candidates for an ICU, while other patients in need of closer monitoring or non-invasive ventilator support may be treated in intermediate care.

A modification of criteria developed and recommended by the American Thoracic Society (ATS)[5] is in use that may assist decisions on treatment and monitoring intensity and ICU admission in hospitalized patients (table II). When at least one of the two major criteria or at least two of the minor criteria identified by the ATS are fulfilled, admission to an ICU should be seriously considered.[85,86]

Table II
figure Tab2

Criteria for severe pneumonia according to the modified American Thoracic Society score[5,85,86] a

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6. Diagnostic Work-Up

The gold standard for verifying the diagnosis of pneumonia is still conventional chest radiography. This allows the verification of new infiltrates, although false negative findings are possible.[87] X-rays may add prognostic information by assessing the extension of infiltrates, bilateral involvement or pleural effusion, and may uncover possibly underlying or accompanying disorders, such as lung cancer or congestive heart failure. Because of easier access, lower radiation exposure and lower costs, conventional x-rays are preferred, although CT is generally considered superior in terms of diagnostic accuracy,[87,88] especially in bedridden patients, for whom chest x-rays appear to be unreliable.[89]

The patient’s history may reveal factors important for treatment decisions, especially the choice of antibacterials. Chronic obstructive or other structural lung diseases should be assessed, as these may be associated with a higher proportion of H. influenzae, S. aureus or P. aeruginosa.[32,33,90] Pretreatment with antibacterials, usually within the previous 3 months, is associated with the occurrence of multiresistant pathogens, as has been shown for β-lactam antibacterials, macrolides and fluoroquinolones.[37,91,92] Age ≥65 years has been reported to be linked to a higher prevalence of Gram-negative pathogens.[36,37,41–43] Chronic corticosteroid medication at a daily dose equivalent to prednisolone ≥10 mg may promote infections with Pseudomonas and Legionella species.[93] Infections with anaerobes and mixed pathogens are more common in patients with suboptimal dental hygiene and/or increased risk for aspiration.[31,94]

For low-risk patients in ambulatory care, the measurement of serum inflammatory markers, such as white blood cell count or C-reactive protein (CRP), and parameters of kidney function (serum creatinine, blood urea nitrogen) is reasonable. If factors predisposing to a shift in the pathogen spectrum are present, especially pretreatment with antibacterials within the previous 3 months, underlying structural lung disease or recurrence of pneumonia, consideration should be given to obtaining a Gram stain and sputum culture; collecting invasively sampled material might also be considered.[5–8]

In addition to CRP and parameters of kidney function, blood parameters such as procalcitonin, glucose level, liver enzymes and an arterial or capillary blood gas analysis are recommended for hospitalized patients with non-severe pneumonia.[5–8] The investigation of sputum or invasive respiratory samples is not recommended. Two blood cultures should be performed to assess bacteraemia and, if present, identify possible causal pathogens and also antibacterial resistance. Blood for the cultures should be obtained before initiation of antibacterial therapy. When a pleural effusion is present, a diagnostic puncture should be performed to differentiate parapneumonic effusion from empyema.[6–8] In patients at risk, a urinary antigen test for L. pneumophila (serogroup 1) can be performed, since this may lead to more rapid diagnosis and treatment of Legionella than the blood culture method. With its relatively high specificity, the urinary antigen test allows a rapid diagnosis when test results are positive.[95,96] However, it should be noted that negative results do not rule out Legionnaire’s disease,[95,96] and that only the serogroup 1 Legionella species, currently the most common group, are covered. Recommendations for the use of a urine antigen test for S. pneumoniae are conflicting.[6–8] British guidelines recommend testing.[7] This view is supported by a recent cohort study, in which urinary testing led to a reduction in the use of broad-spectrum antibacterials in adults hospitalized for community-acquired pneumonia.[97] Another recent study reported a sensitivity and specificity of 88% and 96%, respectively, using a commercially available rapid test.[98] The German guideline does not recommend Streptococcus antigen testing routinely.[8] The reasons are that an empirical therapy should always cover S. pneumoniae as a possible pathogen, and that an infection with mixed pathogens, especially in severe cases, is possible, thus limiting the value of a positive test result.

In hospitalized patients with severe community-acquired pneumonia, the following tests and investigations are also required:[5–8] two blood cultures, as bacteraemia is frequently present; testing of sputum or tracheal or invasively sampled secretions for Gram stain and culture, including resistance testing; urine antigen test for L. pneumophila; and bronchoscopy in selected cases.

7. Antibacterial Treatment

Treatment decisions must take into account a variety of factors. Disease severity, the overall clinical picture and individual patient characteristics should guide considerations. For the cornerstone of therapy, i.e. treatment with antibacterials, assumptions on the likely spectrum of underlying pathogens and their resistance to antibacterials are most important. As the spectrum of pathogens not only varies between but also within countries and regions, regular data updates from appropriate surveillance studies covering local or regional characteristics are recommended. Close collaboration among microbiologists, infectious disease specialists and local physicians caring for patients with community-acquired pneumonia is encouraged.

In patients requiring antibacterial treatment, assessment of kidney function is necessary, as chronic kidney failure and subclinical impairment of kidney function are prevalent in the elderly.[99–101] To estimate the glomerular filtration rate, the most important parameter in the assessment of kidney function, two formulas are in use, the Cockcroft-Gault and the Modified Diet in Renal Disease (MDRD) formula. Both make use of serum creatinine, age, sex and further variables for calculation. The MDRD formula seems better validated, although individuals with normal kidney function and elderly patients aged ≥75 years were not included in the study.[102] Regardless of which formula is used, if dose adjustments of antibacterials are neglected, drug-induced acute kidney failure and serious adverse effects may emerge.[99–101]

Other important considerations for the choice of antibacterials in elderly patients are the expected adverse-effect profiles and interactions between antibacterials and other drugs already in use. Gastrointestinal adverse effects, such as nausea, vomiting or diarrhoea, are frequent and have been reported for most major antibacterial classes, i.e. β-lactams, macrolides and fluoroquinolones.[103–106] In addition, skin rash, blood count alterations and drug fever, especially with prolonged therapy, are typical adverse effects of β-lactams.[104–106] Ototoxicity has been reported for macrolides together with photosensitivity for fluoroquinolones and doxycycline.[104–106] Of special concern in the elderly is the potential for CNS adverse events associated with fluoroquinolones, which may induce or worsen an acute confusional state, somnolence, hallucinations or dizziness.[103] Therefore, these antibacterials should be used with caution, especially in patients with known cognitive impairment or overt dementia. An infrequent yet serious adverse effect is the induction of cardiac ventricular arrhythmias secondary to prolongation of the QT interval. This potential is reported for macrolides and fluoroquinolones, with an elevated risk for patients receiving concurrent antiarrhythmic therapy.[105–107]

In terms of drug-drug interactions, the possible interference of macrolides and fluoroquinolones with antiarrhythmics is most important.[105–107] Another prominent interaction is that of macrolides and doxycycline with drugs metabolized by cytochrome P450 (CYP) 3A4. CYP3A4-inducing agents, such as carbamazepine, rifampicin (rifampin) or phenytoin, may lead to reduced concentrations of macrolides and doxycycline. By contrast, CYP3A4 substrates (e.g. HMG-CoA reductase inhibitors [statins], digoxin, verapamil and warfarin) may induce elevated concentrations of these antibacterials.[105–107]

A compilation of antibacterials most commonly recommended by current guidelines is shown in table III. An overview of the most common adverse effects and possible drug-drug interactions is given in table IV.

Table III
figure Tab3

Antibacterials for the empirical treatment of community-acquired pneumonia according to established guidelines

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Table IV
figure Tab4

Typical adverse effects of and important drug-drug interactions involving β-lactams, macrolides and fluoroquinolinesa

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7.1 Low-Risk Pneumonia in Ambulatory Care

In low-risk community-acquired pneumonia in ambulatory care without predisposing factors for special pathogens, the pathogen spectrum is relatively narrow. For this reason, empirical antibacterial treatment should not be unnecessarily broad, given the importance of preventing avoidable emergence of pathogen resistance.[6–8] For oral treatment, drugs should be selected on the basis of their favourable compatibility and bioavailability. Under these circumstances, an aminopenicillin such as amoxicillin with or without a β-lactamase inhibitor is recommended most frequently.[6–8] US guidelines[5] recommend a macrolide as the first choice of therapy. However, the emerging resistance to S. pneumoniae is of concern. Lack of efficacy of aminopenicillin as monotherapy against M. pneumoniae, C. pneumoniae and Legionella is anticipated, but not considered problematic in low-risk pneumonia.[6–8] In patients with penicillin intolerance or hypersensitivity, macrolides such as clarithromycin, roxithromycin or azithromycin, or the tetracycline doxycycline, may be used.[5–8] The fluoroquinolones levofloxacin and moxifloxacin may also serve as alternatives to aminopenicillins. However, the pathogen spectrum covered by these antibacterials is considered unnecessarily broad in low-risk pneumonia.[6–8] Ciprofloxacin must be avoided because it has inadequate activity against S. pneumoniae,[108] and its use may promote resistance to other fluoroquinolones.[5–8] Antibacterial therapy should be given for at least 5 days and can be stopped 2–3 days after clinical recovery. An exception to this recommendation is azithromycin, for which a treatment duration of 3 days is sufficient because of its long half-life. If treated according to these recommendations, treatment failure in low-risk pneumonia occurs infrequently.[5–8]

When factors predisposing to special pathogens are present, the spectrum may — in addition to S. pneumoniae and H. influenzae — include S. aureus, Enterobacteriaceae, anaerobes, Legionella species and other pathogens. The usual recommendation for an empirical antibacterial treatment is to use a β-lactam antibacterial combined with a β-lactamase inhibitor, for example, amoxicillin/clavulanic acid, which is active against S. aureus, most β-lactamase-producing Enterobacteriaceae and anaerobes.[5–8] Alternatively, the fluoroquinolones levofloxacin and moxifloxacin may be used as a monotherapy, as shown in several randomized controlled trials.[109–111] The advantages of the fluoroquinolones mentioned include high oral bioavailability and a half-life of sufficient duration as to allow once-daily administration. However, given the good overall prognosis of low-risk pneumonia, the adverse effects of these antibacterial agents and the possibility of promoting fluoroquinolone resistance should be weighed against their benefits.[8,112] If a primary infection or co-infection with M. pneumoniae, C. pneumoniae or Legionella species is suspected, combination therapy with a β-lactam antibacterial and a macrolide is warranted.[6–8] In patients who have been pretreated with antibacterials, a drug class different from that used during pretreatment should be chosen as the new antibacterial regimen.[6–8]

If patients prefer ambulatory care or some other reason prevents an otherwise indicated hospital admission, antibacterials should be given in accordance with recommendations for hospitalized patients.

7.2 Hospitalized Patients with Non-Severe Pneumonia

In hospitalized patients with non-severe pneumonia, the spectrum of underlying pathogens is not necessarily different from those in ambulatory patients.[113,114] However, a higher prevalence of Enterobacteriaceae, mixed pathogen infections, anaerobes and multiresistant pathogens is possible, a pattern that is most likely explained by differences in patient characteristics, i.e. a higher proportion of elderly patients with greater co-morbidity and a higher prevalence of antibacterial pretreatment.[115,116] A common recommendation for initial empirical antibacterial therapy is an aminopenicillin in combination with a β-lactamase inhibitor, for example, amoxicillin/clavulanic acid or ampicillin/sulbactam.[5–8] As an alternative, the cephalosporins cefuroxime, ceftriaxone or cefotaxime may be used.[117–119] Two recent meta-analyses did not find a clear benefit for therapy combinations that included fluoroquinolones or macrolides in comparison with β-lactam antibacterial monotherapy.[120,121] A benefit with the use of these combinations was described only in the subgroup of patients with proven Legionella pneumonia.

Studies comparing one of the fluoroquinolones, levofloxacin or moxifloxacin, with a combination of a β-lactam antibacterial plus a macrolide did not reveal any significant differences in outcome.[109,122–124] A recent meta-analysis found fluoroquinolones to be more effective than the combination of a β-lactam antibacterial and a macrolide.[125] However, many studies included in the meta-analysis were of relatively low quality, and a restriction of the analysis to high quality and/or randomized, double-blind, controlled trials did not reveal differences in efficacy. A recent Cochrane review[126] did not include any of the studies comparing fluoroquinolones with the β-lactam antibacterial/macrolide combination because of adherence to strict quality criteria for study inclusion. Azithromycin resulted in comparable success rates to cefuroxime.[69] Therefore, monotherapies with the fluoroquinolones levofloxacin or moxifloxacin or the macrolide azithromycin appear efficacious and safe in hospitalized patients with non-severe community-acquired pneumonia. Besides their antimicrobial action, macrolides and fluoroquinolones seem to have additional immunomodulating effects, which contribute to their clinical efficacy.[127–131] However, as already mentioned, possible adverse effects and the patterns of antimicrobial resistance need to be considered.

With the exception of macrolides and fluoroquinolones, which all have a high oral bioavailability, the initial administration of antibacterials in hospitalized patients should be intravenous.[5–8] This ensures administration of sufficient doses to obtain efficacy and avoids problems with patient compliance. A sequential switch from intravenous to oral application is usually possible within the first 2 or 3 days of therapy, when the patient becomes clinically stable.[5–8] This is achieved when vital parameters normalize (heart rate ≤100 beats per minute, respiratory frequency ≤24 per minute, systolic blood pressure ≥90 mmHg, absence of hypoxaemia), the patient is alert and compliant and nutrition and medication can be taken orally.

Although there is little consensus on the most appropriate duration of antibacterial treatment for community-acquired pneumonia, a meta-analysis suggested that adults with mild to moderate pneumonia can be treated with a regimen of ≤7 days’ duration.[132] The analysis included macrolides, fluoroquinolones, β-lactams and ketolides as antibacterial classes, and the results were consistent among each class. The German guidelines recommend treatment duration of at least 5 days as the shortest duration, provided that clinical stability has been achieved within this time.[8] A duration of >7 days is not generally recommended, except in the case of proven infections with P. aeruginosa, for which treatment for 15 days seems appropriate.[5–8]

The macrolide azithromycin should be considered separately, as its pharmacokinetic properties differ markedly from those of other macrolides. Azithromycin maintains high tissue concentrations for at least 3 days after completion of therapy.[133,134] This implies that therapy with azithromycin for 3–5 days is equivalent to 7–10 days of treatment with another macrolide. Because of its prolonged activity, the efficacy of ‘short-course’ azithromycin is not a general proof for the effectiveness of short-course antibacterial therapy.

Daily clinical assessment of the patient with special emphasis on signs and symptoms indicative of treatment failure may justify shorter treatment durations.[7,8] Serial procalcitonin measurements used to guide antibacterial therapy led to reduced length of hospital stay in one study.[135] Hospital discharge is not possible until clinical stability is achieved.

7.3 Hospitalized Patients with Severe Pneumonia

The spectrum of causal pathogens in severe pneumonia is broader than that in non-severe cases. S. pneumoniae is still the leading pathogen, followed by H. influenzae, S. aureus, L. pneumophila, Enterobacteriaceae, especially Escherichia coli and Klebsiella species, and P. aeruginosa.[5–8] In contrast to non-severe pneumonia, bacteraemia and infections with mixed pathogens are frequent. Diagnostic efforts to isolate a defined pathogen are generally considered necessary in severe pneumonia, as the results of these tests may influence both initial treatment and secondary therapy after initial treatment failure.[5–8] It should be acknowledged, however, that data from a prospective randomized controlled trial do not show a superiority of a pathogen-directed approach over empirical antibacterial treatment in terms of mortality or treatment failure.[136]

The classes of antibacterials with sufficient activity against the pathogens relevant in severe community-acquired pneumonia are ureidopenicillins with a β-lactamase inhibitor (piperacillin plus sulbactam or tazobactam), broad-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime), carbapenems (imipenem, meropenem, ertapenem), macrolides (erythromycin, clarithromycin, azithromycin) and fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin). Although monotherapy with a fluoroquinolone would cover all relevant pathogens mentioned, a combination of antibacterials is usually recommended.[5–8] In the only randomized clinical trial of ICU patients that compared a fluoroquinolone monotherapy (levofloxacin) with a combination of antibacterials (cefotaxime plus ofloxacin) in severe community-acquired pneumonia, levofloxacin showed comparable efficacy.[137] Further evidence suggests comparability of high-dose levofloxacin with ceftriaxone or imipenem,[117,138] and of high-dose ciprofloxacin, partly combined with vancomycin, with β-lactam monotherapy.[139] The evidence, however, is difficult to interpret and compare, as the patient groups evaluated are heterogeneous, with severe cases often being a subgroup only.[109,117,122,138–140] Furthermore, some findings have raised the possibility of inferiority of fluoroquinolone monotherapy compared with combined antibacterial therapies in patients with S. pneumoniae or Pseudomonas bacteraemia[141–144] and Enterobacteriaceae or S. aureus infections.[32,145] Finally, no data are available that included patients with septic shock or invasive ventilator support.

As a first-line therapy for patients with severe community-acquired pneumonia without predisposing factors when P. aeruginosa is the causal pathogen, the combination of a broad-spectrum β-lactam antibacterial (e.g. cefotaxime or ceftriaxone), piperacillin/tazobactam and a macrolide is recommended.[5–8] Monotherapy with levofloxacin or moxifloxacin as an alternative seems possible in patients without septic shock and not requiring invasive ventilator support. In patients with a predisposition for P. aeruginosa, a combination of piperacillin/tazobactam, cefepime, imipenem or meropenem and levofloxacin or ciprofloxacin is recommended.[5–8] Ceftazidime, another β-lactam antibacterial with activity against Pseudomonas species, is also a possible choice. However, it should be noted that the efficacy of ceftazidime against S. pneumoniae and S. aureus is weak in comparison with other β-lactam antibacterials.[146] As an alternative combination therapy, an aminoglycoside, such as amikacin, gentamicin or tobramycin, with a macrolide appears possible. However, aminoglycosides cover a rather narrow microbial spectrum, carry a high potential for toxicity (especially nephro- and ototoxicity), require serum concentration monitoring and achieve only low tissue levels in lung parenchyma. In a recent meta-analysis, combinations with aminoglycosides did not reveal a survival benefit in pneumonia but were associated with a higher rate of adverse effects.[147] By contrast, macrolides and fluoroquinolones induce high tissue levels in combination with a substantially lower rate of toxicity.

The necessary treatment duration in hospitalized patients with severe pneumonia is not known. In one study in patients with ventilator-associated pneumonia, a treatment duration of 15 days was not superior to 8 days of treatment.[148] In cases of proven Pseudomonas infections, however, recurrence was lower with 15 days of therapy,[148] which is also the recommended duration of therapy for severe Legionella pneumonia.[8] Frequent clinical assessment for signs and symptoms of treatment failure is recommended. Serial procalcitonin measurements may further guide decisions on when to end antibacterial treatment or detect complications and treatment failure.[135]

7.4 Adjuvant Therapy in Hospitalized Patients

In patients hospitalized for community-acquired pneumonia, the time from admission to the first administration of an antibacterial is considered prognostically important. Therefore, it is frequently recommended to start antibacterial treatment as soon as the diagnosis is established.[5–8] The earlier recommendation to initiate antibacterial treatment within 4 hours of arrival in the emergency room in patients with suspected pneumonia has been retracted due to multiple concerns including the overuse of antibacterials in cases without an established diagnosis of pneumonia.[149–151] Hypoxaemia is an established risk factor for mortality in community-acquired pneumonia. Thus, oxygen should be given as soon as possible in patients with proven arterial hypoxaemia.[5–8] In patients with known or suspected obstructive pulmonary disease, the possibility of carbon dioxide retention during oxygen supply has to be considered, and carbon dioxide monitoring should be performed regularly by capillary or arterial blood gas analysis.

Volume depletion is frequently seen in elderly patients secondary to fever and/or tachypnoea, acute confusional states, dementia or the presence of dysphagia. Therefore, an objective assessment of the hydration status should be performed immediately to allow initiation of adequate and timely fluid management. All patients should receive conventional or low molecular weight heparin for prophylaxis against deep vein thrombosis.[8] As soon as possible, the patient should be mobilized, and respiratory therapy should be initiated. Smokers should be instructed to avoid further smoking.[5–8]

Of increasing relevance, at least in hospitalized patients, is the emergence of Clostridium difficile-associated diarrhoea.[152–154] This problem is common during or after treatment with antibacterials, and typically occurs in elderly, hospitalized patients with co-morbidity and ongoing acid suppression therapy. Clindamycin, fluoroquinolones and cephalosporins are associated with the highest risk, although virtually all antibacterials have the potential to induce C. difficile-associated diarrhoea.[152–154] Prevention should comprise, among other issues, adequate hygiene and contact precautions and the preferential use of lower risk antibacterials, if possible.

8. Treatment Failure

A clinically stable situation is usually achieved within 3 days after treatment initiation. As mentioned in section 7.2, a patient is clinically stable when vital parameters normalize (i.e. heart rate ≤100 per minute, respiratory frequency ≤24 per minute, systolic blood pressure ≥90 mmHg), hypoxaemia resolves, and the patient is alert and compliant.[5–8] This is the case in the majority of patients. Treatment failure may manifest in two clinical variants with different prognosis. One variant is progressive pneumonia, defined as progressive clinical deterioration with respiratory failure and development of shock necessitating treatment in the ICU, vasopressor therapy and ventilator support. The prognosis for progressive disease, which occurs in an estimated 5–10% of patients, is poor.[5,8] Diagnostic efforts should focus on identifying the infectious causes, with consideration given to S. pneumoniae, Legionella species, S. aureus and other uncommon pathogens such as Acinetobacter species, mycobacteria, other atypical organisms, Nocardia and fungi. Treatment focuses on cardiocirculatory and respiratory support by means of critical care medicine. The second variant, with better prognosis overall, is non-response to the initial therapy characterized by the persistence of initial symptoms without apparent clinical deterioration.[5,8] Half of these patients in fact have only a delayed response, which would not necessarily demand a change in the treatment. However, as these cases cannot easily be distinguished from patients with a true non-response, careful re-evaluation of treatment, particularly the initial choice of antibacterials, and further diagnostic efforts are warranted. Pathogens to consider include Legionella, mycobacteria, fungi, Nocardia and other uncommon pathogens. CT scans of the thorax, bronchoscopy (including the sampling of secretions, transbronchial and/or transthoracic biopsies), ultrasound and echocardiography should be considered.

9. Quality Indicators and Clinical Pathways

Based on a comprehensive literature review, the Research ANd Development (RAND) Corporation developed the Assessing Care Of Vulnerable Elders (ACOVE) criteria for good quality of hospital care in vulnerable elderly patients. The criteria apply to patients aged ≥65 years with functional impairments and at risk for negative health outcomes. The most recent revision, published in 2007,[155,156] lists four quality indicators for hospital care in elderly patients with community-acquired pneumonia: (i) first administration of antibacterials within 4 hours of admission; (ii) oxygen supply in the presence of hypoxaemia; (iii) switch from parenteral to oral administration of antibacterials only when the antibacterials have comparable bioavailability and the patient is clinically stable; and (iv) discharge only when the patient is haemodynamically stable on the discharge day as well as on the previous day. In terms of pneumonia prevention, three other recommendations are made: (i) influenza vaccination; (ii) pneumococcal vaccination; and (iii) counselling for smokers to promote smoking cessation. The quality indicators mentioned are also broadly covered and recommended by current guidelines. However, the extent to which these criteria are used in clinical practice has not been comprehensively assessed.

Clinical pathways have also been developed to guide management of adults with community-acquired pneumonia. At least some evidence suggests that implementing a clinical pathway may lead to a reduction in hospital admissions of low-risk patients and better overall care of hospital patients.[157–160] However, evidence is conflicting in relation to the impact of such pathways on endpoints such as treatment failure or mortality.

10. Conclusions

The management of elderly patients with community-acquired pneumonia is a challenge. Numerous factors should be considered when a treatment strategy has to be developed for a given patient. Furthermore, it is necessary to adhere to certain principles that should guide treatment decisions. First, and most importantly, is the assessment of disease severity. Particularly in the elderly, the individual characteristics of the patient, such as compliance issues, the ability to take oral medication and the availability of adequate social support for at least the time of the acute phase of the illness, should be considered in addition to risk factors included in clinical risk assessment tools such as the CURB-65. Severity assessment is not only important for the decision of whether or not a patient can safely be treated in the ambulatory setting, but also for the first choice of antibacterials, the cornerstone of pneumonia therapy. The first antibacterial regimen is usually empirical and should be adapted to disease severity, the individual risk factors of the patient and the most likely underlying pathogen spectrum. The case of macrolide resistance by S. pneumoniae may serve as an example for the need to assess and regularly update local and regional patterns of antimicrobial resistance that may demand specific adaptations of treatment recommendations included in guidelines. Another important principle during the first days of therapy is regular clinical re-assessment of the patient. This is mandatory for the documentation of clinical stability, which is a prerequisite for the switch from parenteral to oral therapy and also for discharge planning. Furthermore, it enables timely detection of treatment failure or possible complications. In addition to pneumonia-specific aspects, further issues of care in the elderly need to be considered.

Shifts in antimicrobial resistance and the availability of new antibacterials will change future clinical practice for patients with pneumonia. Studies investigating new methods to detect pathogens, to determine the optimal antimicrobial regimen and to clarify duration of treatment may assist in further optimizing the management of elderly patients with community-acquired pneumonia.