Infections in the Elderly

Hans Jrgen Heppner, MD, MHBAa,b,*, Sieber Cornel, MDb, Walger Peter, MDc, Bahrmann Philipp, MDb,d, Singler Katrin, MDb,d
KEYWORDS  Infections  Elderly  Immune senescence  Geriatric  Sepsis  Pneumonia  Functional decline KEY POINTS
 Infectious diseases are very common in the elderly and there is an increasing morbidity and mortality in old age.  The occurrence and course of infection depends, in part, on immune senescence, functional status, and self-independence in daily living.  Appropriate and rapid initiation of supportive care and antimicrobial therapy is crucial for outcome.

BACKGROUND

The western concepts of infection pathogenesis begin with Hippocrates, who saw the dysregulation of the 4 body humors as the cause of disease.1 In antiquity, Galen of Pergamon (the famous physician Claudius Galenus) was already practicing abscess drainage. In founding the modern age of infection management, Semmelweiss, Lister, Pasteur, Koch, Flemming, or Paul Ehrlich contributed major innovations in infection concepts.26 Later, the so-called Taragona strategy,7 themed hit hard and early, was developed based on the ideas of Paul Ehrlich, who proposed frapper fort et frapper vite.8

For all authors there is no conflict of interest. H.J. Heppner has received speakers fees from Pfizer, MSD, Astellas, and Bayer Health Care and is a research fellow of the Forschungskolleg Geriatrie, Robert Bosch Foundation, Stuttgart, Germany. a Department of Emergency and Intensive Care Medicine, Klinikum Nuremberg, Prof.-E.-Nathan-Str. 1, Nuremberg D-90419, Germany; b Institute for Biomedicine of Aging, Friedrich-Alexander-University Erlangen-Nuremberg, Heimerichstr. 58, Nuremberg D-90419, Germany; c Depatment of Intensive Care Medicine, Johanniter Hospital Bonn, Johanniterstr. 3-5, Bonn D-53113, Germany; d Department of Acute Geriatric Medicine, Klinikum Nuremberg, Prof.-E.-Nathan-Str. 1, Nuremberg D-90419, Germany * Corresponding author. Department of Emergency and Intensive Care Medicine, Klinikum Nuremberg, Prof.-E.-Nathan-Str. 1, Nuremberg D-90419, Germany. E-mail address: heppner@klinikum-nuernberg.de Crit Care Clin 29 (2013) 757774 http://dx.doi.org/10.1016/j.ccc.2013.03.016 criticalcare.theclinics.com 0749-0704/13/$ see front matter 2013 Elsevier Inc. All rights reserved.

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Nonetheless, infectious diseases are still the leading cause of death in the elderly. Due to demographic shifts, the number of elderly patients treated for serious infections is increasing. Infections of the urinary tract and the lower respiratory tract (LRTI) dominate in the geriatric population. Although LRTI infections are reported to be the third leading cause of death worldwide, they are of particular importance in the geriatric population.9 Sir William Osler wrote, pneumonia may well be called the friend of the aged more than 100 years ago.10 Infections have a high mortality rate in this patient group. The susceptibility to infection in the elderly is increased by immune senescence as well as altered skin and mucosal barrier function.11
THE GERIATRIC PATIENT

Aging and disease must be distinguished. Aging leads to a reduction in the adaptability of the body to daily requirements, but is not itself a disease.12 Age-related changes in health and age-correlated disease processes condition one another. Current demographic trends clearly show that the proportion of elderly patients in all stages of care is increasing in most of the developed world. This increasing trend is changing the challenges facing global health systems. The management of infectious diseases in geriatric patients in relation to their multiple comorbidities, impending disabilities, and functional impairments is a unique challenge. Typically age-related loss of adaptability (see the definition in Box 1) of the body influences the occurrence, course, and prognosis of infectious diseases. During the physiologic aging process, various organ systems are affected that are important for response to infection. Structural and functional changes take place in the organ systems, which modify patients immune and defense status13 and physiologic stress response. Stress and agerelated alterations in body composition and metabolism can alter the pharmacokinetics and pharmacodynamics of anti-infectives. Comorbidities, functional status of the patient, and attitude to quality of life are of fundamental importance in the elderly in particular. Various patient groups must be distinguished: those that are considerably more agile than may be expected based on calendar age should be distinguished from those that are frail or already dependent on care and can therefore fall back on

Box 1 Definition of geriatrics and geriatric medicine of the European Union of Medical Specialists Geriatric Medicine Section (UEMS-GMS), Malta, May 2008123 Geriatric patients are defined by:  Multimorbidity and  More advanced agea (predominantly 70 years or older)
a Multimorbidity (chronic comorbidities) typical of geriatrics is in this context to be regarded as taking priority over calendar age;

 Or merely by age 80 years or olderb

b

Owing to typically age-related increased vulnerability, for example, due to

 The occurrence of complications and sequelae,  The risk of progressive chronic illness, and  The increased risk of loss of autonomy with a deterioration in self-help status Data from Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J 2005;26(6):113880.

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more modest physical reserves in the case of acute infections (also see Box 2). Studies have demonstrated that the prognosis for severe infections, particularly in geriatric patients more than 80 years of age, is clearly linked to functional status.14 In age-matched groups of patients, the residential environment (whether resident in own household or an institutionalized care facility) is associated with the microbiological etiology of the infections and mortality risk.15 If the degree of activity is compared with the aid of various geriatric assessments, such as activity of daily living scores or the Barthel index, the patient group presenting the highest functional deficit has increased risk of infections with Staphylococcus aureus or gram-negative bacilli.16
SPECIFIC FEATURES OF INFECTIONS IN ELDERLY SUBJECTS

Impairment of the functional status of the patient promotes age-related changes in the immune system and, as a consequence, the occurrence of infections. External factors such as degenerative changes in bone and cartilage that reduce thoracic mobility and consecutively hamper respiratory work also play a role. The decrease in vital capacity and the impairment of pulmonary function17 also influence the course of respiratory tract infections adversely. With an increasing loss of independence and daily skills, the spectrum of pathogens shifts toward S aureus and gram-negative bacilli, including Pseudomonas aeruginosa. With advancing age, infections are increasingly frequent as a cause for inpatient hospital admission or presentation to an emergency department; this applies to patients from long-term care establishments18 and to patients from the domestic environment. The consequence is an increase in the prescription of antimicrobial substances in geriatric patients with all adverse consequences.19
THE AGING IMMUNE SYSTEM

The aging process is accompanied by qualitative and quantitative changes in the immune system. With increasing age, overall immune response becomes less efficient, less appropriate, and occasionally harmful. Within this dysfunctional process, immune dysfunction alters the response to infection in older people (Fig. 1). This process, also called immunosenescence, is characterized by profound changes in T-cell subsets, antigen recognition repertoires, and effector functions. Aging also has a significant impact on the production of circulating cytokines and the circulating cytokine milieu may contribute to the development of age-restricted conditions.20 For example,
Box 2 Causes of increased susceptibility to infection and secondary complications in geriatric patients Morbidity and mortality risks of infections in elderly subjects  Reduced functional reserves  Modified pathogenic spectrum  Reduced defense mechanisms  Repeated/multiple hospital stays  Delayed diagnosis and initiation of therapy  Delayed response to antibiotics  Increased occurrence of adverse drug reactions

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immunesenescence and potential consequences

immune dysfunction

chronic inflammation leading to

increased susceptibility to

vaccination

impaired immune defense

increased sensitivity to pathogens increased infection risk

atherosclerosis osteoporosis diabetes mellitus arthritis

cancer autoimmunediseases

decreased antibody response

rise of morbitity and mortality

Fig. 1. Consequences of immune senescence.

altered antibody production increases fatality from pneumonia. T-cell proliferation and expression are also reduced in old age, conditioned by thymus involution, and the effector cells are of less function.21 Elderly humans are more susceptible to bacterial infections because of declining immune status and this effect depends on a decrease of neutrophil function and reduced neutrophil CD16 expression and phagocytosis.22 This immune senescence also has other clinical consequences, such as impaired response to vaccination,23 contributing to the development of age-associated degenerative diseases. On the potentially beneficial side, immunoglobulin Emediated hypersensitivity reactions are less frequent and allergic symptoms tend to improve with age.
CHRONIC COMORBIDITIES (MULTIMORBIDITY)

The geriatric patient is characterized by chronic comorbidities/multimorbidity, which means the simultaneous existence of multiple chronic conditions requiring medical therapy. The number of chronic conditions increases with increasing age; on average, 3 to 9 concomitant conditions (diabetes mellitus, arterial hypertension, osteoporosis, incontinence, chronic bronchitis, heart failure, impairment of cognitive performance, etc) are to be expected, which inevitably increases the risk of complications and, partially as a result, morbidity and mortality from most infectious diseases increase with ascending age. The most prominent comorbidities triggering infections are diabetes mellitus and chronic heart failure.24,25 Assessments to evaluate the current functional status or decline are necessary to accurately assess severity of infection and prognosis. The bodily changes in older age are best described by the terms frailty and sarcopenia.
FRAILTY

Frailty is a set of symptoms reported in the elderly that describes the vulnerability of the aging body due to various endogenous and exogenous mechanisms.26 Frailty

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should best be described in accordance with Fried and colleagues criteria.27 Closely connected with frailty syndrome is sarcopenia, the pronounced loss of muscle power and muscle mass in the elderly.28 Frailty as an autonomous geriatric syndrome is associated with a less robust response in the elderly patient to stress, injury, and acute diseases, which may be detrimental. In infections of geriatric patients, frailty is associated with a course comprising multiple complications, more difficult convalescence, and higher mortality. Inflammatory processes of low intensity take place continuously as part of the frailty syndrome.29 Independently of the underlying condition, changes in blood clotting activity and often anemia accompany the frailty syndrome.30 Certain laboratory parameters can be used to support the early diagnosis of frailty.31 However, in patients who fulfill the frailty criteria, acute phase proteins such as C-reactive protein (CRP) are increased, which may hamper the diagnosis of an acute infection. The same applies to interleukin-6.32 In acute diseases, susceptibility to infections is increased due to the catabolism-induced loss of muscle mass and functional proteins. Increased levels of inflammatory cytokines, as exist in frailty syndrome, are associated with increased mortality in connection with acute infections.33
SARCOPENIA

Physiologic aging leads to the loss of skeletal muscle mass and thereby to reduced muscle strength and reduced regeneration capacity34 after acute disease events. From about the 50th year of life, approximately 1% to 2% muscle mass is lost each year, and analogously around 1.5% muscle power, with this rate of loss increasing further from the 60th year of life. About 5% to 10% of the elderly overall and about one-half of those over 80 years of age are affected with sarcopenia occurring about twice as frequently as frailty.35 The diagnostic criteria for sarcopenia are listed in Table 1. Consideration of sarcopenia plays an important role in dealing with and treating patients, and also in the prevention of functional loss.36 Irrespective of the underlying disease, sarcopenia is an independent risk factor for mortality.37
DIAGNOSIS

The symptoms of acute infections in the geriatric patient are generally nonspecific. Clinical manifestations of infection in this patient group are often atypical. In LRTIs, the classical symptoms, such as fever, chills, or cough or expectoration, are frequently missing. In the elderly, dyspnea without other major signs and symptoms is not uncommon. A reduced or even nonexistent fever reactioneven in the case of severe respiratory tract infectionshampers diagnosis. The reason for this failure

Table 1 Diagnosis criteria for sarcopenia Diagnostic Criterion Low muscle mass Low muscle power Low physical capacity 2 of 3 criteria must be fulfilled for diagnosis
a b

Scope for Diagnosis DEXAa, BIAb Hand strength measurement Walking speed <0.8 m/s

Dual Energy x-ray absorptiometry. Bioimpedance analysis. Data from Barbieri M, Ferucci L, Rango E, et al. Chronic inflammation and the effect of IGF-1 on muscle strength and power in older persons. Am J Physiol Endocrinol Metab 2003;284:E4817.

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to generate a febrile response resides in impaired heat conservation and changes in central temperature regulation. In about 20% of cases of pneumonia, elderly patients do not exhibit cough, and in 25% to 50% of cases, fever is absent.38 Body temperature is usually central in the diagnosis of infection. However, in older subjects, body temperature is lower than that of younger people and their tolerance of thermal extremes is more limited. The average core body temperature difference between a clinically healthy adult (ages 2064) and an elderly person (ages 6595) is approximately 0.4 C/0.7 F. For the elderly, 37.2 C/98.9 F and not 38.0 C/100 F as in younger adults can be considered to represent a febrile response. A different fever cutoff for patients 75 years and older39,40 with possible infection is required because an inadequate cutoff level might lead to a delay in diagnosis and initiation of treatment.41 Instead of infectious signs typical of younger patients, elderly patients often exhibit atypical presentations including new onset confusion, acute deterioration of mobility, and subtle disturbances of circulatory regulation (hypotension and lactic acidosis without overt toxemia or tachycardia).42 Laboratory inflammatory markers are also often initially absent or only minimally abnormal in the geriatric infected patient so that anti-infective therapy is often started only in a delayed fashion.43 Whenever there is a reasonable suspicion for an infection, a laboratory-based diagnostic evaluation is crucial. Sputum can be taken, but the value of a sputum culture is limited. Culture of other sites can also be useful. Blood cultures should be performed to assess bacteremia/fungemia. Recommendations for the use of a urine antigen test are conflicting.44,45 British guidelines recommend testing for Streptococcus pneumoniae44 to reduce broad spectrum antibacterials in patients with community-acquired pneumonia.46 German guidelines do not recommend this antigen testing as necessary,45 because an empiric therapy should always cover S pneumoniae as a possible pathogen.
VALUE OF BIOMARKERS IN DETECTING INFECTIONS IN THE ELDERLY

Radiological changes of the lungs in geriatric patients with pneumonia are frequently nonspecific and do not always reflect the acute status.47 Given pre-existing comorbidities, infiltrative changes of the lungs may persist for months. The new onset occurrence of the principal symptom of dyspnea, clinical suspicion of infection, and exclusion of other major cardiac or pulmonary comorbidity is crucial. However, an initially erroneous diagnosis in the emergency admission unit leads to incorrect initial therapy and thus to a poorer patient prognosis.48 For that reason, inflammatory markers may be useful. The inflammatory parameters, CRP and procalcitonin (PCT), are helpful for the diagnosis of bacterial infection.49,50 They are useful for predicting the short-term prognosis of patients with community-acquired pneumonia (CAP).51 Applicability to geriatric patients has not yet been clearly established. CRP and the white cell count, like clinical signs and symptoms, are not always reliable parameters in geriatric patients because they may occasionally fall in the normal range (especially in the elderly). Although the inflammatory parameters CRP, PCT, and white cell count are highest whereby a bacterial process (in contrast to atypical or viral processes) is involved in the infection, these markers do not always permit individual differentiation. PCT is nevertheless suitable in estimating severity and prognosis of CAP.51,52 The risk of bacteremia in connection with pneumonia can also be estimated by this marker.51,53 The targeted use of biomarkers directly on admission of the patients, such as PCT or N-terminalproBrain natriuretic peptide, which is a sensible marker for acute cardiac decompensation, can help to avoid therapeutic delay and treatment delay-associated secondary complications.

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DELIRIUM AND INFECTION

Acute confusion or disturbance of consciousness is one of the common atypical (relative to nonelderly) primary manifestations of infection in geriatric patients. Infections are one of the commonest causes of acute disturbances of consciousness in the elderly. The prevalence of delirium of any cause in the elderly is high; cumulatively 14% to 56% in inpatients54 and 10% to 30% at any time during an inpatient stay.55 Among elderly patients with cancer, 25% to 55% of patients who are asymptomatic on admission become delirious during the stay in the hospital.56 In an analysis of 73 consecutive acute admissions of patients older than 70 years with impaired consciousness, the proportion of infections as a triggering cause was 34.3%. Fifty-eight percent of the 64 patients contracting pneumonia as part of a reported legionella outbreak presented with acute encephalopathy, predominantly hypoactive delirium.57 A few were even admitted with a primary neurologic diagnosis rather than as pneumonia. In the S3 guidelines for CAP (based on the CURB-65 score), symptoms of delirium (C 5 confusion) are 1 of 4 criteria that necessitate the inpatient admission.58 In the absence of fever, delirium may frequently be the only symptom with which an acute infection manifests itself in elderly patients. In a Swedish study of 504 outpatient women older than 85 years, a urinary tract infection (UTI) was present in 17.2% (87/ 504), of which 44.8% (39/87) concomitantly had acute delirium. In total, 27.2% (137/ 504) had symptoms of delirium, of which 28.5% concomitantly had a UTI within the previous month. In a multivariate regression analysis, a UTI was significantly (OR 5 1.9) associated with delirium.59 Infections are a very common cause of delirium in the elderly, but various other reasons for delirium may also be found.60 Delirium is a frequent primary reason for admission for elderly patients. Missed or delayed diagnosis and anti-infective therapy for infection as a result of atypical presentation with confusion/delirium can lead to longer hospital admissions, an increased risk of nosocomial infections, increased mortality, and the occurrence of long-term deficits.61
IMPORTANCE OF THE GLOBAL ASSESSMENT IN THE GERIATRIC PATIENT WITH ACUTE INFECTIOUS DISEASES

In elderly patients, acute and chronic conditions lead to impairments of functionality and, connected with this, to losses of independence. A geriatric assessment may identify interventions that also have a positive influence on the acute course of disease by improving functionality. The preventive benefit should also not be underestimated.62 Impaired functionality may indicate previously unrecognized diseases63 and is associated with higher mortality.64 Although performance of the geriatric assessment, in addition to the clinical investigation, does not require special technical instruments, it calls for a trained investigator to achieve the diagnostic and therapeutic objectives (Box 3). The use of standardized methods of investigation and assessment
Box 3 Assessment aims Aims of the geriatric global assessment Identification of functional deficits Acute therapy viewed in conjunction with functionality Adequate preparation for elective treatments Discharge and send home without/with outpatient aids

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(Table 2) is another important requirement for successful performance of the geriatric assessment. Even if many intensivists do not currently undertake the performance of a specific geriatric assessment in critically ill, infected geriatric patients, on-going demographic shifts toward the elderly will likely force consideration of this issue in the near future.65
ASSESSMENT FOR PROGNOSIS

C(U)RB-65 is an easy-to-use tool for severity scores for nonsevere, moderate, and severe pneumonia.66 A score of 2 to 3 points reveals intermediate risk, and a score of 4 defines severe community-acquired pneumonia with a high risk for complications and mortality (Table 3 lists more information on pneumonia severity assessment using CURB-65 and CRB-65). Functional status of the patients is also of importance for prognostication. Being bedridden, admission from a nursing home or other longterm care facility, and being dependent in activities of daily living are also poor prognostic markers.8,67
MAJOR INFECTIONS IN THE ELDERLY Pneumonia

Fever, sweating, cough, purulent sputum, and dyspnea are typical clinical signs of pneumonia in young patients,68 in association with new radiographic shadowing for which is no other explanation.67 As noted, though, many of these signs and symptoms may be substantially blunted in the elderly. Pneumonia in old age should be considered a unique entity with significant age-related differences in epidemiology and etiology, as well as clinical presentation and management.69
Aspiration Pneumonia

Aspiration pneumonia (AsP) arises from misdirection of oropharyngeal secretions with a high bacterial load or gastric material of very low pH from the stomach into the lower respiratory tract.70 The risk of AsP shows a strong age association due to a higher incidence of dysphagia in the elderly.71 These infections are generally mixed, frequently due to anaerobes, S pneumoniae, S aureus, and Haemophilus influenzae, although gram-negative intestinal bacteria (Klebsiella pneumoniae and other Enterobacteriaceae), P aeruginosa (in bedridden patients), and group B streptococci.72 AsP tends to show nonspecific symptoms, such as dyspnea, fever, and general exhaustion, in the elderly. Radiologically, pulmonary infiltrates are detectable mainly in the posterior upper lobe segments in the case of aspiration in the lying position, and generally in the apical lower lobe segments of the right lung in the case of aspiration in the sitting position.70

Table 2 Standardized geriatric assessments (example selection) Assessment Activities of daily living Timed up and go test Minimal mental status test Geriatric depression scale Nutritional risk screening Barthel index Evidence Coping with everyday life Mobility Cognitive performance Mental well-being Nutritional status Need for care

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Table 3 Assessment of the severity of pneumonia in the elderly using the CURB-65 and CRB-65 clinical prediction rules124 Clinical Sign Confusion Urea level >7 m mol/L Respiratory rate 30/min Blood pressure Systolic <90 mm Hg Diastolic <60 mm Hg Age 65 y 1 point 1 point 1 point Score 1 point 1 point 1 point

01 point 5 low risk, ambulatory care; 2 points 5 elevated risk hospital admission; 3 points 5 high risk, urgent hospital admission; 4 5 highest risk, r admission to an ICU. Data from Bauer TT, Ewig S, Marre R, et al. CRB-65 predicts death from community-acquired pneumonia. J Intern Med 2006;260:93101.

UTIs

UTIs are a common reason for elderly patients older than 75 years old to be admitted to the hospital.73 Incontinence, immobility, and chronic bladder catheterization are risk factors. Treatment of asymptomatic bacteriouria does not generally influence mortality or morbidity. However, treatment can occasionally result in antibiotic-associated adverse reactions and the development of resistance.74 As a consequence of agerelated physiologic changes, diagnosis of a true UTI is difficult. Underdiagnosis of UTI occurs with some frequency.75 Antimicrobial therapy is often not concordant with guidelines, given that modification of the standard regimen is often needed for geriatric patients. Patient-related diagnostic criteria and treatment standards specific to the elderly are recommended.75
Bloodstream Infections

Bacteremia is increasing in frequency in the elderly.76 Nonspecific symptoms are common at the initial presentation. Bloodstream infections are a major and increasing cause of morbidity and mortality in the overall and geriatric population, one of the leading causes of death in the hospital.77 Low albumin rate (P<.001), high CRP (P 5 .02), and moderate fever (P 5 .006) are independent risk factors for mortality in the elderly. The parameter with the highest risk was a low albumin rate (<30 g/L). Specific recommendations for management of bacteremia in the geriatric patient are required but not currently in place.78
Fungal Infections

Fungal infections are more frequent and serious in the elderly. Candida albicans still remains the major pathogen but there is an increase of Candida glabrata (associated with higher mortality) infection. Patients with swallowing disorder, acid suppression treatment, or corticosteroid use often show esophageal candidiasis.79 Candiuria is a common finding in the population of older patients with risk factors (chronic comorbidities, polymedication, or incontinence). C albicans and C glabrata are the usual fungal pathogens isolated.80 Candida infection of the skin, mucous membranes, or pressure ulcers is often seen in elderly patients with predisposing factors, particularly diabetes.81 Old age is also a risk factor for invasive candidiasis/candidemia and aspergillosis.82

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Sepsis

Sepsis has a high mortality rate in the elderly. It is also the most common cause of shock83 and among the leading causes of overall mortality globally.84 Case-fatality rates in older age are increasing.85 For clinicians, mastering the increasing complex elements of optimal sepsis management for the wide variety of presenting patients is difficult and new strategies for managing knowledge are necessary. Protocolized care, whether paper-based or electronic, has been shown to be particularly useful.86 Elderly sepsis patients, in particular, must be treated rapidly to optimize outcome and protocolized care may be especially beneficial for that reason.87
ANTIMICROBIAL MANAGEMENT

Antibiotics are among the most frequently prescribed drugs. Their widespread use is primarily responsible for increasing antibiotic resistance, a major problem in older patients, where infections are more common. Antimicrobial therapy has long been recognized as a cornerstone in the treatment of infections.88 Optimal antimicrobial therapy is crucial for surviving severe infections, sepsis, and septic shock89 and inappropriate choices can increase morbidity and mortality.90 The central principle of optimizing antimicrobial therapy is that appropriate antimicrobial therapy has to be initiated as quickly as possible to save the patient suffering from life-threatening infection.91 Antimicrobial treatment decisions are should be based on a variety of different factors, including disease severity, clinical picture, and individual patient characteristics. The validity of assumptions on the likely spectrum of underlying pathogens and their resistance to antibacterials are crucial to initial empiric therapy. As the spectrum of pathogens not only varies between but also within countries and regions,92 regular data updates from appropriate surveillance studies covering local or regional characteristics are recommended. Close collaboration between microbiologists, infectious disease specialists, and local physicians is necessary.93 In elderly patients, assessment of kidney function is especially important because subclinical impairment of kidney function and chronic kidney failure are prevalent. Failure to implement dose adjustment can lead to drug-induced acute kidney failure and other serious adverse effects.9496 The prevalent microbiology of infection is altered in old age, leading to differences in optimal empiric antimicrobial coverage for serious infections. For LRTI, S pneumoniae and S aureus are isolated with increased frequency, whereas a lower incidence of legionella and mycoplasma is found.97100 Gram-negative bacteria are also more frequent as causative pathogens in this age group with functional decline.101,102 In most cases, for serious infections without septic shock, antimicrobial monotherapy is sufficient. In the presence of severe hypotension and shock, combination therapy is beneficial.103,104 Early administration of antimicrobials is a key element in the survival of patients with severe infections.44 In addition, a relationship between antimicrobial delay and the increase of organ failure in patients with severe infections has been shown.105 Several barriers to timely administration of antibiotics can be identified. These barriers include a lack of education, a lack of appreciation of the severity of infection in the elderly, and an increased workload in busy emergency departments106,107 and intensive care units. Atypical presentation, lack of fever, or altered mental status may falsify the clinical picture and lead to delayed treatment.108 The widespread use of antibacterials for infectious diseases has led to an increasing prevalence of resistance of pathogens, thereby increasing the risk of treatment failure, complications, and death from infections. Therefore, it is essential to consider current patterns of antimicrobial

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resistance when making treatment decisions.44,45 Initiation of a microbially inappropriate antimicrobial is equivalent to no antimicrobial at all. Pharmacokinetics and pharmacodynamics including drug distribution and clearance are clearly independently altered in critically ill and geriatric patients. Changes in body composition, drug distribution, and elimination kinetics must be carefully considered in selecting a dosing regime. In addition, adverse effects, such as nausea, vomiting, or diarrhea (seen with b-lactams, macrolides, and fluoroquinolones109111), or acute confusional state, somnolence, seizures, hallucinations, or dizziness (fluoroquinolones110), can be prominent in the elderly, especially in the setting of pre-existing organ dysfunction. Interactions between antibacterials and other drugs already in use must also be considered. An overview of adverse effects and potential drug-drug interactions is seen mostly commonly in the elderly, ill patient, as given in Table 4.
Other Side Effects of Antimicrobial Treatment

Of increasing relevance in the geriatric patient is the appearance of Clostridium difficileassociated diarrhea (CDAD).112114 CDAD typically occurs during or after a course of antibiotic treatment in elderly, hospitalized patients with comorbidituies and ongoing acid suppression therapy. Antibiotic therapy within 6 weeks before CDAD is a strong risk factor.115 In combination with proton pump inhibitors, the risk is even higher,116 leading to a 2.5 to 3.5 higher CDAD-related mortality in elderly patients during severe infections.117,118 Clindamycin, fluoroquinolones, and cephalosporins are associated with the highest risk, although virtually all antibacterials have the potential to induce CDAD.112114 There are a wide range of manifestations, from asymptomatic carriage to fulminant colitis with toxic megacolon. The most common

Table 4 Typical adverse effects and important drug-drug interactions of b-lactams, macrolides, and fluoroquinolines Antibacterial Class b-Lactams Typical Adverse Effects Nausea, vomiting, diarrhea, skin rash, blood count alterations, drug fever Gastrointestinal adverse effects, ototoxicity, ventricular arrhythmias Important Drug-Drug Interactions Uricosuric agents: lower b-lactam excretion Antiarrhythmics, QT-prolonging agents: may induce ventricular arrhythmias CYP3A4-inducing agents (eg, carbamazepine, rifampicin, phenytoin): lower macrolide concentration Competition with other drugs for CYP3A4 (eg, statins, digoxin, warfarin): higher competitor drug concentrations Antiarrhythmics, QT prolonging agents: may induce ventricular arrhythmias Competition by ciprofloxacin with other drugs for CYP1A2 (eg, mirtazapine, warfarin): higher competitor drug concentrations

Macrolides

Fluoroquinolones

Gastrointestinal adverse effects, photosensitivity, confusion, delirium, somnolence, hallucinations, dizziness

Abbreviation: CYP, cytochrome P450.

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presentation includes watery diarrhea (rarely blood), abdominal pain and distension, and fever. For treatment, current antibiotics should be stopped whenever possible and supportive care initiated. Specific therapy consists of metronidazole in uncomplicated infection with vancomycin reserved for severe infection.119 Fidaxomycin, a new macrocylic oral antibiotic, may be particularly useful in critically ill elderly patients with a high risk for a relapse.120122 Relapse within 2 months occurs in about 20% of the patients with standard therapies.
SUPPORTIVE CARE

To achieve treatment success, supportive care, such as early mobilization, fluid management with sufficient hydration, and adequate nutrition, is very important in addition to antimicrobial management. For the elderly patients it is crucial to plan case management for discharge if necessary with preplanned rehabilitation or geriatric day clinic stay to strengthen self-dependent life skills. A series of supportive measures can help prevent infection in the elderly and should be implemented well before problems begin to arise (Box 4). They will also be useful in the convalescence period after serious infection or critical illness.
OUTCOMES

Infections in old age are more frequent, more severe, and associated with a higher mortality than they are in young adults, due to multiple different factors. Aging leads to organ system dysfunction, particularly respiratory, gastrointestinal, and immunologic senescence.69 The management of elderly patients with infections is a challenge. Factors specific to the elderly should be considered in diagnostic and treatment strategies for this group. The accurate assessment of disease severity is especially important in the elderly. The individual characteristics of the patient, such as compliance issues, the ability to take oral medication, independent activities of daily living, and the availability of adequate social support, should be considered. In addition, clinical risk assessment tools (such as the CURB-65 for community-acquired pneumonia) should be used to help determine whether a patient can safely be treated in the ambulatory setting. These tools are also helpful in the selection of the choice of the initial, empiric antimicrobial. Clinical reassessment should be performed regularly during the first days of therapy to document clinical stability, to enable timely detection of treatment failure or possible complications, and also for planning discharge. Treatment guidelines of serious infections should be adapted to accommodate the unique presentation, pathogen profiles, and management challenges of elderly patients.

Box 4 Prophylaxis in old age Approaches to preventing infections in the elderly:  Preservation of mobility and self-dependence  Preservation of muscle mass and body weight  Sufficient hydration  Personal hygiene  Avoid hospital admissions if possible  Vaccination

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Demographic shift toward the geriatric age group and the increasing complexity of infectious disease require strong interdisciplinary patient-centered care. Knowledge of the specific characteristics of serious infections in elderly patients and ongoing research in this area are required to ensure optimum care of this fragile population.

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