Infection in the Elderly

Infect Dis Clin N Am 21 (2007) 711–743

Infection in the Elderly Tin Han Htwe, MDa, Adnan Mushtaq, MDa, Sherry B. Robinson, PhDb, Richard B. Rosher, MDb, Nancy Khardori, MD, PhDa,* a

Division of Infectious Diseases, Southern Illinois University School of Medicine, Post Box 19636, Springfield, IL 62794-9636, USA b Department of Internal Medicine, Southern Illinois University School of Medicine, Post Box 19636, Springfield, IL 62794–9636, USA

With the aging of the population, clinicians will be caring for increasing numbers of elders with infectious disease. Infections in elders are more frequent, are generally more severe, and present differently than those in younger adults [1]. The hospitalization and mortality rates for infectious diseases are highest among persons older than 85 years of age [2]. This is the fastest growing segment of the population and is expected to increase to 7.3 million by 2020. They are generally frailer with several comorbidities [3]. These factors combined with normal aging changes and an increased probability of spending time in hospitals or nursing homes increases risk of infection for elders. Although a relatively small percentage (4.5%) of the over-65 population live in nursing homes, 18.2% of those older than 85 live in nursing homes. Persons older than 65 are hospitalized more than three times the comparable rate for persons of all ages [3]. There are specific infectious disease issues associated with these environments. In the hospital, urinary tract infections are the most common nosocomial infections, primarily caused by indwelling urinary catheters [4]. As many as 40% of indwelling catheters are unnecessary [4]. They are often used inappropriately to manage incontinence or to monitor output even when this can be done through other means [4,5]. Indwelling urinary catheters were associated with higher mortality rates, longer hospital stays, functional decline, and increased chance of nursing home placement [5]. Malnutrition is common in hospital settings, resulting in lack of nutrients needed for proper immune function and adding to the risk of nosocomial

* Corresponding author. E-mail address: [email protected] (N. Khardori). 0891-5520/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.07.006

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infections [6]. Significant malnutrition was found in as many as 69% of geriatric medicine admissions [7]. A common infection control measure in the hospital is isolation, and it may pose special risks to elderly. Compared with a matched group of nonisolated patients, those in isolation were eight times more likely to experience falls, pressure ulcers, and fluid or electrolyte disorders [8]. Major areas of concern for nursing homes are endemic infections, outbreaks, and colonization. Respiratory tract, urinary tract, skin and soft tissue, and gastrointestinal infections are common endemic infections. Common outbreak organisms include influenza A and Escherichia coli. Older persons who reside in nursing homes are more often colonized with resistant gram-negative bacteria, usually acquired from acute care facilities. The persistence of colonization is related to the high number of elders in nursing homes who are functionally impaired and to the close proximity in which they live [9]. Poor oral hygiene is common in nursing homes, increasing the bacterial load and the potential of colonization of the oral cavity [10]. An aggressive approach to oral care has been shown to decrease bacterial load [11]. Additionally, oral care increases secretion of substance P, which has a role in both the cough and swallows mechanisms [11]. Additional issues related to the nursing home and care of the elderly revolve around transfer to acute care hospitals. Greater access to testing, treatments, and closer monitoring may not always be worth the risk of iatrogenic harm that can be caused by institutional transfer. In a large study, increased risks of adverse events, such as delirium and falls, pressure ulcers, and events leading to death, were associated with hospitalization [12]. Use of a clinical pathway for treatment of nursing home residents with pneumonia was effective in improving outcomes of mortality, health-related quality of life, and functional status, and reducing hospitalizations and cost [13].

Immune system in the elderly Changes in the immune system, termed ‘‘immunosenescence,’’ contribute to the decreased ability of elders to overcome infections [14]. Aging changes occur in both cellular immunity and humoral immunity. The T-cell pool changes with aging, related to the involution of the thymus. The proportion of memory T cells increases, whereas the proportion of naive T cells decreases. Memory T cells are cells that have previously been exposed to an antigenic challenge. Naive T cells are those that respond to new pathogens and proliferate in response to their antigens. Studies have shown that increasing age is associated with a dramatic decline of the CD8þ cells, which are markers for naive T-cell output [14,15]. The naive T cell must be able to migrate to the appropriate effector site; express a diverse array of T-cell receptors; and acquire appropriate effector responses, such as the production

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of cytokines. There is disagreement as to whether naive T-cell function changes with aging; however, researchers do agree that there is a significant reduction in number of naive T cells [14,15]. It has been speculated that in the elderly, the delayed response to infections is caused by this larger pool of memory T cells occupying the immunologic space, with little response by the small pool of naive T cells [16]. Recently, changes in the B-cell pool have been studied. The IgM memory B cells, which are responsible for protection against encapsulated bacteria, such as Streptococcus pneumoniae, diminish with aging. Researchers hypothesized that the function of the spleen declines with aging [17]. Other researchers demonstrated increase in CD27þ B cells, which are markers of memory B cells and a decline in CD27 B cells, which are markers for the naive B cells [14,18]. IgD and IgM levels were lower in the elderly [14]. These findings suggest that a smaller portion of the B cell pool is available to respond to new antigenic challenges [14,18].

Clinical features of infection in the elderly Clinicians must be aware that typical signs and symptoms of infections are often subtle in the very elderly [19]. Atypical presentation of infection can lead to delays in diagnosis. The mean oral baseline temperature for older adults has been found to be 97.4 F, with a lack of fever response in around 20% [20]. In a study of 320 patients with pneumonia, a significant inverse relationship was found between age and temperature [21]. Normal temperatures should be established in elders and monitored for changes of 2.4 F over the baseline. Nonspecific symptoms, such as loss of appetite, decline in functioning, mental status changes, incontinence, and falls, may be the presenting signs of infection. The same clinical presentations can be seen in noninfectious diseases in the elderly, which makes the diagnosis even more difficult [1]. Adding to the atypical presentation, about 50% of elders in the nursing home setting have dementia and are unable to describe symptoms [9]. Clinicians need to inquire of first-line staff of any subtle changes in patients’ behavior that may indicate infection-related illnesses.

Skin infections Bacterial, viral, and fungal infections of the skin increase as the host ages [22]. Age related changes affect the ability of skin to resist trauma and the skin’s ability to repair once broken. Because of loss of collagen, the skin will not ‘‘give’’ as well. Dermal-epidermal junctions are flattened, reducing dermal-epidermal adhesion. Minor mechanical trauma can break the skin barrier, and infections often follow. Cellulitis, a bacterial infection of the lower dermis and subcutaneous soft tissue, becomes much more common with aging [22].

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Changes in aging skin delay wound healing, leaving wounds open longer, providing a portal of entry for microorganisms. Epidermis renewal time increases from 20 days to approximately 30 days because of diminished epidermal mitotic activity [23]. The amount of collagen in the dermis decreases as a result of decrease in fibroblasts and an increase in enzymes responsible for collagen degradation. Reduction in collagen synthesis contributes to the slower rate of wound healing and opens a window for infection [24]. Reduction in the size of blood vessels in the dermis decreases vascularization of the skin and impairs delivery of cells to fight skin infections [25]. Aging results in diminished water-binding capacity of the stratum corneum resulting in skin dryness and pruritus, which may cause the elder to scratch the skin [1]. Herpes zoster (shingles) Herpes zoster is caused by the reactivation of varicella zoster virus (VZV) infection, which remains dormant in the dorsal root and cranial nerve ganglia after primary infection (varicella or chickenpox) [26]. The VZV belongs to the human herpes virus family and is also known as ‘‘human herpes virus 3.’’ Herpes zoster is common in the elderly population, associated with declining cellular immunity with aging [26–29]. Epidemiology According to United States administrative databases, the overall incidence of herpes zoster infection is found to be 3.2 per 1000 person years and risk factors are aging, female gender, recent transplantation, HIV infection, and cancer [30]. A recent study in the Netherlands showed that seropositivity for VZV increases with age (97.5%–100% in older individuals) and average annual incidence is 325 per 100,000. Hospitalization and outpatient visit were found to be highest in the elderly population [31]. Clinical features Herpes zoster infection begins with prodromal paindwhich can be continuous or intermittent, sharp or throbbing, or stabbingdranging from 2 to 7 days before the skin lesions appear. The lesions start with an erythematous macular rash that progresses to papular and vesicular stages in 1 to 2 days followed by ulceration and encrusting of lesions in a week. At this time, the affected area presents with all stages of lesions. Appearance of new lesions after 1 week indicates severe immunodeficiency. Encrusted lesions usually resolve at the end of 3 to 4 weeks, but scarring can persist for long periods. Constitutional symptoms, such as fever, weakness, and loss of appetite, can be present in up to 20% of patients. Mucocutaneous lesions, unlike skin lesions, can present as erythematous shallow ulcers, which can be misleading and missed. The lesions are usually limited to a single dermatomal distribution area. But atypical presentations of lesions and multiple dermatomal involvement can be seen in immunocompromised populations [26–29,32,33].

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Serious complications include encephalitis, myelitis, zoster ophthalmicus with or without delayed contralateral hemiparesis, and VZV retinitis causing acute retinal necrosis. The most common complication is the postherpetic neuralgia (PHN), and its incidence increases with age (greater than 55 years) [33]. PHN presents with various types of pain ranging from paresthesia to allodynia (intense pain sensation with otherwise barely perceived stimuli). Generally, persistent pain beyond 90 to 120 days after the appearance of skin lesions is defined as PHN but it can last up to 12 months. Zoster sine herpete is the condition of reactivation of VZV with dermatomal pain without skin lesions but with concurrent positive polymerase chain reaction and serology results [26]. Diagnosis Recognition of the characteristic skin rash and associated clinical scenario usually gives the clinical diagnosis of herpes zoster infection. In atypical presentations, however, the lesions can be deceiving and may need laboratory testing. VZV can be detected by viral culture, polymerase chain reaction, and Tzanck smear of the lesions. The clinical specimen should contain cells from the base of the lesion to give a reliable result. Electron microscopy is the most rapid diagnostic method [34]. VZV antigen can be detected by the fluorescent antibody to membrane antigen, which is cumbersome and time consuming. ELISA for VZV-specific envelope glycoproteins (gpEIA) and latex agglutination, neutralizing antibody test, complement fixation test, radioimmunofluorescence assays, and immunofluorescence antibody test for VZV-specific antibody are commercially available [34]. Treatment The antiviral agents effective against VZV and herpes zoster infection include the nucleoside analogues acyclovir, famciclovir, valacyclovir, ganciclovir, foscarnet, cidofovir, and sorivudine [26,28]. Systemic antiviral treatment is recommended for people older than 50 years with moderate to severe skin rash. The best response is seen if the antiviral therapy is started within 72 hours from the onset of skin rash. After 72 hours, an antiviral agent should still be recommended with new evolving skin lesions and other serious complications. In immunocompromised individuals, nonresolving skin lesions should raise suspicion for acyclovir-resistant VZV infection. Acyclovir was the first antiviral agent approved for the VZV infections [28,29]. Famciclovir has been shown to be more effective than acyclovir in terms of reducing the duration of PHN [35]. Valacyclovir and famciclovir have shown similar efficacy in terms of resolution of acute zoster pain and PHN in a randomized controlled trial involving immunocompetent persons older than 50 years of age [36]. All antiviral treatments have been shown to shorten the duration of PHN, but none of them has been shown to prevent PHN [37,38]. Use of

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corticosteroids has been evaluated in several trials but the results are variable [26]. Use of intrathecal or epidural steroid injection seems to reduce the acute zoster pain without much effect on PHN [39,40]. Prevention Zoster vaccine (Zostavax) is a live attenuated VZV containing a minimum of 19,400 plaque-forming units per dose, which is approximately 14 times higher than that in the varicella vaccine approved for children. It is administered as a single subcutaneous dose of 0.65 mL. It has been recently approved by the Food and Drug Administration in the United States for use in immunocompetent individuals older than 60 years with no previous history of herpes zoster infection. Two doses are recommended in VZVseronegative persons [41–44]. This vaccine has been shown to decrease the acute zoster incidence by 51.3%, PHN incidence by 66.5%, and burden of illness by 61.1% in individuals older than 60 years followed over 3 years. The common adverse reactions were injection site pain, erythema, and varicella rash [45]. A recent study was done in adults older than 50 years with two different vaccine potencies and the results have shown that both vaccines are well tolerated and effective [46]. Pressure ulcers Pressure ulcers are necrotic areas created between the bony points and skin surfaces. These can vary from minor skin breaks to major deep tissue infections penetrating down to bone [47]. It is one of the most disabling and frequently encountered health care problems in the geriatric population. Elderly people are prone to develop pressure ulcers secondary to both extrinsic factors (pressure, friction, shear stress, moisture) and intrinsic factors (aging skin, immobility, poor nutrition, multiple comorbidities, and sedating medications) [47,48]. A recent Italian observational cohort study, which included over 3000 elderly people, showed 50% higher mortality rate in the pressure ulcer group [49]. Epidemiology A point prevalence study in a nursing home showed that up to 6% of residents had infected pressure ulcers [47]. A recent Italian study showed a prevalence of 18% in the frail elderly people living in a community [44]. Overall prevalence of pressure sores varies from 17% to 28%, and 60% of sores occur in people older than 70 years [49]. In another recent German study in nursing home and acute hospital settings, the overall prevalence was found to be 21.1%, with higher prevalence in hospitals compared with nursing homes (24% versus 14%); the most commonly involved sites were the sacral and heel areas. Nursing home residents tend to have more chronic and severe wounds [50]. In a Canadian survey of chronic wounds, pressure sores were the most common cause (37%) [51].

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Clinical features Pressures ulcers can be classified into four stages according to The National Pressure Ulcer Advisory Panel: (1) nonblancheable erythema of intact skin (stage 1); (2) partial-thickness skin loss involving epidermis or dermis (stage 2); (3) full-thickness skin loss extending to fascia (stage 3); and (4) full-thickness skin loss involving muscle, bone, and joints (stage 4). Purple pressure ulcers are a unique form of pressure sores that appears as deep bruises under the intact skin and can rapidly worsen to stage 3 or 4 ulcers [47,48,51,52]. Concomitant illnesses in nursing home residents with pressure ulcers include hypertension, presence of infection elsewhere, poor nutritional status, unfriendly social behavior, and slow response to commands [53]. Common complications of pressure ulcers include cellulitis of surrounding area, contiguous osteomyelitis of nearest bony prominences, and bacteremia with sepsis syndrome [54]. Pressure sores are the second commonest cause of bacteremia, which is usually polymicrobial in elderly people and can be regarded as the source of the sepsis in the absence of any other proved source and especially in the presence of foul smelling discharge and necrotic tissue. In one prospective study of 104 bacteremia episodes in elderly people, nearly 50% of episodes were found to originate from decubitus ulcers carrying a 31% mortality rate. The commonest microorganisms were found to be Proteus mirabilis (19%), followed by Staphylococcus aureus (16%), Bacteroides fragilis (16%), and group A streptococci (10%). Atypical presentation with nonspecific symptoms, such as altered mental status, fatigue, loss of consciousness, and falls, is also not uncommon in the elderly population [47,55]. Contiguous osteomyelitis is another common complication of pressure ulcers, especially with stage 3 and stage 4 ulcers. It can be as high as 38% in infected pressure ulcers. S aureus is commonly found in extremity ulcers and fecal flora, such as B fragilis, is found in sacral and perianal ulcers in addition to S aureus [54,56].

Diagnosis The concordance between the superficial wound swab and deep tissue cultures remains poor. The most reliable method of diagnosis is the deep tissue culture or bone culture in conjunction with clinical and histopathologic evaluation. Among the radiologic investigations, MRI is the most useful method of detecting contiguous osteomyelitis associated with pressure ulcers. Compared with three-phase technetium 99m diphosphate bone scan and gallium scintigraphy, which are more useful in detecting acute hematogenous osteomyelitis, indium-labeled white blood cell scans are more specific for osteomyelitis associated with pressure ulcers [41,47].

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Treatment Management of pressure ulcers should be multidisciplinary. Although treating infection is an important part of the management, complete management includes pressure relief, various kinds of debridement to decrease the bacterial colonization load, and use of appropriate dressings and topical agents [48]. Infections of pressure ulcers tend to be polymicrobial. The initial presumptive antibiotic treatment should provide coverage for both grampositive and gram-negative facultative organisms and anaerobes. For serious infections with systemic involvement, the preferred route is intravenous. Narrow-spectrum antibiotics should be chosen after the results of deep tissue or bone cultures become available [47,54–59]. Broad-spectrum b-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams, b-lactams combined with b-lactamase inhibitors) are generally well tolerated by elderly people. With increasing prevalence of resistant organisms in nursing homes and extended care facilities, such agents as vancomycin, linezolid, daptomycin, and Quinupristin-dalfopristin should be the preferred choice for initial gram-positive coverage. Antipseudomonal b-lactams or quinolones or aminoglycosides should be added to the initial regimen especially when Pseudomonas aeruginosa and resistant gram-negative organisms, such as acinetobactor species, are suspected. If infection with anaerobes is likely, clindamycin or metronidazole should be added. Carbapenems have activity against facultative gram-positive cocci, gramnegative bacilli including P aeruginosa, and most anaerobes. Imipenem should be avoided cautiously in elderly population because it tends to have longer half-life and can cause seizure activity, especially in people with renal insufficiency and central nervous system disorders. Its dosage should be adjusted in renal impairment because its route of excretion is through the kidney. Aminoglycosides have limited usage in elderly people because of well known nephrotoxicity and ototoxicity, particularly when used in conjunction with loop diuretics, nonsteroidal anti-inflammatory drugs, vancomycin, and radiographic contrast agents. Monitoring the serum peak and trough levels is essential. Among the fluoroquinolone group, newer quinolones (gatifloxacin, levofloxacin, moxifloxacin) interact with antiarrhythmics leading to increase in Q-T interval and also produce dysglycemic effect, especially in the elderly population. Ciprofloxacin also increases theophylline levels [54–59]. Scabies Scabies is a dermatologic infection caused by the ectoparasite (mite) Sarcoptes scabiei var. hominis. This mite was first discovered as early as the 1600s but was not identified as the causal agent of scabies infection until

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over a century later. It is mainly transmitted by person-to-person contact and rarely through fomites and through sexual contact. Scabies infection is endemic in tropical and underdeveloped countries, but in developed countries outbreaks occur in schools, prisons, hospitals, nursing homes, and extended health care facilities. Scabies infection is especially common in elderly people living in confined spaces secondary to declining cellular immunity, aging skin, overcrowding, and limited mobility [60–64]. Epidemiology Scabies affects all ages and both genders, but its prevalence has been underreported because it is not one of the notifiable diseases. In a Brazilian study, the prevalence was as high as 8.8% in slum areas [65]. In a United Kingdom survey, the annual incidence varied from 233 to 470 per 100,000 person years [66]. Elderly people living in nursing homes and extended facility facilities are at high risk of developing scabies infection. In a Taiwanese nursing home survey, the prevalence of scabies was found to be approximately 3% [67]. In a Canadian study of 130 long-term health care facilities, 25% of them reported cases of scabies in a 1-year period [68]. Clinical features The classic symptom of scabies infection is pruritus, especially at night time. The pathognomonic sign is the presence of burrows predominantly in interdigital web spaces, flexor surfaces of extremities, and genital areas. Burrows usually present as thin wavy tracts measuring 1 to 10 mm, which are predominantly found in interdigital webs, intertriginous areas, wrist, elbows, ankles, and genital areas. In addition, an erythematous papulovesicular rash may be seen [68,69]. In elderly people, atypical presentations, such as crusted scabies, nodular scabies, and bullous scabies, and a nonpruritic unexplained skin rash are also common. These atypical presentations lead to delayed diagnosis and treatment. In an outbreak of scabies infection in a long-term care facility, only 33% of patients presented with pruritus and most presented with nonpruritic erythematous papulosquamous lesions on the trunk. Because pruritus is the manifestation of delayed hypersensitivity, it can be absent in an elderly population with declining cellular immunity [62,69]. Crusted scabies, also known as ‘‘Norwegian scabies,’’ was first described in 1848. It presents as thick horny layers of crusts or warty lesions harboring millions of mites. The predisposing condition includes immunocompromised states, such as HIV or human T-lymphotropic virus-1 infection, transplant recipients, patients receiving chronic steroid therapy topically or systemically, and neutropenic patients. Complications includes super-infection by group A streptococci or S aureus and persistent postscabies eczema [60,61].

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Nodular scabies, is another atypical presentation of scabies, presents as brownish or reddish pruritic nodules in the axillary, groin, and genital areas. Secondary bacterial infections and chronic dermatitis changes are also common. The lesions can remain unresolved even after optimal treatment. Local corticosteroid treatment can be considered as an option [62]. Bullous scabies is also commonly found in the elderly population. It presents as bullous lesions with variable size and shape and can be mistaken for another dermatosis, such as bullous pemphigoid. It can be distinguished by histologic or microscopic examination of skin scraping. It occurs as a result of strong immune response to the mite antigens. Caution should be used in treating these patients because systemic absorption of topical agents can cause toxicity [62]. Diagnosis Scabies is usually diagnosed clinically mostly by identifying the burrows in predilected areas. History of previous infection and similar lesions among family members are also helpful clues. In situations with atypical lesions and unidentifiable burrows, the direct microscopic examination of skin scraping using potassium hydroxide, saline, or mineral oil is needed for detection of the mite itself or its ova or feces. The best skin specimen can be obtained by scraping the fresh, undisturbed burrow. Although it is not highly sensitive, it is very specific. Other methods include skin biopsy, epiluminescence microscopy, and high-resolution videodermatoscopy (burrow ink test). ELISA essay for scabies has been hindered by several factors, which include lack of in vitro culture system, animal models for human scabies, recombinant purified mite antigens, and cross-reactivity with dust mites [60,63]. Treatment Among the agents effective against scabies infection, 5% permethrin cream, 1% lindane lotion, and oral ivermectin are recommended by the Centers for Disease Control and Prevention. Other agents include crotamiton, benzyl benzoate, malathion, and 6% sulfur ointment. Permethrin has been shown to be the most effective topical agent compared with lindane and crotamiton with low toxicity, and it has been approved for the treatment of scabies in the United States since 1989. It has minimal systemic absorption and allergic activity and it can be used in all populations including infants. It can be applied to the whole body, excluding head and neck, and should to be washed off after 8- to 12-hour application [60,61]. Studies have shown comparable efficacy between 2 doses of oral ivermectin (200 mcg/kg) administered at 2 week interval and a single dose of permethrin cream or lindane [61]. Oral ivermectin, even though not FDA approved, can be used in treatment failure cases with permethrin, especially in demented patients with poor compliance [62,63]. It has no seizure activity since it does not cross the blood brain barrier. It is especially useful in elderly people with dementia and mentally ill with poor compliance with

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topical agents [70,71]. It can also be administered repeatedly in conjunction with topical agents in treating crusted scabies [60,61]. During an outbreak, all the contacts should be treated at the same time regardless of symptoms. Fomites including bed and personal clothing should be washed thoroughly in hot or warm water. Unwashable items should be left unused for a minimum of 3 days. There have been documented cases of treatment failure with strains resistant to topical scabicidal agents including permethrin and lindane. The trend is increasing across the world. New promising agents include the essential oil of the tea tree and the essential oil of the Lippa multiflora Moldenke. Vaccine development targeting the multifunctional enzyme glutathione S-transferase of Sarcoptes scabiei is a promising potential option [60–63]. Onychomycosis (tinea unguium) Onychomycosis is the common chronic fungal infection of the nails mainly caused by dermatophytes [72]. Previously, it was considered a cosmetic problem but it can be a serious health issue especially in the elderly, immunocompromised individuals, patients with diabetes mellitus, and HIV infection [73]. Epidemiology Onychomycosis is one of the top 15 dermatologic diagnoses in the elderly population [74]. In the United States, the overall prevalence of onychomycosis was found to be 8.7% (male more than female) in a study done in Ohio in 1997 [75]. In a recent study, the prevalence was estimated at 6.5% in the Canadian population, with Trichophyton rubrum and Trichophyton mentagrophytes being the most common dermatophytes [76]. In another Canadian multicenter survey, onchycomycosis was more commonly associated with the elderly population and male gender [77]. Risk factors for onychomycosis include aging, nail trauma, atopy, diabetes, chronic immunosuppressive state, and HIV infection. Overall prevalence in the United States population is estimated around 3% in males and 1.4% in females. Higher prevalence is found in high-risk populations and is 30% in people over 60 years [78]. Nondermatophyte-associated onychomycosis ranges from 2% to 15% in various European and Asian countries [79]. Clinical features There are five subtypes of onychomycosis: (1) distal and lateral subungual onychomycosis, (2) proximal subungual onychomycosis, (3) superficial white onychomycosis, (4) Candida onychomycosis, and (5) endonyx onychomycosis and total dystrophic onychomycosis. Distal and lateral subungual onychomycosis is the most common presentation and mainly caused by dermatophytes (T rubrum). Sometimes distal and lateral subungual onychomycosis is caused by nondermatophyte molds (Scytalidium, Scopulariopsis, Fusarium, and Aspergillus), especially in the elderly population [72].

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Superficial white onychomycosis and proximal subungual onychomycosis are less frequently encountered and predominantly caused by dermatophytes. Endonyx onychomycosis usually starts from the distal end of the nail plate and progresses toward the proximal end forming white patches without subungual hyperkeratosis or onycholysis. This type is also caused by Trichophyton species. Candida onychomycosis is mainly caused by Candida albicans and sometimes by other Candida species [72,73,79,80–83]. Diagnosis The current methods for diagnosis of onychomycosis include light microscopy, fungal culture, histopathology with periodic acid–Schiff stain, immunohistochemistry, dual-flow cytometry, vivoconfocal microscopy, scanning electron microscopy, and polymerase chain reaction. KOH mount microscopy and culture and histopathology examination using periodic acid–Schiff stain are the most commonly used methods [80,81,83]. In a recent Iranian study, the most sensitive diagnostic method was found to be direct smear and histopathology, which was 97.8% sensitive and 98% negative predictive value [84]. In a multicenter prospective trial of commercial polymerase chain reaction ELISA diagnostic kit (Onychodiag[R]), accurate results were obtained in both proximal and distal samples within 24 to 48 hours with sensitivity ranging from 75% to 100%. This technique also can provide the identification of fungal species, strain, and subtype [85]. The correct method of obtaining culture samples is important to improve sensitivity. The best specimen is the one taken from the junction between the diseased and normal-looking nail if possible. False-negative results are seen with samples taken only superficially [83]. Treatment Onychomycosis can be treated in various ways: mechanical, chemical, topical, oral, and combination treatment. Mechanical treatment includes debridement, partial or total avulsion of the nail, followed by topical or oral therapy for complete cure. Chemical treatment options include strong chemicals, such as urea ointment, which causes peeling of the infected nail [72]. Use of bifonazole cream containing 40% urea is effective treatment in patients who do not want systemic antifungal treatment [86]. Among topical options, 8% ciclopirox nail lacquer solution is the only Food and Drug Administration approved drug in United States. It is fungicidal and serves as a chelating agent that acts on iron-dependent mitochondrial enzymes of fungi [72,87]. It is applied once daily for 48 weeks. The meta-analysis of worldwide trials shows mycologic cure rate ranging from 47% to 85% at the end of 48-week treatment [87]. Amorolfine 5% nail lacquer is another fungicidal agent that has been shown to be effective in onychomycosis, but it is not Food and Drug Administration approved in the United States [72,89]. AN-2690 is a new

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fungal protein synthesis inhibitor that has better nail penetration and mycologic cure rates compared with existing topical agents [88]. Other less effective topical agents include 28% tioconazole, 2% miconazole tincture, fungoid tincture, 5% tea tree oil, topical ketoconazole, and vitamin E [89]. Oral agents include terbinafine, itraconazole, fluconazole, and griseofulvin. Terbinafine acts as fungicidal agent against dermatophytes but is fungistatic for the nondermatophytes and yeast species. Terbinafine remains the treatment of choice for onychomycosis. Met analysis comparing terbinafine with other oral agents showed that oral terbinafine, 250 mg given orally daily for 12 weeks, provides superior results [72,90,91]. It has also been shown to be an effective and well tolerated agent in diabetic and HIV populations [92]. In a recent Japanese pilot study, terbinafine pulse therapy (one pulse is 500 mg per day given for a week followed by a 3-week drug-free interval) in combination with topical 1% terbinafine cream daily showed complete cure in 77% with 3.7  1.4 pulses [93]. Terbinafine, itraconazole, and fluconazole are more effective treatment for nondermatophyte fungi compared with griseofulvin, which is not effective against Candida and nondermatophyte species. Longer duration of treatment and combination with topical agents are usually necessary for nondermatophytes (Scopulariopsis, Fusarium, Aspergillus species). More randomized prospective trials are need in this area to determine the duration of treatment. Among nondermatophytes, Scytalidium and Onychocola respond very poorly to all oral antifungal agents. There are some successful results in combination with topical agents [78,79,82]. Candida onychomycosis is commonly seen in immunosuppressed patients, especially in chronic mucocutaneous candidiasis. Itraconazole (200 mg per day continuously, or pulse therapy with 400 mg daily for a week with 3 week off interval) and fluconazole (50 mg daily or pulse therapy with 300 mg per week) for 3 weeks for fingernails and 6 weeks for toenails are commonly used regimens. Candida parapsilosis is more susceptible to terbinafine [79,82]. Urinary tract infections Urinary tract infections account for approximately 25% of all community-acquired bacterial infections, and at least 30% of all bacterial infections in elders residing in nursing homes [94]. Thinning of the mucopolysaccharide layer in the urinary epithelium of women allows increased bacterial growth. An important factor in preventing colonization by pathogens is the low vaginal pH, which increases with aging. Vaginal and periurethral antibodies are slightly deficient in elders [95]. Properties of urine that provide some antibacterial activity include the low pH, extremes of osmolarity, high urea, high organic acid concentration, and bactericidal prostatic secretions in men [88]. All of these change with aging, decreasing protection against bacteria. The Tamm-Horsfall protein in the urine adheres to and covers type 1 fimbriae on gram-negative bacteria,

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reducing bacterial attachment to the mucosal surface of the urinary tract. This activity is also decreased in the urine of elders [96]. Regular emptying of the bladder and a brisk urinary flow are mechanical defenses against infection. In the aging bladder, the volume of urine in the bladder required to sense the need to void increases by about 100 mL. Rate of urine flow with each void is also decreased [96]. In addition, bladder prolapse in women and prostatic disease in men may contribute to urinary stasis, contributing to increased prevalence of bacteriuria [95]. Urinary tract infection is the most frequently encountered infection among the elderly population, especially in long-term facility residents [97–99]. Epidemiology Urinary tract infection was responsible for up to 7 million out-patient visits and 1 million emergency room visits, according to the 1997 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey [100]. Twelve percent to 30% of residents of longterm care facilities are found to have a minimum of one episode of urinary tract infection every year, with higher rate of incidence and recurrence in female residents [101]. Asymptomatic bacteriuria is very commonly found in extended care facilities, where the prevalence ranges from 15% to 30% in men and 25% to 50% in women. Institutionalized elderly people with neurologic and urologic disorders have a higher rate of asymptomatic bacteriuria. Asymptomatic bacteriuria has been found to have higher association with aging, diabetes, and previous urinary tract infection [97,98]. In prospective studies, symptomatic urinary tract infection prevalence varies from 0.1 to 2.4 cases per 1000 resident-days, depending on the type of facility and residents [89]. Elderly men are shown to have higher risk of developing urinary tract infection with systemic complications after undergoing invasive urologic procedures without preoperative antibiotic prophylaxis and bowel preparation [98,102]. Clinical features Symptomatic urinary tract infections usually present with local irritative symptoms, such as urgency, increased frequency in cystitis, and costovertebral tenderness in pyelonephritis, and systemic symptoms, such as fever. In the elderly population, the systemic symptoms are frequently absent because of the aging immune system, and the local symptoms are also obscured by the presence of pre-existing chronic genitourinary symptoms, such as incontinence secondary to neurogenic bladder or benign prostatic hypertrophy [97]. Hematuria can represent a sign of infection, although various causes including local trauma or malignancy should be excluded [89]. Although presence of pyuria alone is not significant, its absence can be used to exclude urinary tract infection with high negative predictive value of 80% to 90% [97].

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Diagnosis Diagnosis of urinary tract infection in the elderly population should be made by the combination of clinical and microbiologic findings, because older adults tend to have pre-existing laboratory abnormalities. Presence of pyuria and increased leukocyte esterase and nitrite level should not be interpreted as infection without clinical correlation [99]. Asymptomatic bacteriuria in women is diagnosed by quantitative cultures showing 100,000 colony-forming units per milliliter of the same microorganism in two consecutive urine specimens, whereas in men only a one-time sample is needed. It is not uncommon to find more than one organism in urine cultures, which is frequently mistaken as contamination. A clean catch sample is required for accurate results of urinalysis and culture. For such a specimen, in and out catheterization is recommended for collecting specimen from female patients [97,101]. E coli is the most commonly isolated organism in urine of asymptomatic patients from both community and long-term care facilities. Gram-negative polymicrobial bacteriuria with highly resistant organisms (Citrobactor freundii, Enterobacter cloacae, P aeruginosa, Providencia stuartii) is more frequent in residents of long-term care facilities [103]. Bacteria are the most common cause of urinary tract infection, although sometimes fungi and some viruses can cause infection. Common uropathogenic bacteria are listed as follows [104]: Gram-negative bacteria Escherichia coli Proteus mirabilis Klebsiella species Citrobacter species Enterobacter species Pseudomonas aeruginosa Gram-positive bacteria Coagulase-negative staphylococci Enterococci Group B streptococci Staphylococcus aureus Candia albicans is the most common species found in the urine. Candiduria is associated with female gender, stay in intensive care unit, antimicrobial therapy, and indwelling urinary catheter [104,105]. Treatment Asymptomatic bacteriuria It has been well documented in prospective randomized studies that there is no improvement in survival rate when treated with antimicrobial therapy.

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Mortality tends to increase secondary to adverse side effects from antibiotics and superinfection with resistant organisms. It is not advisable to screen and treat asymptomatic bacteriuria in the elderly population. Usage of natural substances, such as cranberry juice, was also shown to have no added benefit. Screening and treatment of asymptomatic bacteriuria should be undertaken in selected populations, such as the elderly undergoing invasive urologic procedures (eg, transurethral resection of the prostate gland) [101,102,106]. Catheter-related urinary tract infection Patients with indwelling urinary catheters make up about 5% to 10% of long-term care facility residents and most of them are found to have bacteriuria and pyuria [98]. Short-time catheterization usually results in single organism infection, whereas long-term indwelling catheters tend to cause polymicrobial infections [103]. In one study, 100% of all patients with indwelling catheters showed bacteriuria and 70% of them were also found to have pyuria [106]. Catheters contain stagnant urine promoting development of biofilm on the interior surface, which can harbor a large number of microorganisms. It has been shown in prospective trials that simply changing the catheter improves clinical symptoms [98]. Treating asymptomatic bacteriuric patients with catheters has not shown any benefit and actually increases the chances of reinfection with multidrug resistant organisms [106]. In symptomatic patients with catheters, treatment should begin with removal of the catheter to rule out any obstruction followed by microbiologic and radiologic evaluations and initiation of broad-spectrum antibiotics (carbapenems, third- or fourth-generation cephalosporins, quinolones, pipercillin, aztreonam, aminoglycosides) in anticipation of infection with resistant organisms. De-escalation of antibiotics to narrow-spectrum agents should be done after the culture results become available. In case of obstruction, reinsertion of catheters should be avoided. Obstruction is common in patients with urea-splitting organisms (P mirabilis, Proteus vulgaris, P stuartii, Morganella morganii, Staphylococcus saprophyticus, Corynebacterium urealyticum, Mycoplasma urealyticum) [107]. Symptomatic urinary tract infections If the patient with symptomatic urinary tract infection is clinically stable without systemic symptoms, urinary analysis and cultures first should be obtained. After the results are available, the infection should be treated with directed antimicrobial agent. This reduces the empiric usage of broadspectrum antibiotics and emergence of resistant pathogens. Longer duration of antibiotic therapy is needed in the elderly population compared with young adults [97,103,104,108]. Choice of oral antimicrobials includes trimethoprim-sulfamethoxazole, second-generation cephalosporins, fluoroquinolones, or nitrofurantoin. In seriously ill patients with systemic manifestations and upper urinary tract involvement, intravenous therapy with b-lactam agents, such as

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extended-spectrum cephalosporins, carbapenems, aztreonam, and piperacillin, fluoroquinolones, and aminoglycosides, should be started presumptively before the culture results are available. In patients with indwelling catheters, the addition of ampicillin or vancomycin should be considered for enterococcus coverage. Minimum treatment duration of 14 days is recommended [97,103]. Relapse of infection arises from ineffective eradication of infection and recurrence of the infection with the same organism after discontinuation of antibiotics. Thorough evaluation of the genitourinary system is warranted. Reinfection refers to the development of new infection with a different organism within a short period secondary to poor hygiene or chronic conditions unfavorable to free flow during voiding of urine [103]. Based on the expert opinions and clinical experiences, treatment of candiduria should be considered only in special situations including patients with symptoms, neutropenia, renal transplant, and urologic procedures. Choice of treatment includes amphotericin B intravenously or irrigation of bladder, oral or intravenous administration of fluconazole, or oral flucytosine. Bladder irrigation with amphotericin B has shown better initial clearance data but similar long-term results when compared with its oral competitors. Use of oral fluconazole in conjunction with catheter removal leads to better eradication in patients with indwelling catheters and the best result in patients without catheters [105]. With increasing incidence of extended-spectrum b-lactamase producing gram- negative organisms and high levels of resistance to fluroquinolones and cephalosporins in health care–associated settings, carbapenems and piperacillin should be the preferred choices for presumptive antibiotics. In a recent review of 43 episode of bacteremia caused by the extended-spectrum b-lactamase producing E coli, 46% originated from the urinary tract [109]. In a review of staphylococcal bacteriuria, 70% of samples were from extended care facility residents and 82% of them had an indwelling catheter. Most (86%) of the isolates were methicillin-resistant S aureus. Keeping these data in mind, the presumptive use of antibiotics for gram-positive coverage with anti–methicillin-resistant S aureus agents, such as vancomycin, should be considered in seriously ill long-term facility residents [110]. Prophylactic antibiotics should be used only in patients undergoing invasive urologic procedures. Suppressive antibiotics should be used only in selected cases, such as continuously symptomatic patients, or to prevent the recurrence of struvite stones [97]. Respiratory tract infections Age-related changes that predispose elders to respiratory infections include reduced mucociliary clearance, lung elasticity, chest compliance, muscle strength, and cough reflex [19]. Most bacterial pneumonias are the result of microaspiration of bacteria from oral secretions. Oral clearance seems to be maintained until the pharynx becomes colonized with

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pathogenic bacteria. Cilia that line the nasal epithelium and trachea decrease in number with aging, and mucociliary clearance time is increased [95]. Changes in elastin and collagen in the lung matrix diminish the elastic recoil of the lung. Decrease in elastin and loss of alveolar pores in the collagen fiber network cause enlargement of air spaces and allow small airways to close more readily [111,112]. The chest wall becomes less compliant because of narrowing of the intervertebral disk spaces, calcification of intercostal cartilages, and kyphosis. Respiratory muscles including the intercostal muscles and diaphragm weaken [19]. These changes result in incomplete lung expansion, air trapping, accumulation of secretions, and less effective coughing [111]. Pneumonia As stated by Sir William Osler, ‘‘in old age, pneumonia may be latent, coming on without chill, the cough and expectoration are slight, the physical signs ill defined and changeable, and the constitutional symptoms out of all proportion’’ [113]. In the United States, pneumonia and influenza together are the sixth leading cause of death [114]. About half of all cases of pneumonia are patients 65 years of age and older [115]. Etiologic agents The microbial causes of pneumonia vary according to severity of illness and environmental factors. Common causes of community-acquired pneumonia in elderly patients are shown in Table 1. Streptococcus pneumoniae accounts for most cases of communityacquired pneumonia in the elderly. Although Chlamydia or Mycoplasma infections occur in elderly persons, such infections are relatively more common in younger populations. Elderly patients with comorbid conditions like cardiopulmonary or renal disease and diabetes have increased likelihood of acquiring pneumonia caused by gram-negative organisms, such as P aeruginosa [116]. The pathogens responsible for pneumonia in elderly patients living in longterm care facilities are listed in Table 1. The etiology of nosocomial and hospital-acquired pneumonia in elderly patients is also shown in Table 1. Clinical features Classic symptoms of pneumonia including fever, chills, cough, expectoration, and shortness of breath are seen less frequently in the elderly population. Instead, they may present with atypical manifestations, such as delirium, worsening of chronic confusion, weakness, lethargy, increased falls, and other nonrespiratory symptoms [117,118]. These nonspecific symptoms of pneumonia in elderly people may contribute to delayed diagnosis and treatment and subsequent increased mortality.

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Table 1 Common microbial causes of pneumonia in the elderly Community-acquired pneumonia

Pneumonia in long-term care facilities

Pneumonia in hospitalized patients

Streptococcus pneumoniae

Enteric gram-negative bacilli Oral aerobes and anaerobes (aspiration) Staphylococcus aureus

Enteric gram-negative bacilli Oral aerobes and anaerobes (aspiration) Staphylococcus aureus

Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Influenza and other viruses

Streptococcus pneumoniae Legionella pneumophila Moraxella catarrhalis Other gram-negative pathogens, including Acinetobacter baumani and Stenotrophomonas maltophilia (rarely) Influenza and other viruses

Haemophilus influenzae Enteric gram-negative bacilli Staphylococcus aureus Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila

Influenza and other respiratory viruses

Diagnosis The diagnostic work-up for pneumonia remains the same for all patients in all age groups. Chest radiograph is the gold standard for diagnosis, but it is important to know that pneumonia in an elderly patient who is dehydrated may not show infiltrate or consolidation on chest radiograph. Findings may appear after hydration [119]. Sputum Gram stain with culture and blood cultures are recommended in all elderly patients with pneumonia. Initial work-up should include complete blood count with differential, serum electrolytes with creatinine, and pulse oximetry. Treatment Initial presumptive antimicrobial therapy for pneumonia in elderly patients should be based on residence of the patient at the time of infection. Appropriate antibiotic regimen in setting of community-acquired pneumonia in the elderly may include a third-generation cephalosporin (ceftriaxone or cefotaxime) and a macrolide (azithromycin or clarithromycin) or monotherapy with antipneumococcal fluoroquinolones (levofloxacin or moxifloxacin). Pneumonia in the elderly living in long-term care facilities should be treated either with a respiratory fluoroquinolone alone or with macrolide (azithromycin or clarithromycin) plus amoxicillin-clavulanate [120]. Antibiotic therapy in cases of nosocomial pneumonia may include an antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus a respiratory fluoroquinolone. Additionally, vancomycin or linezolid should be considered for treatment of pneumonia in elderly patients if the local hospital or extended care facility has high methicillin-resistant S aureus prevalence rates.

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It is important to remember, however, that initial antimicrobial regimen should always be modified if a specific pathogen is isolated from respiratory specimen cultures. Timely administration of an appropriate antibiotic is essential in improving patient outcomes. In a large study by Meehan and colleagues [121], approximately 75% of patients who received the first dose of antibiotic within 8 hours on arrival at the hospital had significantly lower 30-day mortality than those who received the first dose of antibiotic at a later time. Viral pneumonia Community-acquired pneumonia in elderly patients can also be viral in etiology. Respiratory viruses of importance in this setting are influenza virus, parainfluenza virus, respiratory syncytial virus, and human metapneumovirus. Influenza Influenza is seen typically in winter months in the United States. Influenza is efficiently transmitted by small aerosol particle generated by coughing and sneezing. This, combined with a short incubation period of 2 to 3 days, facilitates frequent outbreaks in confined settings, such as nursing homes and other group homes. Clinical manifestations of influenza in elderly patients may be atypical and differ from those in younger adults. Cough, fever, and acute onset of illness had only 30% positive predictive value in elderly outpatients with influenza compared with 78% positive predictive value for younger adults [122]. Cough, fever, and chills may still be the predominant symptoms, however, combined sometimes with altered mental status. Secondary bacterial pneumonia is an important complication of influenza, and staphylococci and streptococci are common bacterial pathogens [123]. Diagnosis of influenza A and B is made by viral culture (gold standard) and rapid antigen testing from nasopharyngeal Dacron swab. Antiviral drugs available for treatment of influenza include amantadine; rimantadine (influenza A only); and oseltamivir and zanamivir (influenza A and B). Oseltamivir has been shown to reduce the duration and severity of acute symptoms of influenza and is approved for use in patients with influenza within the first 48 hours of onset of symptoms [124,125]. Oseltamivir and zanamivir are also available for prophylaxis in elderly unvaccinated patients in cases of exposure to influenza. Annual influenza vaccine (inactivated) is recommended for elderly persons 65 years and older, persons aged 50 to 64 years particularly if they have high-risk medical conditions, and residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions [126]. Vaccination remains the most effective way of reducing morbidity and mortality associated with influenza in elderly persons as demonstrated in a meta-analysis done by Gross and colleagues [127].

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Human metapneumovirus Human metapneumovirus is a newly described respiratory virus identified by a Dutch researcher in 2001 in young children with respiratory illness resembling respiratory syncytial virus bronchiolitis [128]. Most studies identified this virus in children. Only limited data are available on human metapneumovirus infection in elderly and institutionalized adults. The clinical characteristics of human metapneumovirus pneumonia in elderly patients are not very distinctive from those caused by other respiratory viruses and may be somewhat less severe than influenza and respiratory syncytial virus infection [129]. Boivin and colleagues [130] reported an outbreak of human metapneumovirus infection associated with high morbidity and mortality in a long-term care facility, which was also the first reported outbreak of human metapneumovirus infection in this setting. Tuberculosis Epidemiology Because of decreased cell-mediated immunity, underlying acute or chronic diseases, malnutrition, and other reduced immune defenses with aging, the elderly are more prone to tuberculosis (TB) infection as a result of reactivation of previously acquired latent infection. After its peak in 1992, the annual incidence of TB has been decreasing in the United States [131]. Since national reporting began in 1953, the lowest number was recorded in 2005 when a total of 14,093 TB cases (4.8 cases per 100,000 populations) were reported [132]. Patients over 65 years of age comprise over half of all TB cases in the United States [133]. Among the elderly population, nursing homes residents have higher rates of TB infection as compared with elderly residing in the community [134]. In this section the focus is on pulmonary TB. Clinical features Clinical features of TB in elderly patients are usually nonspecific and atypical. Symptoms may include unexplained weight loss, cough, fever, night sweats, hemoptysis, and failure to thrive. It may also cause impaired cognitive status with other nonspecific manifestations. The atypical and different clinical manifestations of TB in the elderly as compared with younger population may cause a delay in diagnosis and subsequent increased morbidity and mortality in this age group [135]. The physical examination findings in elderly patients with TB are usually also nondiagnostic and nonspecific. Diagnosis Because of its atypical manifestations in elderly patients, TB may remain undiagnosed and unrecognized for a period of time, which means a high index of suspicion is needed by the clinician. Helpful diagnostic studies

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include chest radiograph, tuberculin skin test, and any appropriate specimen for microbiologic or histologic examination and routine blood counts and chemistry. A positive skin test means previous or current infection with Mycobacterium tuberculosis, but a negative skin test does not rule out the diagnosis. Findings of pulmonary TB on chest radiograph usually include infiltrate or cavitary lesion in one of the upper lobes, but it is important to remember that in elderly patients, mid or lower zone infiltrates may predominate on chest radiograph [136]. The gold standard for the diagnosis of TB is culture-isolation of the organism from secretions or from a tissue-fluid specimen, which can take up to 6 weeks to grow on special culture media. The need for a rapid diagnostic test has been met by molecular methodologies including nucleic acid amplification tests, which allow detection of the M tuberculosis complex in clinical specimens and provide rapid diagnostic information generally within 24 to 72 hours. Treatment Treatment of pulmonary TB in elderly patients does not differ from other age groups. The treatment regimen for most elders with previously untreated TB should consist of an initial 2 months of isoniazid, rifampin, pyrazinamide, with or without ethambutol, followed by isoniazid and rifampin for an additional 4 months [137]. The continuation phase of treatment should be extended to 7 months (9 months total duration) in patients with cavitary pulmonary TB caused by drug-susceptible organisms when the sputum culture remains positive at 2 months of treatment or in patients who did not receive pyrazinamide during the initial phase of treatment [138]. Because of adverse effects of these medications, it is important to monitor liver function profile periodically, especially in elderly patients. Current recommendations for management of latent TB are treatment with isoniazid for 9 months. Treating latent TB infection in nursing home residents with positive tuberculin skin test remains debatable. A study done by Stead and colleagues [139] showed that 3.8% of men and 2.3% of women who were tuberculin positive on admission to nursing homes developed active disease. Because of adverse effects of isoniazid treatment, authors did not recommend treatment for every one with latent TB in this population group. They showed, however, that 11.6% of men and 7.6% of women developed active disease without treatment of latent TB infection but only 0.2% with treatment of latent TB infection. Latent TB treatment was clearly beneficial in patients who converted tuberculin skin test after admission to nursing homes. Gastrointestinal tract infections Effective salivary flow and swallowing are important protective mechanisms against pathogens in the oral cavity [19]. Dental research has determined that there is an age-related decline in saliva output and alterations

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in antimicrobial proteins in saliva. The histatins that have anticandidal effect are in particular decreased [140]. Many elders complain of xerostomia and the problem is aggravated by medications [19]. Tongue strength decreases with aging, and swallowing is generally slower. These factors increase the risk of aspiration pneumonia, should the elder experience a cerebrovascular or neurodegenerative disease [141]. Decreased gastric acid secretion was once thought to be a normal aging change that increased the risk for infections. These studies, however, predated discovery of Helicobacter pylori. Recent studies conclude that gastric acid secretion is not decreased with aging [142]. Decreased gastric acid secretion may be the result of mucosal atrophy secondary to the high prevalence of infection with H pylori, with approximately 50% of older adults infected [143]. Whatever the cause of decreased secretion, achlorhydria increases the risk of further bacterial and fungal infections [144]. Recent research has demonstrated that there is no overgrowth of bacteria in the intestine of elders. Bacterial overgrowth appears only in functionally impaired elders, presumably related to decreased motility of the intestine from immobility [145]. Age-related changes in the microflora of the intestine have been identified. Protective bifidobacteria and anaerobes both decrease, whereas Enterobacteriaceae increase. The decrease in anaerobic flora reduces the elders’ defense against enteric pathogens and may favor gastrointestinal infections with organisms like Clostridium difficile [146]. Clostridium difficile–associated diarrhea Clostridium difficile is a well recognized cause of diarrhea in the elderly population. History of C difficile infection dates back to 1974 when Tedesco and colleagues [147] reported cases of pseudomembranous colitis. Because of its frequent association with clindamycin, it was called ‘‘clindamycinassociated colitis.’’ It was not until 1978 when the cause of pseudomembranous colitis was identified as C difficile [148]. Epidemiology There has been a significant increase in the incidence and severity of C difficile–associated diarrhea over the last few years. This organism is endemic not only in hospitals but also in long-term care facilities. C difficile is the most common cause of nosocomial diarrhea. There also has been a rise in incidence of community-acquired cases of C difficile–associated diarrhea, even without prior antibiotic exposure. A new, highly virulent strain of C difficile has appeared that is less responsive to standard therapy and associated with high recurrence rate. An example is a regional outbreak in Que´bec, Canada, in 2004 reported by Loo and colleagues [149]. Similar outbreaks have been reported from different hospitals in the United States [150]. This new epidemic strain is B1/NAP1 of toxinotype III and is positive for binary toxin. Recent studies have supported the hypothesis that this new strain produces 16 to 23 times excessive toxin A and B in vitro than do other strains [151,152].

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Risk factors Colonization with C difficile is common in residents of long-term care facilities and may be asymptomatic. It is only under selection pressure of antibiotics when suppression of indigenous bowel flora causes proliferation of C difficile, which then becomes a pathogen and causes diarrhea. Prior exposure to antibiotics is the major risk factor for the disease. Even brief exposure to a single antibiotic can cause C difficile–associated diarrhea. Antibiotics of particular concern include clindamycin, second- and thirdgeneration cephalosporins, and fluoroquinolones. Clinical manifestations Symptoms and signs typically occur after 5 to 10 days of antibiotic treatment but may vary from the first day of antibiotic treatment and up to 10 weeks after stopping antibiotic. Common symptoms and signs in the elderly include diarrhea, abdominal cramping, fever, and leukocytosis. Occasionally, leukocytosis without diarrhea may be the only manifestation of C difficile infection. Toxic megacolon is an important complication of C difficile infection associated with high morbidity and mortality and can present in elderly patients as acute abdominal syndrome without diarrhea. Diagnosis The gold standard and most specific test for the diagnosis of C difficile– associated disease is cell cytotoxin assay. The most sensitive test is stool culture for C difficile [153]. Both of these tests have relatively slow turnaround time and may require more than 1 day to yield results. The most widely used method of diagnosing C difficile infection is by detection of C difficile toxins in stool specimens. Enzyme immunoassay detects both toxins A and B. This test has a rapid turnaround time and is also very specific (75%–100%) but not as sensitive (63%–94%) [154]. Repeat stool testing can increase the sensitivity of this test. Treatment and prevention Implicated antimicrobial agents for predisposing to C difficile–associated diarrhea should be promptly discontinued. Oral metronidazole is considered the drug of first choice for most cases. For recurrent and severe C difficile infection and for those not responding to metronidazole, oral vancomycin should be used. Antiperistaltic agents, such as diphenoxylate hydrochloride and loperamide, should be avoided. There is little evidence to suggest that these agents lead to symptomatic improvement. Strict infection-control measures, including contact precautions, are recommended for all patients with C difficile–associated diarrhea. Because alcohol is ineffective in killing C difficile spores, hand washing with soap and water is recommended instead of alcohol-based waterless hand sanitizers after contact with patients with C difficile–associated disease during an outbreak [155]. Of particular importance is antimicrobial stewardship with restriction of offending antimicrobial agents in a given setting.

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Helicobacter pylori Helicobacter pylori was first isolated in 1982 in humans when Marshall and Warren [156] identified and subsequently cultured the gastric bacterium, Campylobacter pyloridis, later reclassified as H pylori [156,157]. Epidemiology The worldwide prevalence of H pylori infection increases with age, with prevalence rates of 40% to 60% in asymptomatic elderly individuals and about more than 70% in elderly patients with gastroduodenal disease [158,159]. Residing in a nursing home is a significant risk factor for H pylori infection [160]. There is also a strong correlation between duration of stay at a nursing home and prevalence of H pylori infection [160,161]. Regev and colleagues [160] showed that elderly subjects who had stayed in nursing homes for more than 15 months had significantly higher colonization rates with H pylori compared with subjects with shorter duration of institutionalization. Clinical outcomes of Helicobacter pylori infection in elderly patients The clinical presentation of H pylori is highly variable and is influenced by both microbial and host factors. It may cause an acute upper gastrointestinal illness with nausea and upper abdominal pain. Vomiting and fever may also be present. Symptoms last from 3 to 14 days. After H pylori acquisition, virtually all persons develop colonization that may persist for years. The clinical sequelae of long-term colonization with H pylori include chronic gastritis, gastric or duodenal ulcer, gastric adenocarcinoma, and gastric lymphoma. Gastric cancer is the second most frequent cause of cancer-related death in the world. The role of this organism in carcinogenesis has been well established [162,163]. Most gastric lymphomas arise from B lymphocytes and are termed ‘‘mucosa-associated lymphoid tumors.’’ H pylori significantly increases the risk of gastric mucosa-associated lymphoid tumors. Multiple studies have demonstrated an association between H pylori infection and mucosa-associated lymphoid tumors, and eradication of H pylori often leads to improvement in tumor histology [164,165]. Diagnosis Helicobacter pylori colonization or infection can be detected by invasive or noninvasive methods. Noninvasive diagnostic tests include urea breath test, serologic test, and stool antigen assay. The stool antigen assay is also helpful in determining whether H pylori eradication has occurred after treatment. Elderly patients and those with alarming symptoms, such as gastrointestinal bleeding, anemia, or weight loss, should undergo endoscopy with biopsy for diagnosis of H pylori infection [166]. Upper gastrointestinal endoscopy is almost always indicated in elderly patients with new or alarming abdominal symptoms. When endoscopy is indicated, the test of choice is

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usually a urease test on the antral biopsy specimen. A study done by Abdalla and colleagues [167], however, showed that rapid urease test performed on antral biopsies has a lower sensitivity in patients 60 years and older as compared with subjects younger than 60 years. This suggests that in elderly patients, a gastric biopsy should be taken not only from the antrum but also from the body of the stomach. If the initial urease-based test or histologic test is negative, a second test should be performed for H pylori [158]. Treatment Triple proton pump inhibitor–based treatment regimens are shown to be effective and well tolerated in the elderly population. In addition to a proton pump inhibitor, triple therapy usually includes amoxicillin plus clarithromycin, or clarithromycin plus metronidazole, or amoxicillin plus metronidazole. The most commonly recommended first-line treatment regimen for H pylori is triple therapy with a proton pump inhibitor (eg, pantoprazole, 40 mg twice daily; lansoprazole, 30 mg twice daily; omeprazole, 20 mg twice daily; rabeprazole, 20 mg twice daily; or esomeprazole, 40 mg once daily), amoxicillin (1 g twice daily), and clarithromycin (500 mg twice daily) for 7 to 14 days. Studies in elderly subjects have demonstrated that a 1-week course of proton pump inhibitor–based triple regimens are highly effective [168]. In elderly patients, proton pump inhibitor–based triple therapy may include clarithromycin at a lower dose of 250 mg twice daily (as opposed to 500 mg twice a day) combined with standard dosage of proton pump inhibitor and either amoxicillin or metronidazole [158]. Resistance of H pylori to antibiotics is a major issue. Resistance is more common to metronidazole as compared with clarithromycin and observed rarely with amoxicillin. Summary Many functional, demographic, and immunologic changes associated with aging are responsible for increasing the incidence and severity of infectious diseases in the elderly. The same factors are also responsible for subtle or atypical clinical presentations. Often, the management is complicated by age-related organ system changes (eg, renal insufficiency). Because many of the elderly are on multiple medications for underlying illnesses, antimicrobial therapy needs to be chosen with drug interactions and adverse events kept in mind. Common infections seen in the elderly are infections of skin and soft tissue (including pressure ulcers) and of the urinary tract, respiratory tract, and gastrointestinal tract. Elders in acute and extended care facilities carry an added burden of acquiring infections, including those caused by antibiotic-resistant organisms. The use of infection control practices and vaccines is often suboptimal in this patient population. The hospitalization and mortality rates for infectious diseases are highest among persons older than 85 years. Because this is the fastest growing

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