Download Antimicrobial Resistance and Aging: Beginning of the End of the

Antimicrobial Resistance and Aging: Beginning of the End
of the Antibiotic Era?
Thomas T. Yoshikawa, MD
Throughout the history of mankind, infectious diseases have
remained a major cause of death and disability. Although
industrialized nations, such as the United States, have experienced significant reductions in infection-related mortality and morbidity since the beginning of the “antibiotic
era,” death and complications from infectious diseases remain
a serious problem for older persons. Pneumonia is the major infection-related cause of death in older persons, and
urinary tract infection is the most common bacterial infection seen in geriatric patients. Other serious and common
infections in older people include intra-abdominal sepsis,
bacterial meningitis, infective endocarditis, infected pressure ulcers, septic arthritis, tuberculosis, and herpes zoster.
As a consequence, frequent prescribing of antibiotics for older
patients is common practice. The large volume of antibiotics
prescribed has contributed to the emergence of highly resistant pathogens among geriatric patients, including methicillinresistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and
multiple-drug-resistant gram-negative bacilli. Unless preventive strategies coupled with newer drug development are
established soon, eventually clinicians will be encountering
infections caused by highly resistant pathogens for which
no effective antibiotics will be available. Clinicians could then
be experiencing the same frustrations of not being able to
treat infections effectively as were seen in the “pre-antibiotic
era.” J Am Geriatr Soc 50:S206–S209, 2002.
Key words: aging; antimicrobial resistance; long-term care
facility
INFECTIONS AS A MAJOR CAUSE OF MORBIDITY
AND MORTALITY IN OLDER PEOPLE
Throughout the history of mankind, infectious diseases
have remained a major cause of death and disablement.
Today, infectious diseases account for one-third of all
From the Department of Internal Medicine, Charles R. Drew University of
Medicine and Science, Los Angeles, California.
Address correspondence to Thomas T. Yoshikawa, MD, Chairman,
Department of Internal Medicine, Charles R. Drew University of Medicine
and Science, King-Drew Medical Center, 12021 South Wilmington Avenue,
Los Angeles, CA 90059. E-mail: [email protected]
JAGS 50:S226–S229, 2002
© 2002 by the American Geriatrics Society
deaths in the world; the World Health Organization estimates that nearly 50,000 people die each day throughout
the world from infectious diseases.1 However, in industrialized nations, such as the United States, infectious disease–related deaths have been substantially reduced since
the advent of the “antibiotic era,” which began in the
early 1950s. In 1900, at a time when infections were the
leading cause of death in the United States, the average life
expectancy at birth was approximately 47 (46 for men
and 48 for women).2 Childhood deaths secondary to infections were very high. The major causes of death were
smallpox, cholera, diphtheria, typhoid fever, plague, tuberculosis, typhus, scarlet fever, rheumatic fever, measles,
mumps, pertussis, poliomyelitis, and syphilis. Many of
these diseases also caused complications leading to severe
disabilities (e.g., paralysis from polio, valvular heart disease from rheumatic fever, and neurological deficits and
heart disease from syphilis).
The older population (aged 65 and older) was only
4% of the entire population in the United States in the
early 1900s.3 Modern discoveries in medicine based on the
germ theory provided the advances to reduce the morbidity and mortality from infectious diseases, especially in
children. These advances included antibiotics, vaccination,
antisepsis, public health measures, and public sanitation.
As a result, average life expectancy at birth has dramatically increased over the past 50 years to approximately 75
in the United States,3 with older persons accounting for
13% of the total U.S. population.3 Moreover, the top 10
causes of death are no longer infections; cardiovascular
diseases, cancer, and stroke are now the top three causes
of death in adults, including older people, in the United
States.4 Nevertheless, with aging, infectious diseases have
re-emerged as important causes of death, disability, and
functional decline.5 Pneumonia and influenza are the
fourth-leading causes of death in older adults, and bacteremia is the ninth leading cause of death.4
SPECIAL PROBLEMS ASSOCIATED WITH
INFECTIONS IN OLDER PEOPLE
Not only are older persons at greater risk of dying from
infections or suffering serious complications, they also
have a higher susceptibility to select types of infections.
Those infections associated with high mortality, morbid-
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JULY 2002–VOL. 50, NO. 7, SUPPLEMENT
ity, and susceptibility include pneumonia, urinary tract infection (UTI), skin and soft tissue infections, bacterial
meningitis, infective endocarditis, septic arthritis, tuberculosis, intra-abdominal infections (primarily cholecystitis,
diverticulitis, perforated/ruptured appendicitis, and abscesses), and herpes zoster.6,7 It is well recognized that immune function, particularly cell-mediated immunity, decreases with aging.8 In addition, older people suffer more
chronic diseases, some of which (e.g., cancers, connective
tissue diseases) affect the integrity of host resistance. Thus,
it is most likely the combined effects of age-related decline
in host resistance and the presence of underlying diseases
and disabilities that contribute to the greater vulnerability
of older persons to infections and their complications.
With the rising numbers of older people, including
those aged 80 and older, the incidence and prevalence of
chronic diseases, physical disabilities, and cognitive impairment increase substantially. The demand and need for
long-term care concomitantly rise. Presently, more than
1.5 million people live in nearly 17,000 nursing facilities
in the United States.9 The skilled nursing facility (SNF) residents are generally very old (mean age 80–85) and frail,
often cognitively impaired, physically dependent, and
highly vulnerable to infections. Moreover, the setting of an
SNF is favorable for regular exposure to microorganisms
because of frequent contacts with other residents and staff
in a closed environment; limited ventilation, filtration, and
removal of recirculated air (which could contain pathogens); and free movement of other residents who may be
harboring infections.10 Thus, the finding of fever and infection in residents of long-term care facilities (LTCFs)
such as SNFs is a common occurrence.11 Infections are also
the most common reason an SNF resident is transferred to
an acute care facility.12,13 The most common infections encountered in residents of SNFs are pneumonia, UTI, and
skin/soft tissue infections, which together account for approximately 75% of all nursing facility–acquired infections.14
The difficulties in diagnosing infections in LTCFs are
enormous because of atypical clinical manifestations of
diseases in older people (to be discussed below), lack of an
adequate number of highly-trained medical personnel in
such facilities (predominantly nursing assistants) to make
an appropriate assessment of the resident, limited contact
by a primary care physician with the resident, minimal to
no availability of on-site laboratory and radiology tests,
and uncertainty of the primary clinician with respect to
initiating diagnostic interventions in the absence of a clearcut advance directive.11 Consequently, empirical antimicrobial therapy without microbiological data is common
practice in the long-term care setting; the vast majority of
prescribed antibiotics are ordered without direct examination of the resident by the primary care provider.9,11
The clinical diagnosis of infection in older adults, especially very old and frail people, can often be challenging.
Fever is the cardinal manifestation of infection, but, in approximately 20% to 30% of older persons with serious infections, fever is absent or blunted in comparison with
younger adults.15 Suboptimal temperature response to an
infection has been described in older patients with pneumonia, infective endocarditis, meningitis, tuberculosis, and
bacteremia.15 Moreover, infection in geriatric patients may
ANTIMICROBIAL RESISTANCE AND AGING
S227
not elicit typical symptoms of a specific type of infection
(e.g., cough and sputum with pneumonia, dysuria with
UTI) and may manifest as cognitive impairment, decline in
functional independence, falls, urinary incontinence, anorexia, weight loss, and weakness. These atypical presentations of infections in older patients cause delays in diagnosis and treatment and contribute to increased morbidity
and mortality. Alternatively, experienced and knowledgeable clinicians may assume that older persons with such
nonspecific symptoms may be harboring a serious infection and empirically initiate antimicrobial therapy without
objective evidence for an infectious disease, which increases the prescribing of antibiotics in this population.
The causative pathogens of common infections in
older people tend to be more diverse than in younger patients with the same disease. As examples, communityacquired pneumonia in younger adults is predominantly
caused by Streptococcus pneumoniae, Chlamydia pneumoniae, and Mycoplasma pneumoniae, whereas older patients with pneumonia in the community and long-term
care setting may have gram-negative bacilli as one of the
causes of their lung infection.16 UTI in adults tends to be a
disease of women and is caused by Escherichia coli in
nearly 90% of uncomplicated infections.17 In contrast, E.
coli accounts for approximately 60% to 70% of cases of
UTI in older adults, with other gram-negative bacilli and
enterococci often being isolated.18 Under these circumstances, antimicrobial therapy will often consist of broadspectrum drugs with activity against both gram-positive
and gram-negative bacteria. Broad-spectrum antibiotics
will have a greater effect on indigenous microflora and
promote colonization and growth of antimicrobial-resistant organisms.
FACTORS PROMOTING DEVELOPMENT OF
ANTIMICROBIAL-RESISTANT PATHOGENS
IN OLDER PATIENTS
The emergence of infections caused by antibiotic-resistant
pathogens is a growing problem and has now become a
major health issue in LTCFs.19 This is a major challenge to
clinicians, given the problems encountered with attempting to diagnose and treat infections in LTCFs (as described
earlier). Furthermore, with limited resources for implementing infection-control measures and procedures, such
antibiotic-resistant organisms will be extremely difficult to
control and contain.
Resistant organisms are found in healthcare facilities
such as LTCFs probably because of transfer to the LTCF
of patients who are colonized or infected with such pathogens at other institutions. Excessive and inappropriate
use of antibiotics, especially broad-spectrum antimicrobial
agents, select for the emergence of resistant pathogens.20
Prescribing antibiotics for unproven bacterial infections
(e.g., upper respiratory viral infections) or “prophylactic”
antibiotics for residents/patients with chronic urinary
catheters are examples of inappropriate administration of
these agents. Prolonged use of these drugs beyond the
standard recommended duration for treating common infections (e.g., 7–10 days for UTI) increases the risk of selecting for resistant pathogens with each additional day of
unnecessary treatment.20 Factors that increase the probability of microbial colonization (and subsequent infection)
S228
YOSHIKAWA
are also common in residents of LTCFs (malnutrition, immunosuppressed state, urinary catheters, feeding tubes,
pressure ulcers, and chronic immobility).20 Finally, inadequate adherence to infection-control measures such as frequent hand washing contributes to the spread of all types
of microorganisms, including resistant pathogens, throughout the facility and to its employees and residents.
IMPORTANT RESISTANT PATHOGENS
The most frequently isolated resistant pathogens in the
older population have been penicillin-resistant Streptococcus pneumoniae (PRSP), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci
(VRE), and multiple-drug-resistant gram-negative bacilli
(MDRGNB).21 In a recent study of a skilled-care facility,
43% of 117 study participants were colonized with one or
more resistant pathogens, which included MRSA (24% of
participants), resistant gram-negative bacilli (33%), and
VRE (3.5%).22
Penicillin-resistant Streptococcus pneumoniae prevalence is the highest in the very young (under 5) and the
very old (65 and older). In a recent surveillance study conducted in eight states by the Centers for Disease Control
and Prevention, the prevalence of PRSP was 32.2% in
children under 5 and 24.2% in adults aged 65 and older. 23
More importantly, during 1995 to 1998, the proportion of
PRSP increased from 21% to 25%, and PRSP isolates resistant to three or more classes of antibiotics increased
from 9% to 14%.23
Multidrug-resistant pneumococci have been reported
as causes of serious infections in older residents of LTCFs.
In one LTCF in Oklahoma, 23% of 74 residents were colonized with a pneumococcus resistant to penicillin, cefotaxime, cefaclor, erythromycin, trimethoprim-sulfamethoxazole, clindamycin, tetracycline, and chloramphenicol. 24
Twelve residents of the same facility were hospitalized for
pneumonia in 1996; three of the hospitalized residents with
bacteremia died. In such cases, quinolones (e.g., levofloxacin, moxifloxacin) and vancomycin should be considered
as potentially effective therapy.
MRSA was one of the earlier resistant pathogens that
was described as a major clinical problem in LTCFs.25
They have been reported in a variety of LTCF settings in
the United States, including community, Veterans Affairs,
large, small, adult, pediatric, rural, and urban.25 Unfortunately, resistance to methicillin (nafcillin, oxacillin) is not
the only issue; MRSA is generally resistant to all cephalosporins and quinolones as well.26 Vancomycin has become the mainstay of therapy for MRSA,26 but recent
studies indicate the frightening evidence of emergence of
Staphylococcus aureus with resistance to vancomycin (vancomycin-intermediate Staphylococcus aureus (VISA)).27 Presently, it appears that the newer agents, quinupristin/dalfopristin (a streptogramin) and linezolid, may be active against
MRSA and VISA.28,29
VRE has also become a major concern for clinicians
caring for patients in acute hospitals and LTCFs. Studies
conducted primarily in older patients indicate that treatment with an anti-anaerobic antibiotic regimen promotes
stool colonization with VRE.30 Agents lacking anti-anaerobic activity, such as dicloxacillin, levofloxacin, ciproflox-
JULY 2002–VOL. 50, NO. 7, SUPPLEMENT
JAGS
acin, and trimethoprim-sulfamethoxazole, had the least
effect on increased VRE colonization in the stool.30 One
study in a LTCF indicated that adherence to infection control practices by resident care staff of the LTCF was associated with absence of VRE colonization among the residents.31 Presently, the treatment of serious VRE infections
is limited primarily to quinupristin/dalfopristin and linezolid.28,29 However, these drugs may not be available or
practical for treating LTCF residents with VRE infections.
In LTCF residents with uncomplicated UTI caused by
VRE, nitrofurantoin and doxycycline maybe effective depending on the sensitivity of the organism to these agents.
A variety of gram-negative bacilli resistant to many
antibiotics have been reported, especially in older patients
being treated for UTI in LTCFs.21 Some common mechanisms of resistance include extended-spectrum beta-lactamases, which render many antibiotics inactive, including
ceftazidime, inhibitor-resistant beta-lactamases (beta-lactamases produced by bacteria that are resistant to beta-lactamase inhibitors), and enzymatic inactivation of aminoglycosides (acetylation, phosphorylation, nucleotidylation).20
Such high prevalences of MDRGNB have limited the use of
many beta-lactam agents and other antibiotics in the treatment of common infections such as UTI. In many instances,
clinicians have opted to begin treatment with quinolones for
serious UTI caused by gram-negative bacilli.32
These examples of drug-resistant pathogens suggest a
continuing growth in the numbers and types of microbial
organisms becoming increasingly resistant to the effects of
antibiotics. More importantly, the organisms are often resistant to multiple drugs and, in some instances, resistant
to virtually every available antibiotic. Indeed, with essentially no effective antimicrobial agents against some of
these pathogens, we would be returning to the “pre-antibiotic era.”
Thus, strategies for the prevention of developing drugresistant pathogens; limiting transmission of these resistant pathogens to highly vulnerable persons, such as older,
frail, disabled, and immunocompromised people; careful
and limited usage of drugs effective against such resistant
pathogens (e.g., vancomycin, quinolones, streptogramins,
linezolid); and development of newer and more effective
agents against these organisms will be critical if we are to
limit or eliminate morbidity and mortality from serious infections caused by resistant organisms.
ACKNOWLEDGMENTS
The author is not a consultant for any pharmaceutical
company and does not receive research funding from such
companies.
REFERENCES
1. Kupersmith C. Three Centuries of Infectious Disease: an Illustrated History
of Research and Treatment. Greenwich, CT: Greenwich Press, 1998.
2. U.S. Department of Health and Human Services, Public Health Service, National Center for Health Statistics. Health United States 1985, (DHHS Publication No. (PHS) 86–1232). Hyattsville, MD: U.S. Department of Health
and Human Services, 1986.
3. U.S. Bureau of the Census. Decennial Censuses of Population, 1900–1980
and Projections of the Population of the United States: 1982–2050 (advance
report). Current Population Reports Series P-25, No. 922. Washington, DC:
U.S. Bureau of the Census, 1982.
4. National Center for Health Statistics. Leading causes of death and number of
deaths according to age: United States, 1980 and 1993. In: Health United
JAGS
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
JULY 2002–VOL. 50, NO. 7, SUPPLEMENT
States, 1995 (DHHS Publication No. (PHS) 96–1232). Hyattsville, MD: U.S.
Department of Health and Human Services, 1996.
Yoshikawa TT. Geriatric infectious diseases: An emerging problem. J Am
Geriatr Soc 1983;31:34–39.
Yoshikawa TT. Important infections in elderly persons. West J Med 1981;
135:441–445.
Yoshikawa TT. Perspective: Aging and infectious diseases: Past, present, and
future. J Infect Dis 1997;176:1053–1057.
Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect
Dis 2000;31:578–585.
Warshaw G, Mehdizadeh S, Applebaum RA. Infections in nursing homes: Assessing quality of care. J Gerontol A Biol Sci Med Sci 2001;56A:M120–M123.
Yoshikawa TT, Norman DC. Infection control in long-term care. Clin Geriatr Med 1995;11:467–480.
Bentley DW, Bradley S, High K et al. Practice guideline for evaluation of fever
and infection in long-term care facilities. Clin Infect Dis 2000;31:640–653.
Irvine PW, Van Buren N, Crossley K. Causes for hospitalization of nursing
home residents: The role of infection. J Am Geriatr Soc 1981;32:103–107.
Mulligan T. Parenteral antibiotic therapy for patients in nursing homes. Rev
Infect Dis 1991;13(Suppl 2):180–183.
Yoshikawa TT, Norman DC. Approach to fever and infection in the nursing
home. J Am Geriatr Soc 1996;44:74–82.
Norman DC. Fever in the elderly. Clin Infect Dis 2000;31:148–151.
Marrie TJ. Community-acquired pneumonia in the elderly. Clin Infect Dis
2000;31:1066–1078.
Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary
tract infection. Infect Dis North Am 1997;11:551–581.
Nicolle LE. Urinary tract infection. In: Yoshikawa TT, Norman DC, eds. Infectious Disease in the Aging: A Clinical Handbook. Totowa, NJ: Humana
Press, Inc., 2001, pp 99–111.
Bonomo RA, Rice LB. Emerging issues in antibiotic-resistant infections in
long-term care facilities. J Gerontol A Biol Sci Med Sci 1999;54A:B260–B267.
Bonomo RA. Multiple antibiotic-resistant bacteria in long-term-care facilities: An emerging problem in the practice of infectious diseases. Clin Infect
Dis 2000;31:1414–1422.
ANTIMICROBIAL RESISTANCE AND AGING
S229
21. Yoshikawa TT. VRE, MRSA, PRP, and DRGNB in LTCF: Lessons to be
learned from this alphabet. J Am Geriatr Soc 1998;46:241–243.
22. Trick WE, Weinstein RA, DeMarais PL et al. Colonization of skilled-care
facility residents with antimicrobial-resistant pathogens. J Am Geriatr Soc
2001;49:1–7.
23. Whitney CG, Farley MM, Hadler J et al. Increasing prevalence of multidrugresistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;
343:1917–1924.
24. Centers for Disease Control and Prevention. Outbreaks of pneumococcal
pneumonia among unvaccinated residents in chronic-care facilities—Massachusetts, October 1995; Oklahoma, February 1996; and Maryland, MayJune 1996. MMWR Morb Mortal Weekly Report 1997;46:60–62.
25. Mylotte JM, Karuza J, Bentley DW. Methicillin-resistant Staphylococcus aureus: A questionnaire survey of 75 long-term care facilities in western New
York. Infect Control Hosp Epidemiol 1991;13:711–718.
26. Bradley SF. Methicillin-resistant Staphylococcus aureus infection. Clin Geriatr Med 1992;8:853–868.
27. Wenzel RP, Edmond MB. Vancomycin-resistant Staphylococcus aureus: Infection control considerations. Clin Infect Dis 1998;27:245–251.
28. Rybak MJ, Hershberger E, Moldovan T et al. In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci
and enterococci, including vancomycin-intermediate and resistant strains. Antimicrob Agents Chemother 2000;44:1062–1066.
29. Chien JW, Kucia M, Salata RA. Use of linezolid, an oxazolidinone, in the
treatment of multidrug-resistant gram-positive bacterial infections. Clin Infect Dis 2000;30:146–151.
30. Donskey CJ, Chowdhry TK, Hecker MT et al. Effect of antibiotic therapy on
the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000;343:1925–1932.
31. Silverblatt FJ, Tibert C, Mikolich D et al. Preventing the spread of vancomycin-resistant enterococci in a long-term care facility. J Am Geriatr Soc 2000;
48:1211–1215.
32. Warren JW, Abrutyn E, Hebel JR et al. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in
women. Clin Infect Dis 1999;29:745–758.