Infectious diseases can pose a major threat to older adults. Susceptibility to infection increases with age, and treatment is often complex due to multiple comorbidities and decreased organ functional reserves. Older adults can present atypically with infections, which increases the risk of a delayed or missed diagnosis.1 Common infections in older adults include pneumonia, urinary tract infections (UTIs), skin infections, and chronic disease exacerbations (which may also require antimicrobial treatment). However, the frequent use of antimicrobials in older adults has led to concerns about antimicrobial drug resistance and the need for improved stewardship.
It is estimated that at least 30% of antibiotics prescribed in the US are not needed.2 Judicious use of antimicrobials is warranted because adverse drug reactions and Clostridium difficile infection (CDI) are leading causes of morbidity and mortality in older adults.3 CDIs are becoming more prevalent, including antibiotic-resistant strains that can often lead to hospitalizations in older adults.3 Polypharmacy, poor adherence to treatment, greater severity of illness, and comorbidities are common factors in older adults that can impact treatment success. Increased individual variation secondary to altered pharmacokinetics and pharmacodynamics also makes prescribing a challenge in these patients.1,4,5
Aging immune system and risk of infection
Age-related physiologic changes place older adults at higher risk for infectious diseases. Immunosenescence affects all branches of the immune system (cellular, humoral, and innate immunity). Significant changes include atrophy of the thymus, a reduction in lymphocytes, altered B- and T-cell function, changes in cytokines and growth factor secretion, and changes in antibody production and antibody response.
By age 75, the thymus gland is nothing more than fatty scar tissue. It is responsible for T-lymphocyte development in childhood that will last a lifetime; the total number of T-lymphocyte cells does not significantly decrease with age, but the T-cell subset populations change.6 The cumulative effects of aging on T-helper cell function are most pronounced, affecting both cellular and humoral immunity. T-cell mediated defects increase the risk of intracellular pathogens, such as Listeria monocytogenes, Salmonella spp., Legionella spp., and mycobacterial infections.5
Although B-cell numbers are not significantly affected by aging, B-cell ability to respond to antigens is limited. Encapsulated bacteria such as Streptococcus pneumoniae are associated with B-cell mediated defects and lowered antibody production.1 There can also be a reduced response to immunizations and reactivation of latent infections, such as Mycobacterium tuberculosis and varicella-zoster virus.5 Overall, fewer mature B and T cells are produced with age.7 Chronic low-grade inflammation in older adults that can be observed by increased proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, can further compromise the immune system.7
The effects of proinflammatory cytokines include oxidative stress, lowered antioxidants, and increased cortisol levels that can further accelerate the decline in immunity.7 Changes in growth factor secretion associated with aging have implications in the development of cardiovascular disease, type 2 diabetes mellitus (T2DM), and retinal eye disease.8
The most common infectious diseases among older adults are UTIs, lower respiratory tract infections, and skin and soft tissue infections that occur across settings (community, hospital, or long-term-care [LTC] facilities).1,5 Bloodstream infections are more likely to be found in the hospital, and gastrointestinal (GI) infections are more common in community dwellers and LTC facility residents.1
Comorbidities in the older adult population—particularly chronic cardiac and pulmonary diseases—can increase susceptibility to infection. Comorbid conditions include chronic inflammatory diseases (chronic obstructive pulmonary disease, atherosclerosis, diabetes mellitus) that produce proinflammatory cytokines and have been linked to higher risk for infections, such as pneumonia.7,9 Medical devices such as indwelling urinary catheters, joint prostheses, pacemakers, and artificial cardiac valves can also be risk factors for infection.1
Older adults living in institutions are particularly challenged in host defenses and environmental risk factors. Host defenses in this population can be compromised by dysphagia, malnutrition, and poor oral hygiene, which are often related to dementia. Communal living can promote rapid transmission of respiratory and GI infections, including multidrug-resistant organisms. The severity of infection increases with age, and prognosis of recovery has been linked to functional status in those over age 80, leaving LTC facility residents at a high risk for poor outcomes, including death.5,10
Atypical presentation of infectious disease in older adults
Ms. M, 75, lives in an LTC facility. She has a history of hypertension, chronic kidney disease (stage 2), and T2DM. The nursing staff reports a decrease in her appetite and a decline in her ability to participate in activities of daily living. Ms. M complains of being tired and not feeling like her normal self but offers no other specific complaints. She is afebrile.
Diagnosis of an infection may be delayed in part because of the unusual way older adults present with the signs and symptoms of illness. This can be further complicated by the presence of comorbidities that the clinician may consider as the cause of the complaint instead of infection. The added challenge of cognitively impaired older adults who may not be able to provide a history of present illness requires even more vigilance from the clinician. The usual febrile response that accompanies infection may be blunted, absent, or have a delayed onset, such as with Ms. M in the case example.1,5
Normal baseline temperature of older adults is lower than younger adults, and this can lead to missing a significant rise in body temperature. Furthermore, other signs of inflammation, such as leukocytosis, may not be present. Approximately half of older adults with an infection will not have localizing symptoms or findings on physical exam that suggest infection, and that same percentage will have normal lab results.1
The blunted or lack of inflammatory response is largely responsible for this unexpected or atypical presentation. Therefore, it is essential that infection be considered in older patients even if the signs of inflammation are absent; however, diagnostic criteria for the specific infection should be met before prescribing antibiotics.1,5,11 The McGeer Criteria for Infectious Syndromes in Older Adults is a helpful evidence-based framework for clinicians who are trying to diagnose infections in older adults.1,11
Pharmacodynamics and pharmacokinetics in older adults
There is no clear and definitive picture of pharmacodynamics and aging. Changes in how the aging body responds to a given drug may be related to several factors, such as the availability of receptors (increase or decrease), receptor affinity, and postreceptor alterations. A receptor can be defined as any functional macromolecule in a cell to which a drug binds to produce its effects. For example, beta-adrenergic blocking agents are generally less effective in older adults than in younger adults, even when they have the exact same drug concentrations. It could be a reduction of beta-receptors in older adults or a reduction in the affinity of the beta-receptor for the agent that produces this change in drug response.12,13
Older adults may experience more intense effects of drugs, which suggests a possible increase in receptors, stronger receptor affinity, or both. Affinity refers to the strength of the attraction between a drug and a receptor. Examples of drugs that produce strong effects in older adults include warfarin and central nervous system depressants. Impairment of homeostatic mechanisms such as fluid and electrolyte balance and acid-base balance can also play a role in how the body responds to a certain drug. It can be difficult to predict drug response, as age-related changes can vary greatly from person to person. There is limited information on the pharmacodynamics of antimicrobials in older adults, but it should be considered when a drug does not have the desired effect.12
Disease and the aging process can affect all phases of pharmacokinetics. The extent of age-related changes varies greatly among patients because general health and fitness are major contributors to a slower aging process. Starting in early adulthood, there is a gradual and progressive decline in organ function. Reduced hepatic and renal function has the greatest influence on the body's sensitivity to drugs. Pharmacokinetics is how drugs move through the body in four phases: absorption, distribution, metabolism, and excretion (see Effects and implications of aging on pharmacokinetics).9
A long-standing clinical pearl for prescribing drugs to older adults is to “start low and go slow” when initiating and titrating drug therapy; however, this approach can lead to suboptimal clinical outcomes, particularly with antimicrobial therapy. It can be a delicate balance to provide aggressive antimicrobial dosing to achieve a satisfactory clinical response without doing harm to the aging body.1 Adverse drug reactions (ADRs) are seven times more likely to occur in older adults than younger adults. ADRs account for 16% of hospital admissions and 50% of medication-related deaths in older adults.13
The increase in ADRs is related to multiple factors that often accompany the aging process, including greater severity of illness, the presence of comorbidities, inadequate supervision of therapy, and poor patient adherence.1,9 The majority of ADRs in older adults can be avoided by taking a few measures that are effective in reducing their incidence:13
- Take a thorough drug history, including over-the-counter medications, to decrease the incidence of drug-to-drug interactions.
- Consider pharmacodynamic and pharmacokinetic changes that may occur with aging and understand that there is wide individual variation.
- Start at a low dose if indicated.
- Closely monitor plasma drug levels if indicated and the clinical response.
- Order the simplest treatment regimen possible.
Careful consideration of potential drug-to-drug interaction is important when prescribing antimicrobials (see Common antimicrobial-induced interactions and adverse reactions in older adults).1,11,13 Commonly used drugs in older adults can potentially interact with many antimicrobials, including warfarin, loop diuretics, digoxin, antacids, and proton pump inhibitors (PPIs). In some cases, another class of antimicrobial is indicated, whereas in others, increased patient monitoring will suffice. For example, frequent monitoring of the international normalized ratio (INR) for patients taking warfarin is warranted because studies show exposure to a variety of antimicrobial agents (azoles and other classes of antifungals, macrolides, trimethoprim/sulfamethoxazole, penicillins, and cephalosporins) is associated with increased bleeding.14
A baseline kidney function test and ongoing monitoring during therapy are warranted prior to starting aminoglycosides.13 It is essential that the prescriber knows all medications the patient is taking as well as accurate information on alcohol, tobacco, and recreational drug use to minimize drug-to-drug interactions. This includes the type of substances used, how often, and for how long the patient has been using them. Abstaining from alcohol is important whenever drug-induced hepatitis is a concern (for example, with antifungal medications).12,13
Common medications can interact with antimicrobials. For example, HMG-CoA reductase inhibitors (statins) can interact with certain macrolides to increase the risk of rhabdomyolysis by inhibiting the CYP3A4 isoform of cytochrome P450. Fortunately, azithromycin, a commonly prescribed macrolide, does not inhibit CYP3A4, but clarithromycin and erythromycin do.14 Older adults with T2DM may experience severe hypoglycemic episodes when taking certain antimicrobials. The underlying mechanism is likely that certain antimicrobials may inhibit the CYP2C9-mediated sulfonylurea metabolism, causing increased bioavailability of sulfonylurea medication; however, it is equally important to be aware that clarithromycin and fluoroquinolones should be used with caution in patients with diabetes mellitus and avoided if possible.14
Another major contributing factor in ADRs in older adults is polypharmacy. Polypharmacy is often defined as taking five or more medications, but it can be medically necessary to use multiple medications to treat a chronic disease. In addition, older adults can have multiple chronic diseases, allowing this threshold to be easily met or exceeded. There should be a diagnosis for each drug the patient is taking. It is also important to include start and stop dates for antimicrobials and to set times to evaluate response to treatment. Long-term use of antimicrobials should also be evaluated for effectiveness and necessity to continue.4,10
As the number of medications taken rises, the risk of drug-to-drug interactions also rises. In 1 year, the average older adult with five or more chronic illnesses will see 11 different providers, make 37 provider office visits, and fill 50 prescriptions.1 This reinforces the importance of having a primary care provider coordinate the patient's overall treatment plan. Technology-driven prescribing with electronic prescriptions can assist in alerting providers to potential drug-to-drug interactions and polypharmacy issues via the electronic health record. Asking patients to bring all current medications to each clinic visit so a review can be completed is recommended.4
Mr. K, 60, lives in an assisted living facility. He had a stroke 3 years earlier. He has some mild short-term memory deficits and right hemiplegia. Mr. K comes to the clinic because of a nagging cough after a recent upper respiratory infection. The cough is productive with small-to-moderate amounts of yellow sputum. He also complains of chest discomfort with the cough but denies any fever or chills. Mr. K is worried that he has pneumonia and wants an antibiotic. He is given a prescription for azithromycin.
Antimicrobial resistance is a growing problem, and the leading risk factors for having a drug-resistant pathogen include recent use of antibiotics, age younger than 2 years or older than 65, day-care center attendance, exposure to children, multiple comorbidities, recent hospitalization, and immunosuppression.15 Outbreaks of multidrug-resistant organisms are often reported in LTC facilities. Colonization with resistant pathogens occurs in both institutionalized and community-dwelling older adults.5 Excessive and inappropriate use of antimicrobial agents is a major factor in the development of drug resistance.2 Common examples include the use of antibiotics in viral infections, inadequate dosing, excessive duration of therapy, and increased empirical use of broad-spectrum antibiotics when not required.11
In the case of Mr. K, he likely has a viral infection with acute bronchitis, and antibiotics would not be indicated. Antimicrobial stewardship strategies include meeting diagnostic criteria for an infectious disease, treatment pathways for specific infectious diseases, formulary restrictions, dose optimization, prospective audits of prescribed antimicrobials, and continuing education for prescribers.10,16
Drug therapy based upon culture and sensitivity specimen reports using the drug with the lowest minimum inhibitory concentration is preferred.15 However, this is not always feasible in primary care clinics due to lack of insurance coverage, so treatment may be delayed. Consider obtaining a culture and sensitivity specimen if there is no response to treatment within 48 hours. Duration of therapy should be the shortest recommended length. These considerations highlight the importance of timely follow-up with the patient when prescribing antimicrobials.
In addition to the concern about the development of drug-resistant organisms, there is the negative effect of antibiotic exposure on the older adult's microbiome. The most common example is CDI. C. difficile is an anaerobic, Gram-positive, spore-forming, toxigenic bacterium that is one of the most common causes of healthcare-acquired diarrhea in the US.17 Antibiotic-associated pseudomembranous colitis pathogenesis begins with alteration of the normal microflora due to antibiotic exposure in the gut.18
Older adults are more susceptible to CDI due to age-related decline in immunity and are at higher risk for the more severe form of infection. Patients over age 65 have a greater chance of developing CDI compared with younger patients.18 Long-term PPIs may also be an additional risk factor for CDI. This risk is related to the reduced gastric acid secretion that may allow C. difficile to survive longer in the GI tract.17 It is not uncommon for older adults to be on long-term PPIs; this serves as a reminder to discontinue antiulcer and gastroesophageal reflux disease medications that are no longer needed. However, there is no recommendation for discontinuing PPIs as a preventive measure for CDI.17
There are many considerations when prescribing antimicrobials to older adults. The aging immune system impacts infection risk and severity, which at times makes recognizing an infection difficult. Aging alters pharmacokinetics and pharmacodynamics in ways that increase ADRs and suboptimal treatment success. Comorbid conditions with multiple prescribers increase the risk of drug-drug interactions. The growing problem of antibiotic resistance and CDI highlights the need for antibiotic stewardship. Prescribers must be diligent to prevent unnecessary antimicrobial use and when used to monitor the older adult's response closely.
Effects and implications of aging on pharmacokinetics12,13
Absorption: Aging can increase gastric pH, decrease absorptive surface area, decrease splanchnic blood flow, decrease GI motility, and delay gastric emptying. The rate of absorption may be slowed, and drugs requiring a high-acid environment may have reduced absorption. Less drug absorption means less clinical efficacy.
Distribution: Older adults have higher body fat, decreased lean body mass, decreased total water, decreased serum albumin, and decreased cardiac output. Lipid-soluble drugs may be stored longer in the body; concentrations of water-soluble drugs may be increased. The number of sites where drugs bind to protein will be decreased, causing an increase in free drug levels. Only unbound or free drugs are able to reach their site of action. Bound drugs can lower therapeutic drug levels, leading to a blunted or no response to treatment; free drugs can lead to toxicity and overdose.
Metabolism: Decreased hepatic blood flow, decreased hepatic mass, and decreased activity of hepatic enzymes are associated with aging. Half-life of drugs increases, giving a prolonged drug effect. First-pass metabolism is decreased, leading to higher active drug levels in circulation.
Excretion: Aging is associated with decreased renal blood flow, decreased glomerular filtration rate, decreased tubular secretion, and decreased number of nephrons. Creatinine clearance can be used as an index of kidney function in older adults, however it may be normal due to decline in muscle mass, so levels may be normal in reduced kidney function.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
antibiotic resistance; antibiotic stewardship; antibiotic use; antimicrobials; geriatrics; infectious disease; older adults