334 Harrington and Barrett that the information and clinical approach to patient care contained in this chapter will be helpful to healthcare professionals in LTCFs who face a myriad of com- plex management issues concerning viral hepatitis. REFERENCES 1. Centers for Disease Control and Prevention: Hepatitis Surveillance Report No. 57, Atlanta, Centers for Disease Control, 2000. 2. Alter M, Mast E. The epidemiology of viral hepatitis in the United States. Gastroen- terol Clin North Am 1994; 23:437–455. 3. Shapiro C, Coleman P, McQuillan G, Alter M, Margolis H. Epidemiology of hepati- tis A: Seroepidemiology and risk groups in the USA. Vaccine 1992; 10(Suppl 1): S59–S62. 4. Szmuness W, Dienstag J, Purcell R, Stevens C, Wong D, Ikram H, Bar-Shany S, Beasley R, Desmyter S, Gaon J. The prevalence of antibody to hepatitis A antigen in various parts of the world: A pilot study. Am J Epidemiol 1977; 106:392–398. 5. Papaevangelou G. Epidemiology of hepatitis A in Mediterranean countries. Vaccine 1992; 10(Suppl 1):S63–S66. 6. Floreani A, Chiaramonte M. Hepatitis in nursing homes. Incidence and management strategies. Drugs Aging 1994; 5:96–101. 7. Lednar W, Lemon S, Kirkpatrick J, Redfield R, Fields M, Kelly P. Frequency of ill- ness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 1985; 122:226–233. 8. Forbes A, Williams R. Increasing age: An important adverse prognostic factor in hep- atitis A virus infection. J R Coll Physicians Lond 1988; 22:237–239. 9. Braconier J, Nordenfelt E. Serum hepatitis at a home for the aged. Scand J Infect Dis 1972; 4:72–82. 10. Wright R. Hepatitis B and the HbBAg carrier: An outbreak related to sexual contact. JAMA 1975; 232:717–721. 11. Chiaramonte M, Floreani A, Naccarato R. Hepatitis B virus infection in homes for the aged. J Med Virol 1982; 9:247–255. 12. Centers for Disease Control and Prevention. Nosocomial hepatitis B virus infection associated with reusable fingerstick blood sampling devices—Ohio and New York City, 1996. MMWR 1997; 46(10):217–221. 13. Alter MJ, Margolis HS, Krawcynski K. The natural history of acquired hepatitis C in the United States. N Engl J Med 1992; 327:1899–1905. 14. Goodson J, Taylor P, Campion E, Richter J, Wands J. The clinical course of acute hepatitis in the elderly patient. Arch Intern Med 1982; 142:1485–1488. 15. Sonnenblick M, Oren R, Tur-Kaspa R. Non-A, non-B hepatitis in the aged. Postgrad Med J 1990; 66:462–464. 16. Laverdant C, Algayres J, Daly J, Molinie C, Flechaire A, Valmary J, Saliou P. Viral hepatitis in patients over 60 years of age: Clinical, etiologic and developmental as- pects. Gastroenterol Clin Biol 1998; 13:499–504. 17. Alter M. Epidemiology of hepatitis C in the West. Semin Liver Dis 1995; 15:5–14.
Hepatitis 335 18. Floreani A, Bertin T, Soffiati G, Naccarato R, Chiaramonte M. Anti-hepatitis C virus in the elderly: A seroepidemiological study in a home for the aged. Gerontology 1992; 38:214–216. 19. Simor A, Gordon M, Bishai F. Prevalence of hepatitis B surface antigen, hepatitis C antibody, and HIV-1 antibody among residents of a long term care facility. J Am Geriatr Soc 1992; 40:218–220. 20. Rabicetta M, Attili A, Mele A, DeSantis A, Chionne P, Cristiano K, Spada E, Giu- liani I, Carli L, Goffredo F. Prevalence of hepatitis C virus antibodies and hepatitis C virus RNA in an urban population. J Med Virol 1992; 37:87–92. 21. Chien N, Dundoo G, Horani M, Osmack P, Morley J, DiBisceglie A. Seroprevalence of viral hepatitis in an older nursing home population. J Am Geriatr Soc 1999; 47:1110–1113. 22. Marcus E, Dahoudi N, Tur-kaspa R. Hepatitis C virus infection among elderly pa- tients in a geriatric hospital. Arch Gerontol Geriatr 1994; 19:213–221. 23. Baldo V, Floreani A, Menegon T, Angiolelli G, Trivello R. Prevalence of antibodies against hepatitis C virus in the elderly: A seroepidemiological study in a nursing home and in an open population. The Collaborative Group. Gerontology 2000; 46:194–198. 24. Sampietro M, Caputo L, Corbetta N, Annoni G, Ticozzi A, Longhi G, Orlandi A, Ver- goni C, Fiorelli G. Hepatitis G virus infection in the elderly. Ital J Gastroenterol Hep- atol 1998; 30:524–527. 25. Lee W. Acute liver failure. N Engl J Med 1993; 329:1862–1872. 26. Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G, Yvonne T, Degott C, Be- zlaud A, Rueff B, Benhamou J. Multivariate analysis of prognostic factors in fulmi- nant hepatitis B. Hepatology 1986; 6:648–651. 27. Takahashi Y, Kumada H, Shimizu M, Tanikawa K, Kumashiro R, Omata M, Ehata T, Tsuji T, Yasunaga M. A multicenter study on the prognosis of fulminant viral hep- atitis: Early prediction for liver transplantation. Hepatology 1994; 19:1065–1071. 28. MacMahon M, James O. Liver disease in the elderly. J Clin Gastroenterol 1994; 18:330–334. 29. Horiike N, Masumoto T, Nakanishi K, Michitaka K, Kurose K, Ohkura L, Onji M. Interferon therapy for patients more than 60 years of age with chronic hepatitis C. J Gastroenterol Hepatol 1995; 10:246–249. 30. Yamada G, Takatani M, Kishi F, Takahashi, Doi T, Tsuji T, Shin S, Tanno M, Urdu M, Kolberg J. Efficacy of interferon alfa therapy in chronic hepatitis C patients de- pends primarily on hepatitis C TNA level. Hepatology 1995; 22:1251–1354. 31. Tong M, El-Farra N, Reikes A, Co R. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995; 332:1463–1466. 32. Sallie T, Di Bisceglie A. Viral hepatitis and hepatocellular carcinoma. Gastroenterol Clin North Am 1994; 19:1065–1071. 33. McMahon B, Alberts S, Wainwright R, Bulkow L, Lanier A. Hepatitis B-related se- quelae: Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990; 150:1051–1054. 34. Mazzalla G, Accogli E, Sottili S. Alfa interferon treatment may prevent hepatocellu- lar carcinoma in HCV-related liver cirrhosis. J Hepatol 1996; 24:141–147.
336 Harrington and Barrett 35. Beasley R. Hepatitis B virus: The major etiology of hepatocellular carcinoma. Can- cer 1988; 61:1942–1956. 36. Collier J, Curless R, Bassendine M, James O. Clinical features and prognosis of hep- atocellular carcinoma in Britain with respect to advancing age. Age Ageing 1994; 23:22–27. 37. Management of hepatitis C. NIH consensus statement no. 105. 1997 March 24–26; 15(3):1–41. 38. Smith PW, Rusnak PG. Infection prevention and control in the long-term facility. Am J Infect Control 1997; 25:488–512. 39. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immu- nization Practices (ACIP). MMWR 1999; 48(RR-12):1–37. 40. Bader T. Hepatitis A vaccine. Am J Gastroenterol 1996; 91:217–222. 41. Centers for Disease Control and Prevention. Immunization of health-care workers: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR 1997; 46(RR-18):1–42. 42. Centers for Disease Control and Prevention. Recommendations for prevention and control of Hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998; 47(RR-19):1–39. 43. Lindsay Kl, Hoofnagle JH. Serological tests for viral hepatitis. In: Kaplowitz, N. (ed): Liver and Biliary Diseases. Baltimore, Williams, & Wilkins 1992:195–206. 44. Dienstag JL, Wands JR, Isselbacher KJ. Acute hepatitis. In 12th ed JD Wilson, E Braunwald, KJ Isselbacher, RG Petersdorf, JB Martin, AS Fauci, RK Root (eds.). Harrison’s Principles of Internal Medicine. New York, McGraw-Hill, 1991, pp 1322–1337.
20 Vaccinations Stefan Gravenstein Eastern Virginia Medical School, Norfolk, Virginia I. INFECTION, AGING, AND IMMUNE RESPONSE Probably the most profound effect of immunosenescence in old age is the in- crease in infectious morbidity and mortality. The impact of a number of infec- tions increase with age, including influenza, pneumonia, Clostridium difficile di- arrhea, nosocomial infections, and recrudescent latent infections such as herpes zoster (1). Unfortunately, the use and abuse of antimicrobial agents selects for subsequent resistant and often unusual microorganisms that may spread from the primary source patient. This is particularly true for methicillin-resistant Staphy- lococcus aureus (MRSA), and Streptococcus pneumoniae. The latter is becom- ing increasingly resistant to standard antimicrobial therapy, is a leading cause of morbidity and mortality, and stands out among resistant organisms in that the most important of the pathogenic strains are vaccine preventable. Immunose- nescence also results in atypical presentations of infections in old age, poten- tially obscuring the diagnoses of influenza and pneumococcal pneumonia (2). Infections also occur more frequently and are longer in duration in elderly peo- ple (3). It is likely, largely due to immunosenescence, that old individuals, particu- larly the very old, may fail to respond as efficiently to therapy for infection such as C. difficile or influenza, may develop infections by unusual pathogens such as Listeria monocytogenes, or experience reactivation of quiescent diseases such as shingles. The level of integrity of the immune and inflammatory response to in- fection is the principle driver of many of the resulting symptoms and the impaired response. Typical signs of infection can be absent and a keen index of suspicion is necessary for an adequately inclusive differential diagnosis in old age. Elderly patients may not develop the spiking fevers, leucocytosis, or prominent inflam- 337
338 Gravenstein matory infiltrates on chest X-ray as younger patients with pneumonia. Lower baseline temperatures may require monitoring the change in temperature, rather than the absolute temperature in old age (4). The need for efficacious vaccinations for elderly patients is pressing, and immunization is one of the few tools to cost effectively defend against infections, especially in settings where transmissibility may contribute to the impact of the disease. A second consideration for vaccine use is for employees of long-term care facilities (LTCFs). Part of good facility management includes protecting residents and employees from infections (e.g., influenza) potentially introduced by employees and transmitted by residents (e.g., hepatitis, influenza). A. Vaccine Utilization in Long-Term Care Facilities Despite the overwhelming evidence of risk for vaccine-preventable illnesses and their morbidity and mortality in LTCF residents, vaccination rates remain suboptimal. A survey of Minnesota LTCFs in 1993 observed 12-month resident immunization rates for influenza (flu), pneumococcal, and tetanus/diphtheria vaccines of 84%, 11.9%, and 2.9%, respectively (5). One-third of the nursing homes surveyed failed to offer influenza vaccines to residents admitted during flu season. Written policies for influenza vaccine were present in 69% of the survey respondents, but only one-third had policies for pneumococcal vaccine, and less than 20% had policies for tetanus/diphtheria administration. In an eval- uation of policies and procedures and vaccination rates in 1,270 LTCFs in Canada, pneumococcal vaccination rates of less than 10% were observed in al- most half the facilities surveyed, even if the province agreed to pay for the vac- cine (6). B. Efforts to Increase Vaccine Utilization One of the most important steps to improve vaccine utilization in an institutional setting is through the implementation of standing orders for routine vaccination in a sustainable immunization program. Policy statements and manuals have been written to aid in the development of such policies (7). It is also important that there is a consensus among staff members, the infection control profes- sional, medical director, administration, and others about the importance of vac- cination in this setting. Creating a vaccination program team with defined roles and responsibilities and setting a specific measurable vaccination goal can help create that consensus. Other methods that have been found to increase utilization include having a written and well-defined program and plan. The plan should include assessing the immunization status of newly admitted or transferred residents, offering vaccina- tion to new and current residents on the basis of standing order protocols, and
Vaccinations 339 conducting an annual vaccination campaign each year, such as in conjunction with annual influenza vaccination. Immunization programs should also include annual inservice of staff members, personal physicians, and medical directors. The inser- vice can provide an overview of the facility’s vaccination policy, vaccine effec- tiveness, recommendations, record-keeping requirements, infection control, and indications for and contraindications to vaccination. An often-overlooked component of programs is evaluation. Improving fu- ture vaccination utilization may depend on successes and failures of past vaccina- tion programs. Periodically reviewing current resident and employee vaccination status and comparing that with the baseline or prior status, assessing efficiency of administration schedules, evaluating the number of residents and staff not appro- priately vaccinated and the reason why, and other measurements can help the pro- gram team identify areas for improvement. II. INFLUENZA Older adults, considered those aged 65 and older, currently account for more than 90% of the deaths attributed to pneumonia and influenza (8). In an evaluation of influenza-related deaths from 19 epidemics occurring from 1972 to 1973 through 1994 to 1995, the influenza-related death rate ranged from 30 to more than 150 per 100,000 persons aged 65 and older (9). Influenza-related illness costs more health- care dollars and lives lost than any other viral illness in the United States. National hospital discharge data indicate an average of 114,000 excess hospitalizations an- nually related to influenza. Since 1968, the greatest number of hospitalizations have occurred during epidemics caused by type A (H3N2) viruses, where an esti- mated 142,000 influenza-related hospitalizations occurred per year, and more than 40% of those were in individuals aged 65 and older (10) (see Chapter 13). Outbreaks of influenza are related to two phenomena: antigenic drift and antigenic shift. Because the influenza virus genome is segmented so that different combinations of segments yield a phenotypically different virus, when recombi- nation of the genetic segments occurs, antigenic shift is possible. Antigenic drift resulting from single nucleic acid substitutions of the genome also occurs. These phenomena enable the influenza virus to escape immune recognition and allow annual epidemics (with antigenic drift) or pandemics (with antigenic shift) to oc- cur. In the 1997/1998 season, for example, a mismatch between the vaccine com- ponent and the most prevalent epidemic influenza A virus was identified in the Netherlands and caused the influenza epidemic related to antigenic drift, and this strain circulated worldwide, causing significant morbidity and mortality for the ensuing three seasons (11). Elderly persons are at increased risk for influenza complications related to secondary bacterial infection, and they are more likely to require hospitalization
340 Gravenstein and experience a higher mortality rate. In LTCFs, up to 70% of the residents may contract influenza-like illnesses during an outbreak; during nonepidemic years an attack rate of 5% to 20% is the norm. The case fatality ratio during an outbreak may be as high as 30% (12). Because individuals older than age 80 are the fastest growing segment of the U.S. population (13), the impact of influenza will con- tinue to intensify unless we attain better control of the disease. A. Vaccine Effectiveness The cornerstone of influenza prevention remains vaccination. Vaccination is far more cost-effective than the alternative intervention, that is chemoprophylaxis with amantadine or other antivirals (14). A well-matched vaccine is effective in reducing the incidence and severity of influenza illness, but even a poorly matched vaccine can provide benefit. Vaccination can reduce the number of influenza-re- lated hospitalizations, radiologically diagnosed cases of pneumonia, and deaths (14–16). Despite high resident vaccination rates in LTCFs, outbreaks of influenza occur annually (17). The influenza vaccine can fail to provide the intended protection because of several factors, including immune senescence, weak vac- cine immunogenicity, lack of herd immunity, antigenic drift, or antigenic shift. Because of advanced age and underlying disease, not all healthy elderly (18) and only about half of LTCF residents develop “protective” vaccine-in- duced antibody titers compared with 70% to 90% of young healthy adults; even fewer elderly develop substantial cellular immunity (19,20). Supplemental vac- cination and vaccines with higher concentrations of antigen have not consis- tently demonstrated increased antibody response in elderly persons, but they have demonstrated more side effects (21). Nevertheless, elderly persons may benefit from vaccination despite low antibody titers; the influenza illness may be less severe and the risk of complications, hospitalization, and death may be reduced. Results from retrospective vaccine efficacy studies vary from 30% to 80% (16). However, one prospective study suggested that the Centers for Disease Control and Prevention (CDC) case definition for influenza may only be 61% sensitive and 63% specific for detecting laboratory-confirmed H3N2 influenza (22). The low sensitivity and specificity of this case definition (i.e., oral tem- perature 100° F accompanied by either sore throat, cough, or coryza) may occur because the clinical features of an influenza illness are largely indistinguishable from other viral illnesses that occur primarily during the influenza season. Ad- ditionally, the sensitivity of the case definition for influenza may be reduced be- cause elderly persons are less likely to have a fever in response to infection and, therefore, do not meet the temperature requirement of the case definition (23). Clinical influenza may also be attenuated in previously vaccinated individuals,
Vaccinations 341 further compromising the case definition’s sensitivity. Thus, retrospective stud- ies reporting vaccine efficacy relying on clinical symptoms for case detection may underestimate the ability of the vaccine to prevent infection. Nevertheless, when infection occurs in vaccinated individuals, the vaccine is effective in pre- venting serious morbidity and death (14). Reduction of influenza-associated hos- pitalization and death has been reported in both community and LTCF settings (14,15). B. Indications Annual influenza vaccination is recommended for high-risk individuals and their caregivers, including physicians. High-risk individuals include residents of LTCFs, persons aged 50 and older, those with chronic disorders of the pulmonary or cardiovascular system, and those requiring regular medical follow-up or hospi- talization during the preceding year because of chronic metabolic disorders, renal dysfunction, hemoglobinopathies, or immunosuppression (8). Annual influenza vaccination rates in LTCFs across the United States range from 0 to 100%, but are now estimated to exceed an average of 80% nationwide (12,16,24). The proportion of vaccinated LTCF staff is frequently less than 30% (16). The rate of vaccination of LTCF residents and staff depends on the energy and enthusiasm of the medical director, director of nursing, and infection control practitioner, as well as implementation of LTCF educational programs and vacci- nation policies. One purpose of influenza immunization programs in LTCFs is to induce herd immunity, thereby reducing the probability of virus transmission within a population (25). The ambitious vaccination rate of 80% for residents and staff is calculated to generate herd immunity and is a minimum goal that LTCFs should set. C. Administration and Revaccination An intramuscular injection of 0.5 ml of the trivalent influenza vaccine through a 1-inch needle is recommended in the United States. Half-inch needles may fail to reach the muscle of older individuals because of changes in body composition (i.e., reduced lean muscle mass, increased fat). Subcutaneous and intradermal routes have been used, but their efficacy has not been adequately compared. An- nual vaccination is necessary, as the protective response to current influenza vac- cines is short-lived and the virus’ rapid antigenic change reduces the previous year’s vaccine effectiveness. The question of optimum timing of the influenza vaccine is important and not easily answered. If vaccination takes place too early, protective antibody titers may no longer be present when the virus circulates, whereas late vaccination per-
342 Gravenstein mits viral exposure before protective antibody develops. Because it may take 4 to 6 weeks for elderly individuals to develop optimum antibody titers, it is advisable to vaccinate 4 to 6 weeks before the influenza season is expected (26). In most states, vaccination during November is reasonable, whereas vaccination during August and September is usually premature. Influenza typically circulates from December to March, justifying vaccination of new staff and residents in January or later. When an influenza outbreak is identified, unvaccinated staff and residents should be reoffered the vaccine. Those accepting the vaccine during an influenza A outbreak should also be offered adjunctive therapy with an antiviral agent (amantadine, rimantadine, zanamivir, or oseltamivir) for the 2-week interim after vaccination to allow time to develop vaccine-induced immunity. Neuraminidase inhibitors (zanamavir and oseltamivir) also are effective in reducing influenza B illness (27–29). At the very least, unvaccinated persons should be offered chemo- prophylaxis with amantadine (if at low risk for side effects), rimantadine, or a neu- raminidase inhibitor for the duration of the influenza A outbreak. Most outbreaks are associated with influenza A; however, if influenza B is identified, amantadine or rimantadine is ineffective because of lack of activity against influenza B, and a neuraminidase inhibitor is the acceptable prophylaxis option. Dosing information is presented in Table 1. Clinical trials with new vaccines have met with variable success. Ap- proaches to enhance immunogenicity have included use of biological response Table 1 Daily Dosage of Influenza Antiviral Medications for Prophylaxis in LTCF Residents During an Outbreak Daily dose Antiviral agent Ͻ 65 yrs Ն 65 yrs Duration** Amantadine (Influenza A only) 100 mg twice daily* 100 mg/day 14 days Rimantadine (Influenza A only) 100 mg twice daily† 100 mg/day 14 days Zanamivir ‡‡ 10 mg/day 10 mg/day 14 days Oseltamivir‡‡ 75 mg/day 75 mg/day 14 days * Consult the drug package insert for dosage recommendations for administering amantadine to persons with creatinine clearance 50 ml/min/1 .73m2. ** 14 days is the recommended duration of prophylaxis for influenza outbreak control. For prophylaxis of a roommate, 7 to 10 days should be a sufficient duration of drug administration. † A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance of 10 ml/mm. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. ‡‡ Neither zanamivir nor oseltamivir are approved for prophylaxis. Abbreviation: LTCFs, Long-term care facilities.
Vaccinations 343 modifiers (30,31), adjuvants (32), protein conjugates (33), and cold-adapted (34) vaccine constructs. Several of these have provided evidence of improved im- munogenicity and even clinical efficacy in ambulatory or long-term care settings, yet none has demonstrated an advantage sufficient for the manufacturers to bring them to market in the United States. D. Safety A presumption of adverse effects to influenza vaccine, particularly influenza ill- ness, has impacted the rate of influenza vaccine uptake by individuals (35). The current, commercially available vaccine, because of its noninfectious particles, is incapable of causing influenza infection. Respiratory illness occurring tempo- rally after vaccination is merely coincidental. About 30% of recipients complain of injection site tenderness for 1 to 2 days after administration. Fever, malaise, or myalgia occurs in less than 10% of individuals and most often in persons naïve to the influenza vaccine. The rate of systemic reactions in elderly persons is similar to that in saline placebo recipients (36). Although rare, hypersensitiv- ity reactions to vaccine components, residual egg proteins, or preservatives is possible. The influenza vaccine is contraindicated in individuals with anaphy- lactic hypersensitivity to eggs. Only the 1976 influenza vaccine was signifi- cantly associated with the Guillain-Barre syndrome, and although this relation- ship appears to be real, its impact should be small (Ͻ 1/1,000,000 vaccinated) (37). III. PNEUMOCOCCAL VACCINE A. Microbiology and Clinical Disease of Pneumococci Reduced immunocompetence because of age, disease, or drug therapy should be considered when assessing risk for pneumococcal disease. Streptococcus pneu- moniae, a gram-positive bacterium, also referred to as pneumococcus and Diplo- coccus pneumoniae, is a normal inhabitant of the nasopharynx. Before the widespread availability and use of antibiotics, S. pneumoniae could frequently be isolated from the nasopharynx of individuals (up to 70%); however, the rate of colonization is believed to be much lower today (i.e., Ͻ 40%) (38). Microbi- ologically, pneumococci are gram-positive, nonsporulating, encapsulated, lancet-shaped diplococci, although they may also grow in chains. The capsule is the antigenic determinant in the current pneumococcal vaccine. Historically, pneumococci have been exquisitely sensitive to penicillin an- tibiotics. However, the prevalence of penicillin-resistant pneumococci is on the rise worldwide, including the United States (39). This poses interesting implica-
344 Gravenstein tions for future antimicrobial treatment of these infections and reinforces the need for prevention as a primary management strategy for pneumococcal disease. The presence of S. pneumoniae in the nasopharynx is usually without se- quelae, as it resides without inducing an inflammatory response. In individuals with a fully competent immune system, infection is usually avoided. However, when the bacterium makes its way into the lung, an inflammatory response (i.e., pneumonitis) follows, which progresses to pneumonia. Risk factors for pneu- mococcal infections include conditions that predispose an individual to aspira- tion of pneumococci into the lung. These factors include: dementia, stupor, other conditions, such as stroke, with abnormal swallowing, chronic obstructive pulmonary disease, alcoholism, and seizure disorders. Nasogastric tubes, which contribute to aspiration, regardless of their specific placement in the gas- trointestinal tract, should be considered in assessing aspiration risk. Alterations of sensorium and sedation associated with antipsychotic and anxiolytic therapy, are another concern. Many of these conditions are common in nursing facilities, placing this population at considerable risk for pneumococcal infec- tions. Reduced immunocompetence because of age, disease, or drug therapy should be considered when assessing the risk for pneumococcal disease. One study found the incidence of pneumococcal disease to be 70 cases per 100,000 in individuals older than age 70 compared with five cases per 100,000 in younger adults (40). Prevention of pneumococcal disease holds great promise for affecting the incidence of disease in the elderly and immunocompromised populations. Pneumonia is the most prevalent expression of infection with S. pneumo- niae. Other infections associated with pneumococcus include otitis media, sinusi- tis, meningitis, septic arthritis, pericarditis, endocarditis, peritonitis, cellulitis, glomerulonephritis, and sepsis (especially postsplenectomy). B. Pneumococcal Vaccine The first use of pneumococcal vaccination dates back to the early 1900s when a crude, monovalent vaccine was used to prevent pneumonia in South African dia- mond miners. A vaccine containing 14 different strains of S. pneumoniae was first licensed for use in the United States in 1977. Numerous studies have documented the efficacy of the first 14-valent and the current 23-valent vaccine in preventing pneumococcal pneumonia and bacteremia in elderly persons. However, underuti- lization of pneumococcal vaccine has resulted in outbreaks in nursing facilities, underscoring the need for appropriate utilization of the vaccine (41–43). Studies have shown the vaccine to be cost effective. Still, the public health benefits of this vaccine have been received with little enthusiasm. The Advisory Committee on Immunization Practices of the CDC recommends pneumococcal vaccine for the
Vaccinations 345 individuals at risk for pneumococcal disease (Table 2) (44). In addition, revacci- nation is recommended for persons aged 65 and older if they received the vaccine 5 or more years previously and were younger than age 65 at time of vaccination. The pneumococcal vaccines available today, Pneumovax® 23 (Merck and Company) and Pnu-Immune® 23 (Wyeth-Lederle Laboratories), contain 25 mcg of capsular polysaccharide antigen for each of the 23 most prevalent and pathogenic S. pneumoniae serotypes in a 0.5-ml dose. The current vaccine was li- censed in 1983 as a replacement for the 14-valent vaccine that contained 50 mcg of each serotype and had been available since 1977. The new vaccine was devel- oped to provide a broader spectrum of coverage of S. pneumoniae serotypes im- plicated in pneumococcal disease. The composition of the current vaccine was re- cently compared against the respiratory isolates obtained in a national surveillance study conducted from 1987 to 1988 (45). The most common pneumococcal serotype encountered was type 3 (13.1%), followed by 19F, 23F, 6B, 14, 4, and 6A. All of these serotypes, which comprised 74.9% of the respiratory isolates in the study, were included in the current 23-valent pneumococcal vaccine. When cross-reactive serotypes (i.e., when antibody specific for one serotype or pneu- mococcal strain will cross-react with or also bind another serotype or pneumo- coccal strain) were considered, 89% of the respiratory disease isolates were in- cluded in the protective spectrum of the current vaccine. These data were more recently confirmed, with 93% of serotypes implicated in infections in the popula- tion being represented in the 23-valent vaccine (46). Theoretically, the 23-valent pneumococcal vaccine should provide an individual with the ability to develop immunity against the S. pneumoniae strains most commonly implicated in dis- ease. The clinical experience with this vaccine has generated considerable contro- versy regarding its efficacy and cost effectiveness. C. Efficacy Efficacy has been measured in clinical and serologic terms (see antibody response below). Numerous clinical trials on pneumococcal vaccine efficacy have been conducted in the United States. The clinical efficacy has varied considerably be- tween trials ranging from negligible to effective in three-fourths of patients. The Department of Veterans Affairs Cooperative Study was one of the few random- ized controlled trials of pneumococcal vaccine efficacy; however, it has been crit- icized because it was underpowered and had too few pneumonia cases observed to draw generalizable conclusions (47). Out of a study population of 2,295, there was one proven case of pneumococcal infection among 1,175 vaccine recipients. A total of 43 infections of proven and probable cause were identified. In two other trials conducted in individuals older than age 50, efficacy was 69% and 70%, re- spectively (48,49). A recent randomized trial in Finland comparing pneumococ- cal and influenza vaccination to influenza vaccine alone demonstrated a protective
Table 2 Recommendations for Adult Immunization in LTCFs Vaccine name For whom it is recommended Schedule Contraindications and 346 Gravenstein and route precautions (mild illness Influenza • All residents and staff who have direct contact • Given every year is not a contraindication) Give IM with residents. • October through November is the • Previous anaphylactic Pneumococcal • Adults who are age 50 or older optimal time to receive an annual flu reaction to this vaccine, polysaccharide • Adults Ͻ age 50 yrs with medical problems such shot to maximize protection, but the to any of its vaccine may be given at any time during components, or to eggs. Give IM or SQ as heart disease, lung disease, diabetes, renal the influenza season (typically dysfunction, hemoglobinopathies, December through March) or at other • Moderate or severe immunosuppression, and/or those living in times when the risk of influenza exists. acute illness. chronic care facilities • May be given anytime during the • People working or living with at-risk people influenza season • Previous anaphylactic • All healthcare workers and those who provide • May be given with all other vaccines but reaction to this vaccine key community services. at a separate site or to any of its • Routinely given as a one-time dose; components. • Adults who are age 65 or older administer if previous vaccination • Adults age Ͻ 65 y who have chronic illness or history is unknown, • Moderate or severe • One-time revaccination is recommended acute illness. other risk factors including chronic cardiac or 5 years later for people at highest risk of pulmonary diseases, chronic liver disease, fatal pneumococcal infection or rapid alcoholism, diabetes mellitus, CSF leaks, as well antibody loss (e.g., renal disease) and for as persons living in special environments or people Ն age 65 and older if the 1st social settings (including Alaska natives and dose was given prior to age 65 and Ն 5 certain American Indian populations). Those at years have elapsed since previous dose. highest risk of fatal pneumococcal infection are • May be given with all other vaccines but persons with anatomical or functional asplenia, at a separate site. sickle cell disease, immunocompromised persons including those with HIV infection, leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, generalized malignancy, chronic renal failure, or nephrotic syndrome, those receiving immunosuppressive chemotherapy (including corticosteroids), and those who received an organ or bone marrow transplant.
Td (Tetanus, • All adolescents and adults • Booster dose every 10 years after • Previous anaphylactic Vaccinations diphtheria) • After the primary series has been completed, a completion of the primary series of 3 or neurological reaction doses to this vaccine or to any Give IM booster dose is recommended every 10 years. of its components. Determine if patients have received a primary • For those who have fallen behind: The Varicella series of 3 doses. primary series is 3 doses: • Moderate or severe Give SQ • A booster dose as early as 5 years later may be acute illness. needed for the purpose of wound management, • Give dose #2 four weeks after #1. such as pressure sores. • #3 is given 6–12 months after #2. • Previous anaphylactic • May be given with all other vaccines but reaction to this vaccine • All susceptible adults and adolescents should be or to any of its vaccinated. Make special efforts to vaccinate at a separate site. components. suspectible persons who have close contact with • Two doses are needed. persons at high risk for serious complications • Dose #2 is given 4–8 weeks after dose • Pregnancy, or (e.g., healthcare workers and family contacts of possibility of immunocompromised persons) and susceptible #1. pregnancy within 1 persons who are at high risk of exposure (e.g., • May be given with all other vaccines but month. teachers of young children, day care employees, residents and staff in institutional settings such as at a separate site. • Immunocompromised colleges and correctional institutions, military • If the second dose is delayed, do not persons because of personnel, adolescents and adults living with mallgnancies and children, nonpregnant women of childbearing repeat dose #1. Just give dose #2. primary or acquired age, and international travelers who do not have cellular evidence of immunity). immunodeficiency Note: People with reliable histories of including HIV/AIDS. chickenpox (such as self or parental report of Note: For those on disease) can be assumed to be immune. For high-dose adults who have no reliable history, serological immunosuppressive testing may be cost effective as most adults with therapy, consult ACIP a negative or uncertain history of varicella are recommendations immune. regarding delay time. (continued) 347
Table 2 (Continued) 348 Gravenstein Vaccine name For whom it is recommended Schedule Contraindications and and route precautions (mild illness is not a contraindication) Varicella Unlabeled use: Prevention of herpes zoster and • If blood products or (Continued) post herpetic neuralgia in the elderly. immune globulin have been administered during the past 5 months, consult the ACIP recommendations regarding time to wait before vaccinating. • Moderate or severe acute illness. Note: Manufacturer recommends that salicylates be avoided for 6 weeks after receiving varicella vaccine because of a theoretical risk of Reyes syndrome. Adapted from the Advisory Committee on Immunization Practices (ACIP) by the Immunization Action Coalition with review by ad hoc team, October 2000. Abbreviation: LTCFs, Long-term care facilities; IM, Intramuscular1y; SQ, Subcutaneous1y; CSF, Cerebrospinal fluid; HIV, Human immunodeficiency virus; AIDS, Acquired immunodeficiency syndrome.
Vaccinations 349 efficacy for pneumonia of 71% in individuals older than age 70 with an additional risk (other than age alone) for contracting pneumonia (i.e., those also with heart disease, lung disease, bronchial asthma, alcoholism, or who were institutionalized or permanently bedridden) (50). The study was conducted in a population-based cohort using data from 1982 to 1985. Generalizability of the study is also limited because vaccine efficacy in one population does not necessarily imply efficacy in another. Individuals with acquired immunodeficiency syndrome, young adults, children, and the elderly may all respond differently to the vaccine and require in- dividual study to demonstrate efficacy. D. Antibody Response Another method of evaluating the efficacy of vaccination is by assessing the anti- body response to vaccination. It is assumed that if an individual develops antibody to the vaccine antigen, they will be protected from infection on future exposure. Most healthy adults are able to generate a satisfactory antibody response to the serotypes in the pneumococcal vaccine (51). In the populations at risk, however, the antibody response is inconsistent. In immunocompetent adults who are at in- creased risk of pneumococcal disease or its complications, or who are age 65 or older, antibody responses have been variable. In the healthy elderly patient, a lower antibody response has been observed compared with younger healthy adults (52–54). This would not have been predicted because pneumococcal vaccine is composed of polysaccharide antigens that should generate a T-cell independent B- cell response, and B-cell responses are less affected by advancing age. However, T-dependent B-cell responses do decline with age, such as for peptides and gly- coproteins (e.g., influenza vaccine) suggesting there may be a T-cell-dependent component to pneumococcal vaccine response. Objective measurements of health status and consideration of nutritional status, presence of malignancy, or known immunodeficiency, administration of immunosuppressant therapies, and anergy status may assist in identifying residents most likely to respond to pneumococcal vaccine. The currently available pneumococcal vaccines are composed of purified capsular polysaccharide antigens. Polysaccharide vaccines are less immunogenic than other vaccines that are composed primarily of protein antigens (i.e., live or killed bacteria, viruses, or toxoids). A pneumococcal conjugate vaccine has re- cently been approved for use in children (Prevnar® by Wyeth-Lederle Laborato- ries), but is not appropriate for use in adults. Several advances in the knowledge of protein conjugate technology, im- munobiologics, and antigenic determinants that relate to protection by pneumo- coccal vaccines are in various stages of development and promise to improve pneumococcal vaccine efficacy. As noted before, current protein conjugates are already in the marketplace, but these vaccines have not been appropriate for use
350 Gravenstein in adult populations. However, combining cytokines with the existing or conju- gated vaccines (55) may provide a targeted approach relevant to immunosenes- cence. Selecting different cross-reactive epitopes by using a protein rather than polysaccharide-based antigen, such as with pneumococcal specific protein A, may allow a trivalent to pentavalent formulation to generate protection against the ma- jority of serotypes rather than just 25% as is the case for the 23-valent polysac- charide formulation (56). These latter approaches hold the greatest promise for vaccines to address the challenge of antibiotic-resistant carriage and invasive dis- ease in old and immune compromised populations. E. Cost Effectiveness Physicians and other clinical decision-makers are becoming more conditioned to consider the cost of a therapeutic intervention before accepting it into their gen- eral practice. Pneumococcal vaccine has undergone this scrutiny and negative per- ceptions may partially explain the low utilization of the vaccine. Until recently, population-specific efficacy data have been equivocal, and high-risk populations have a more variable antibody response, compromising measures of efficacy. Healthcare practitioners, therefore, may not consider pneumococcal vaccination a therapeutic priority based on the available data. Contributing to the confusion re- garding vaccine use was the Immunization Practices Advisory Committee’s (ACIP) recommendation. The recommendation was equivocal until 1984, 7 years after the 14-valent vaccine was licensed for use (57). Several studies addressing the cost savings potential of the vaccine have since been published and support its use. The cost savings of the vaccine were evaluated in a retrospective study of Blue Cross/Blue Shield recipients in Minnesota using medical and pharmaceuti- cal claims information (49). In persons at risk for developing pneumonia who are older than age 50, the cost savings associated with use of the vaccine was $141 per person or a total observed cost savings of $141,098 for each 1,000 persons vacci- nated. Using a Markov decision-tree model in two hypothetical cohorts, one vaccinated with pneumococcal vaccine and the other unvaccinated, a cost-effec- tiveness analysis for elderly individuals aged 65 and older was conducted (58). A net savings of $8.27 and a gain of 1.21 quality-adjusted days of life per person vaccinated were identified at an estimated savings of $194 million dollars and 78,000 years of healthy life for the 23 million elderly people unvaccinated using 1993 data. In an analysis assuming an 8-year duration of immunity, the cost to Medicare in treating pneumonia would be the same as the cost of the vaccine (59). F. Safety The currently available pneumococcal vaccines are safe. The reactions to initial administration have been characterized as follows: erythema and pain at the in-
Vaccinations 351 jection site in 50% or more of persons; fever, myalgia, and severe local reactions in less than 1% of persons vaccinated (44); and anaphylactoid reactions that are reported to occur in approximately 5 cases per million (57). Neurological compli- cations of immunization, which have been reported to occur with vaccines derived from whole, killed organisms or live-attenuated organisms, have not been associ- ated with pneumococcal vaccine (60). The product information for the two pneu- mococcal vaccines currently available mentions a temporal association of use with neurological disorders such as paresthesias and acute radiculoneuropathy, in- cluding Guillain-Barrè syndrome. However, there are no case reports in the med- ical literature to support this observation, a presumed but unproven adverse effect of administration of some other vaccines (60). Revaccination with the pneumococcal vaccine has been reported to result in more severe local reactions when the administration time between the primary and secondary doses was less than or equal to 13 months, but low in individuals who could not recall when prior vaccination occurred (61,62). The incidence of ad- verse effects is similar for revaccination and primary immunization when revac- cination occurs more than 4 years after the initial dose of vaccine. As noted in Table 2, revaccination should be considered for those individuals at highest risk for pneumococcal disease and/or complications. G. Drug Interactions Administration of pneumococcal vaccine and influenza vaccine in separate intra- muscular sites has not resulted in an increase in adverse effects or change in im- munogenicity and is accepted by the CDC when necessary to administer two or more vaccines concurrently. Corticosteroids and other immunosuppressant drugs (e.g., alkylating agents, antimetabolites, antithymocyte antibodies, cyclosporine, and radioisotopes) may interfere with the antibody response to vaccines. Vaccine administration should be delayed for 3 to 12 months after discontinuing immuno- suppressant therapy. IV. TETANUS AND DIPHTHERIA VACCINES A. Tetanus Tetanus is one of the oldest diseases known to man. National surveillance began in the United States in 1947 when the incidence was 0.39 per 100,000 person- years. The incidence has declined to a current rate of 0.02 per 100,000 person- years (based on 1997 data; 48 reported cases) (63). The risk of tetanus, however, is twofold higher in individuals aged 60 and older compared with those aged 20 to 59 and more than 12-fold that of persons age 5 to 19.
352 Gravenstein Tetanus is a disease caused by Clostridium tetani, a spore-forming, gram- positive, anaerobic bacillus. It is widely distributed in soil that has been fecally contaminated by humans and animals and is considered part of the indigenous in- testinal microbial flora of humans and animals (64). The disease caused by C. tetani toxin results in prolonged muscular spasms of both the flexor and extensor muscle groups. Advanced tetanus shows generalized flexion contractures with prolonged spasm of the masseter muscle (lockjaw). Respiratory failure, caused by involvement of the muscles of respiration, may also occur and result in death. The risk for tetanus and its associated mortality increases with age (Fig. 1). The case-fatality ratio for the elderly, based on CDC data from 1995 to 1997, is 18%. Elderly persons are more prone to this disease principally because protec- tive antitoxin levels decline with age, at least in frail populations. Healthy, inde- pendently living elderly have been shown to retain vaccine immune responses similar to younger populations (65). Pressure ulcers, vascular ulcers, and surgical wounds are also more common in older people, placing hospitalized and institu- tionalized elderly persons at risk for tetanus. Fecal incontinence, a common prob- lem for many frail elderly, further makes pressure ulcers high-risk lesions for potential contamination with C. tetani. In a population-based serologic survey of immunity to tetanus in the United States, the prevalence of tetanus immunity was Figure 1 Reported number of tetanus cases, average and annual incidence rates, and sur- vival status of patients, by age group—United States, 1995–1997. Source: Centers for Dis- ease Control and Prevention, Ref. 63.
Vaccinations 353 28% among persons aged 70 and older compared with 80% among younger indi- viduals (66). In LTCF residents, studies in individuals with an average age of ap- proximately 80 years have found protective antitetanus antibodies in 29% to 51% of individuals (67,68). Protective antibody titers decline with age, especially in el- derly women, whereas elderly men with previous military service show better im- munity to tetanus (69). Besides immunization, more attention to appropriate care of wounds has contributed to the reduced incidence of tetanus in this country. However, individ- uals lacking a primary series of vaccination, particularly elderly women, occa- sionally are identified. In these individuals, if a contaminated wound is found, tetanus immune globulin should be given. A booster alone is appropriate if the pa- tient completed a primary series but has not received tetanus toxoid within the pre- ceding 5 years. A thorough attempt should be made to determine the primary im- munization status of all LTCF residents. Patients with unknown or uncertain previous immunization histories should be considered to have no previous tetanus toxoid doses. Persons who had military service since 1941 can be considered to have received at least one dose, although most may have completed a primary se- ries. However, this cannot be assumed for everyone. The number of people at risk for tetanus will increase unless elderly persons are more conscientiously given tetanus toxoid vaccines. B. Diphtheria First described in 1821 by Pierre Brettonneau, illness with Cornyebacterium diphtheriae is now extremely rare in the United States with only a few cases re- ported each year, primarily in nonimmunized elderly individuals (70). The pathogenesis of diphtheria begins with C. diphtheriae mucosal colonization of the nose or mouth. Toxin elaboration causes tissue necrosis and local inflamma- tion followed by absorption of the toxin, which has particular topism for cardiac, neural, and renal cells. Clinical manifestations appear after tissue fixation of toxin with myocarditis appearing 10 to 14 days and peripheral neuritis 3 to 7 weeks after onset of disease. Tonsillar and pharyngeal diphtheria is character- ized by anorexia, malaise, low-grade fever, and sore throat (71). Severe cases are associated with increasing toxemia, resulting in myocarditis, arrhythmias, congestive heart failure, stupor, coma, and death with 6 to 10 days. Cutaneous diphtheria is an indolent skin infection that often occurs at sites of burns or other wounds and is more common in warmer climates and conditions of poverty, overcrowding, and poor hygiene (72). Widespread use of diphtheria toxoid in the United States has limited the an- nual occurrence of the disease to practically nil, with one case reported to the CDC in 1999 (70). More than 90% of diphtheria cases occur in adults, virtually all of whom are unprotected. Adult susceptibility to diphtheria reflects reduced lifetime
354 Gravenstein exposure (to C. diphtheriae) and failure to administer the primary series of the vaccine and decadal boosters throughout life. 1. Effectiveness Tetanus-diphtheria toxoids (Td) are among the most immunogenic of vaccines indicated for older adults, and they are virtually 100% effective in immunocom- petent adults who have kept their vaccination status up to date. Naturally ac- quired immunity to tetanus toxin does not occur, and natural immunity to diph- theria occurs in only 50% of individuals who acquire the disease. Evidence indicates that complete primary immunization with tetanus toxoid provides 10 or more years of protection. Appropriately timed boosters are needed to main- tain antitoxin titers. Recent outbreaks of diphtheria in other countries highlight the risk of out- breaks of diphtheria (73–76). After a 23-year period without reported cases of diphtheria, the disease re-emerged in Sweden. Ninety-five percent to 99% of the children were vaccinated and 81% of the population younger than age 20 had protective immunity, but only 19% of women and 44% of men older than age 60 had protective immunity (77). All those individuals who died or had neuro- logical complications had low levels of antibodies, whereas 33 of 36 symptom- free carriers of the same strain had protective antibody titers. In an evaluation of 676 cases of hospitalized diphtheria cases in Khrgyzstan in 1995, the case fatal- ity ratio was 3% (76). In the United States, the number of older adults with pro- tective antibody to both tetanus and diphtheria is similarly low, making an ex- perience similar to the one in Sweden likely if we are unable to better vaccinate our population (78). 2. Indications All elderly persons should be actively immunized against both tetanus and diph- theria through the initial primary series and then revaccinated every 10 years. Anyone who has not received the complete primary series should complete it with the combined Td vaccine, although earlier doses need not be repeated if the sched- ule is delayed. A booster dose even 30 years after primary vaccination results in rapid protection for both tetanus and diphtheria. Getting the series up to date is es- pecially relevant if travel to developing countries is anticipated. Tetanus-diphtheria prophylaxis is recommended with clean, minor wounds if the primary series is incomplete or the last booster vaccination was more than 10 years ago. More serious wounds require both active and passive immunization with tetanus immune globulin. The cost effectiveness of tetanus immunization, specifically booster doses, has been questioned (79). Because tetanus is rare, the cost of each case prevented and its associated year of life gained is high, therefore, some experts have recom-
Vaccinations 355 mended targeting high-risk adults, such as those with vascular ulcers or those seen at time of injury, for revaccination (80). 3. Administration and Revaccination Tetanus toxoid (TT) is produced singly or in combination with Td with or without whole-cell or acellular pertussis vaccine. In elderly LTCF residents, Td is the rec- ommended preparation. The primary series used for adults consists of two 0.5-ml doses of Td given intramuscularly 1 to 2 months apart, followed by a third 0.5-ml dose 6 to 12 months later. The Td vaccine contains only 10% of the diphtheria tox- oid contained in the pediatric diphtheria-tetanus-pertussis (DTP) vaccine, making it much less reactogenic. 4. Adverse Reactions Present vaccines have been well tolerated with minimal reactions. The high reac- togenicity of childhood DTP vaccines has been largely attributed to the pertussis component, and that has been minimized with the transition to an acellular for- mulation of pertussis antigen. The only contraindication to tetanus and diphtheria toxoid is a history of a neurological or severe hypersensitivity reaction after a pre- vious dose, or sensitivity to the preservative. In previously immunized adults, the local reaction rate is 40% to 50%. Less than 10% of vaccines develop an area of redness or swelling larger than 5 cm (81). Potential side effects include local re- actions, fever, chills, hypersensitivity, arthralgia, rash, and encephalopathy. Re- actions may be related to high antitoxin titers or mediated by hypersensitivity to the mercury preservative. V. VARICELLA VACCINE As noted in Table 2, varicella immunization is recommended for all individuals in LTCFs, including residents and staff, who have no history of primary varicella in- fection (chicken pox). It has been suggested, as naturally occurring varicella inci- dence declines because of increasing use of varicella vaccine in children, that the rate of herpes zoster will increase (82,83). Herpes zoster is a prevalent condition in LTCF residents, with a high prevalence of complications, most notably pos- therpetic neuralgia (see Chapter 17). Varicella vaccine has been shown to boost cell-mediated immunity to varicella zoster virus in elderly individuals (84). It is hoped that this boost will result in a decreased incidence of herpes zoster in the el- derly. Large scale clinical trials are currently underway at the National Institutes of Health to study this issue extensively. Interested readers are referred to pub- lished reviews of this issue (85–87).
356 Gravenstein VI. VACCINATION OF HEALTHCARE WORKERS IN LTCFs Immunization of healthcare workers is recommended by a number of organiza- tions to prevent the spread of infection to the frail elderly residing in LTCFs, and the recommended vaccine uptake for providers having direct contact with resi- dents is also at 80%. The rate of immunization among LTCF staff remains low, despite these recommendations (6). The effect of vaccinating healthcare workers in geriatric long-term care hospitals on the incidence of influenza, lower respiratory tract infections, and death has been evaluated (88). In the hospitals where healthcare workers were vaccinated, influenza-like illness occurred in 7.7% of unvaccinated patients com- pared with 0.9% of vaccinated patients. Fewer patients died in hospitals where healthcare workers were vaccinated than in hospitals where healthcare workers were not vaccinated (10% vs 17%, respectively). Clinical data regarding the efficacy of vaccination of healthcare workers with respect to benefit to the resident population is primarily on influenza vacci- nation; however, it is reasonable to encourage pneumococcal vaccination, in ad- dition to annual influenza vaccination to reduce carriage of pathogenic and an- tibiotic-resistant strains and hepatitis vaccination to protect staff from infected residents. For maximum compliance, vaccinations should ideally be offered free to employees, and vaccine status should be reviewed upon employment and an- nually at the time influenza vaccination is reoffered. A formal policy regarding vaccination status review, and inclusion annual education regarding the impor- tance of vaccination to employees and residents will help build compliance. Also, policy review and enforcement should be assigned to the infection control practi- tioner, backed with authority consistent with local, state, and federal statutes. VII. SUMMARY Infectious diseases are an important underlying cause of much of the morbidity and mortality experienced in long-term care settings. This risk is in part the result of the nature of a closed setting, close living environment affecting disease trans- missibility, and the susceptibility of the resident population owing to both the na- ture of the underlying diseases and age-related immune decline. Vaccination is an important part of the overall infection control program for LTCFs. The currently available vaccines that should be part of the standing orders at the time of admis- sion to the facility are pneumococcal, tetanus/diphtheria, and influenza vaccines. Standing orders or policy driving the standing order should include review proce- dure for past vaccination, timing for initial and repeat vaccination, and review of contraindications for vaccinations. For healthcare staff, these three vaccines, in addition to the hepatitis vaccine, should be placed in the facility’s infection con-
Vaccinations 357 trol policy and ideally be readily available and included in employee benefits to improve compliance. Newer vaccines are currently under development that may provide significantly better safety profiles and immunogenicity. Shingles from herpes zoster may prove to be a vaccine-preventable disease. Although not dis- cussed here, the role of vaccines is expanding from a current preventive strategy to likely include treatment modalities for various diseases, including, for example, osteoporosis and Alzheimer disease in the next decades. The LTCF practitioner will be challenged but wise to stay abreast of developments of vaccine benefits, policy, and strategies to maximize uptake of both residents and staff. REFERENCES 1. Smith PW, Roccaforte JS, Caly PB. Infection and immune response in the elderly. Ann Epidemiol 1992; 2:813–822. 2. Berman P, Hogan DB, Fox RA. The atypical presentation of infection in old age. Age Ageing 1987; 16:201–207. 3. Kohn P. Cause of death in very old people. JAMA 1982; 247:2793–2797. 4. Castle SC, Norman DC, Yeh M, Miller D, Yoshikawa TT. Fever response in elderly nursing home residents: Are the older truly colder? J Am Geriatr Soc 1991; 39:853–857. 5. Nichol KL, Grimm MB, Peterson DC. Immunization in long term care facilities: Poli- cies and practice. J Am Geriatr Soc 1996; 44:349–355. 6. McArthur MA, Simor AE, Campbell B, McGeer A. Influenza and pneumococcal vac- cination and tuberculin skin testing programs in long-term care facilities: Where do we stand. Infect Control Hosp Epidemiol 1995; 16:18–24. 7. Centers for Disease Control and Prevention. Use of standing orders programs to in- crease adult vaccination rate (ACIP). MMWR 2000; 49(RR-1):15–26. 8. Centers for Disease Control and Prevention. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000; 49(RR-3):4–5. 9. Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on mortality: Introducing a severity index. Am J Public Health 1997; 87:1944–1950. 10. Simonsen L, Fukuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on hospitalizations. J Infect Dis 2000; 181:831–837. 11. De Jong JC, Beyer WE, Palache AM, Rimmelzwaan GF, Osterhaus AD. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A (H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. J Med Virol 2000; 61:94–99. 12. Patriarca PA, Weber JA, Parker RA, Hall WN, Kendal AP, Bergman DJ, Schonberger LB. Efficacy of influenza vaccine in nursing homes. JAMA 1985; 253:1136–1139. 13. Schneider EL, Guralnik JM. The aging of America. Impact of health care costs. JAMA 1990; 263:2335–2340.
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Vaccinations 359 30. Badamchian M, Goldstein AL, Sztein MB. Immune and neuroendocrine modulation with thymosins: Current status of recent clinical trials in the United States. Int J Neu- rosci 1990; 51:365–367. 31. Gravenstein S, Duthie EH, Miller BA, Roecker E, Drinka P, Prathipati K, Ershler WB. Augmentation of influenza antibody response in elderly men by thymosin alpha one. A double-blind placebo-controlled clinical study. J Am Geriatr Soc 1989; 37:1–8. 32. De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, Senatore F, Verweij P, Fritzell B, Podda A. Safety and immunogenicity of MF59-adjuvanted in- fluenza vaccine in the elderly. Vaccine 1999; 17:3094–3101. 33. Gravenstein S, Drinka P, Duthie EH, Miller BA, Brown CS, Hensley M, Circo R, Langer E, Ershler WB. Efficacy of an influenza hemagglutinin-diphtheria toxoid con- jugate vaccine in elderly nursing home subjects during an influenza outbreak. J Am Geriatr Soc 1994; 42:245–251. 34. Treanor JJ, Betts RF. Evaluation of live, cold-adapted influenza A and B virus vac- cines in elderly and high-risk subjects. Vaccine 1998; 16:1756–1760. 35. Centers for Disease Control. Adult immunization: knowledge, attitudes and prac- tices-DeKalb and Fulton Counties, Georgia, 1988. MMWR 1988; 37:657–664. 36. Margolis KL, Nichol KL, Poland GA, Pluhar RE. Frequency of adverse reactions to influenza vaccine in the elderly. A randomized, placebo-controlled trial. JAMA 1990; 264:1139–1141. 37. Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, Clark S, Haber P, Stolley PD, Schonberger LB, Chen RT. The Guillain-Barre syndrome and the 1992–1993 and 1993–1994 influenza vaccines. N Engl J Med 1998; 339: 1797–1802. 38. Musher DM. Infections caused by Streptococcus pneumoniae: Clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 1992; 14:801–809. 39. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drug- resistant pneumococcal infections in the United States. JAMA 1994; 271:1831– 1835. 40. Breiman RF, Spika JS, Navarro VJ, Darden PM, Darby CP. Pneumococcal bac- teremia in Charleston County, South Carolina. A decade later. Arch Intern Med 1990; 150:1401–1405. 41. Quick RE, Hoge CW, Hamilton DJ, Whitney CJ, Borges M, Kobayashi JM. Under- utilization of pneumococcal vaccine in nursing home in Washington State: Report of a serotype-specific outbreak and a survey. Am J Med 1993; 94:149–152. 42. 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, May-June 1996. MMWR 1997; 46:60–62. 43. Nuorti JP, Butler JC, Crutcher JM, Guevara R, Welch D, Holder P, Elliott JA. An out- break of multidrug-resistant pneumococcal pneumonia and bacteremia among un- vaccinated nursing home residents. N Engl J Med 1998; 338:1861–1868. 44. Advisory Committee on Immunization Practices. Prevention of pneumococcal dis- ease. MMWR 1997; 46:1–24.
360 Gravenstein 45. Jorgensen JH, Howell AW, Maher LA, Facklam RR. Serotypes of respiratory isolates of streptococcus pneumoniae compared with the capsular types included in the cur- rent pneumococcal vaccine. J Infect Dis 1991; 163:644–646. 46. Shapiro ED, Berg AT, Austrian R, Schroeder D, Parcels V, Margolis A, Adair RK, Clemens JD. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325:1453–1460. 47. Simberkoff MS, Cross AP, Al-Ibrahim M, Baltch AL, Geiseler PJ, Nadler J, Rich- mond AS, Smith RP, Schiffman G, Shepard DS. Efficacy of pneumococcal vaccine in high-risk patients: Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 315:1318–1327. 48. Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988; 108:653–657. 49. Gable CB, Holzer SS, Engelhart L, Friedman RB, Smeltz F, Schroeder D, Baum K. Pneumococcal vaccine: Efficacy and associated cost savings. JAMA 1990; 264:2910–2915. 50. Kivola I, Sten M, Leinonen M, Makela PH. Clinical efficacy of pneumococcal vac- cine in the elderly: A randomized, single-blind population-based trial. Am J Med 1997; 103:281–290. 51. Austrian R, Douglas RM, Schiffman G, Coetzee AM, Koornhof HJ, Hayden-Smith S, Reid RD. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians 1976; 89:184–194. 52. Roghmann KJ, Tabloski PA, Bentley DW, Schiffman TG. Immune response of elderly adults to pneumococcus: Variation by age, sex, and functional impairment. J Gerontol 1987; 42:265–270. 53. Musher DM, Luchi MJ, Watson DA, Hamilton R, Baughn RE. Pneumococcal polysaccharide vaccine in young adults and older bronchitics: Determination of IgG responses by ELISA and the effect of adsorption of serum with nontype-specific cell wall polysaccharide. J Infect Dis 1990; 161:728–735. 54. Landesman SH, Schiffman G. Assessment of the antibody response to pneumococcal vaccine in high-risk populations. Rev Infect Dis 1981; 3(suppl):S184–S196. 55. Buchanan RM, Briles DE, Arulanandam BP, Westerink MA, Raeder R H, Metzger DW. IL-12-mediated increases in protection elicited by pneumococcal and meningo- coccal conjugate vaccines. Vaccine 2001; 19:2020–2028. 56. Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae. Vaccine 2000; 19(suppl 1):S87–S95. 57. Centers for Disease Control. Update: Pneumococcal polysaccharide vaccine usage— United States. MMWR 1984; 33:273. 58. Sisk JE, Moskowitz AJ, Whang W, Lin JD, Fedson DS, McBean Am, Plouffe JF, Cetron MS, Butler JC. Cost-effectiveness of vaccination against pneumococcal bac- teremia among elderly people. JAMA 1997; 278:1333–1339. 59. Sisk JE, Riegelman RK. Cost effectiveness of vaccination against pneumococcal pneumonia: An update. Ann Intern Med 1986; 104:79–86. 60. Fenichel GM. Neurological complications of immunization. Ann Neurol 1982; 12:119–128.
Vaccinations 361 61. Borgono JM, McLean AA, Vella PP, Woodhour AF, Canepa I, Davidson WL, Hille- man MR. Vaccination and revaccination with polyvalent pneumococcal polysaccha- ride vaccines in adults and infants. Proc Soc Exp Biol Med 1978; 157:148–154. 62. Siber GR, Gorham C, Martin P, Corkery JC, Schiffman G. Antibody response to pre- treatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin’s disease. Ann Intern Med 1986; 104:467– 475. 63. Bardenheier B, Prevots DR, Khetsuriani N, Wharton M. Tetanus surveillance— United States, 1995–1997. MMWR 1998; 47:1–13. 64. Gerding DN, Peterson LR. Infections caused by anaerobic bacteria. In: Shulman ST, Phair JP, Peterson LR, Warren JR (eds). The Biologic and Clinical Basis of Infectious Disease. WB Saunders, Co, Philadelphia, 1996, pp. 414–438. 65. Carson PJ, Nichol KL, O’Brien J, Hilo P, Janoff EN. Immune function and vaccine responses in healthy advanced elderly patients. Arch Intern Med 2000; 160: 2017–2024. 66. Gergen PJ, McQuillin GM, Kiely M, Ezzati-Rice TM, Sutter RW, Virella G. A pop- ulation-based serologic survey of immunity to tetanus in the United States. N Engl J Med 1995; 332:761–766. 67. Ruben F, Nagel J, Fireman P. Antitoxin response in the elderly to tetanus-diphtheria (TD) immunization. Am J Epidemiol 1978; 108:145–149. 68. Weiss BP, Strassburg MA, Feeley JC. Tetanus and diphtheria immunity in an elderly population in Los Angeles County. Am J Public Health 1983; 73:802–804. 69. Gareau AB, Eby RJ, McLellan BA, Williams DR. Tetanus immunizations status and immunologic response to a booster in an emergency department geriatric population. Ann Emerg Med 1990; 19:1377–1382. 70. Centers for Disease Control and Prevention. Final 1999 reports of notifiable diseases. MMWR 2000; 49:841–858. 71. Shulman ST. Bacterial infections of the upper respiratory tract. In: Shulman ST, Phair JP, Peterson LR, Warren JR (eds). The Biologic and Clinical Basis of Infectious Dis- eases. WB Saunders, Co., Philadelphia, 1997, pp. 74–97. 72. Hofler W. Cutaneous diphtheria. Int J Dermatol 1991; 30:845–857. 73. Rappuoli R, Perugini M, Falsen E. Molecular epidemiology of the 1984–1986 out- break of diphtheria in Sweden. N Engl J Med 1988; 318:12–14. 74. Galazka A. Implications of the diphtheria epidemic in the former Soviet Union for immunization programs. J Infect Dis 2000; 181(suppl 1):S244–S248. 75. Lodha R, Dash NR, Kapil A, Kabra SK. Diphtheria in urban slums in north India. Lancet 2000; 355:204. 76. Kadirova R, Kartoglu HU, Strebel PM. Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995. J Infect Dis 2000; 181(suppl 1):S110–S115. 77. Christenson B, Bottiger M. Serological immunity to diphtheria in Sweden in 1978 and 1984. Scand J Infect Dis 1986; 18:227–233. 78. Crossley K, Irvine P, Warren JB, Lee BK, Mead K. Tetanus and diphtheria immunity in urban Minnesota adults. JAMA 1979; 242:2298–2300. 79. Mathais RG, Schechter MT. Booster immunization for diphtheria and tetanus: No ev- idence of need in adults. Lancet 1985; 1:1089–1091.
362 Gravenstein 80. Hutchison BG, Stoddart GL. Cost-effectiveness of primary tetanus vaccination among elderly Canadians. Can Med Assoc J 1988; 139:1143–1151. 81. Bjorkholm B, Granstrom M, Wahl M, Hedstrom CE, Hagberg L. Adverse reactions and immunogenicity in adults to regular and increased dosage of diphtheria vaccine. Eur J Clin Microbiol 1987; 6:637–640. 82. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch In- tern Med 1995; 155:1605–1610. 83. Garnett GP, Grenfell BT. The epidemiology of varicella-zoster virus infections: The influence of varicella on the prevalence of herpes zoster. Epidemiol Infect 1992; 108:513–528. 84. Levin MJ, Barber D, Goldblatt E, Jones M, LaFleur B, Chan C, Stinson D, Zerbe GO, Hayward AR. Use of a live attenuated varicella vaccine to boost varicella-specific im- mune responses in seropositive people 55 years of age and older: Duration of booster effect. J Infect Dis 1998; 178(suppl 2):S109–S112. 85. Levin JM, Hayward AR. The varicella vaccine. Prevention of herpes zoster. Infect Dis Clin North Am 1996; 10:657–675. 86. Raeder CK, Hayney MS. Immunology of varicella immunization in the elderly. Ann Pharmacother 2000; 34:228–234. 87. Schmader K. Postherpetic neuralgia in immunocompetent elderly people. Vaccine 1998; 16:1768–1770. 88. Potter J, Stott DJ, Roberts MA, Elder AG, O’Donnell B, Knight PV, Carman WF. In- fluenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 1997; 175:1–6.
21 Pathogenesis and Molecular Mechanisms of Antibiotic Resistance Robert A. Bonomo Case Western Reserve University, Cleveland, Ohio I. INTRODUCTION The infectious disease challenges facing clinicians committed to the care of the growing number of elderly will be great (1). It is estimated that the incidence of infection in long-term care facilities (LTCFs) in the United States ranges between 1 to 10 per 1000 days of care (2,3). Surveys of medication use in nursing homes indicate that antibiotics account for nearly 40% of all medications prescribed in LTCFs (4,5). Most of the antibiotic use is empiric, without the benefit of accurate culture data or information regarding susceptibility to guide clinicians. This in- tense antibiotic usage creates selective pressure for the emergence of resistance. Because elderly patients are mobile between acute care settings, LTCFs, and the community, the movement of the elderly in the healthcare system has played a ma- jor role in the evolution of antibiotic resistance in this population. II. ANTIBIOTIC RESISTANCE IN LTCFs In the past decade, the increasing prevalence of antibiotic-resistant pathogens in LTCFs has emerged as a major concern (6–11). In many publications, LTCFs are regarded as “reservoirs of resistant pathogens.” In LTCFs, resistance to -lactam antibiotics (especially third-generation cephalosporins), -lactam -lactamase in- hibitor combinations, macrolides, trimethoprim-sulfamethoxazole (TMP-SMX), 363
364 Bonomo fluoroquinolones, aminoglycosides, vancomycin, and linezolid are becoming ma- jor fears for clinicians prescribing antibiotics in LTCFs. Understanding how these resistant pathogens emerge in the setting of antibiotic use remains a critical tool in the design of strategies aimed to stem this problem (10,12,13). A. The Emergence of Resistant Pathogens in LTCFs Long-term care facilities are prime settings for the emergence of resistant bacte- ria for several reasons. The principal explanation may be that patients colonized with resistant pathogens are transported between acute care facilities and LTCFs: this can facilitate the spread of antibiotic-resistant pathogens from the endemic en- vironment (hospital) to a nonendemic one (LTCF). The best-studied example of this is the spread of methicillin-resistant Staphylococcus aureus (MRSA) (14,15) (see Chapter 22). Many LTCF residents also suffer from conditions, such as mal- nutrition or skin and soft tissue breakdown, that place them at risk for coloniza- tion and infection by resistant bacteria. Moreover, the frequent presence of in- dwelling foreign material, such as percutaneous endoscopic gastrostomy (PEG) tubes and indwelling bladder catheters, have been identified as risk factors for col- onization and infection by multiresistant bacteria (16). Many of these devices are placed in the acute care setting and become colonized with resistant pathogens prevalent in the hospital. Ultimately, these pathogens become endemic in LTCFs as patients undergo convalescence. Another major factor in the establishment of resistant pathogens in LTCFs may be related to lapses in infection control procedures (hand washing) (2). When resources are limited and the number of patients cared for increases, hand wash- ing becomes increasingly difficult. Lastly, excessive use of antimicrobial agents can easily select for resistant pathogens. This has been the major cause for the emergence of ceftazidime-resistant gram-negative bacilli (acquisition of point mutants that confer novel hydrolytic properties to these -lactamases) (17,18). Not only are individual resistance determinants evolving, but so are the plasmids encoding these genes. Many ceftazidime-resistance genes are encoded on large plasmids containing multiple resistance determinants (17). Why are antibiotics used so readily in LTCFs? The uncertainties of diagnosis of infection inherent in caring for the elderly drive empirical use. The diagnosis of infection may be extraordinarily difficult in the elderly population in LTCFs (19), where functional decline may be a more important clue to the presence of infection than fever. Furthermore, the fear of fatal clinical failure (unrecognized sepsis) often influences antibiotic choices, making it difficult to resist using broad-spectrum agents to cover all clinical possibilities (even if infection is not a likely cause). Ret- rospective studies demonstrate that in more than one-third of cases, the evidence to start an antibiotic is inadequate (20–23). Unfortunately, this inappropriate use of an- tibiotics impacts the LTCF-resistant microflora of the nursing home.
Antibiotic Resistance 365 B. Pathogenesis of Infections in the Elderly and the Impact of Antibiotic Resistance The most vulnerable older adults are more likely to be exposed to a larger number of infectious agents (24). The development of infected pressure ulcers, nursing home-acquired aspiration pneumonia, and catheter-associated urinary tract infec- tions (UTI) are all “high inoculum” infections. Furthermore, these infections all oc- cur in the setting of altered natural barriers. Malnutrition, poor skin integrity, di- minished gag reflex, and poor bladder emptying all contribute to the impaired host defense. In addition, the loss of helper T-cell function with age, decreased response to mitogens, and altered interleukin-2 production contribute to the susceptibility to infection (see Chapter 4). The higher the inoculum of infection and the more com- promised the host defenses are, the more likely that the same pathogen that rarely causes infection in the young will cause significant infection in the elderly (24). In fact, the mortality rates of pneumonia and sepsis are three times greater in the el- derly when compared with the young; pyelonephrititis carries a 10 times greater mortality (1,24). Most disturbing is that these syndromes appear many times with the absence of fever—a poor prognostic sign. A decline in functional status may be the only clue to infection. Guidelines have been published to assist the clinician with the assessment of infection and the initiation of therapy (25). In the setting of LTCFs where antibiotic resistance is endemic, treatment of these infections becomes even more problematic. For example, the fear of ampi- cillin or TMP-SMX-resistant Escherichia coli or Klebsiella pneumoniae may force a clinician to consider use of a third-generation cephalosporin, -lactam -lactamase inhibitor combinations, or quinolone therapy for the treatment of a UTI. The problem becomes more acute when empirical treatment of nursing home-acquired aspiration pneumonia is considered. Despite the knowledge that Streptococcus pneumoniae is the most common pathogen and that Legionella is uncommon in certain geographic areas, should the clinician always choose a quinolone to “cover penicillin-resistant pneumococci” and “atypicals?” Should empirical treatment for MRSA and anaerobes be added also? If one considers ev- ery possibility, it is easy to see how broad-spectrum therapy results. Omission of the appropriate antibiotic (i.e., choosing the incorrect empirical therapy) can re- sult in a fatal outcome. However, it is recognized that methicillin-resistant Staphy- lococcus aureus (MRSA) are no more virulent than methicillin susceptible Staphylococcus aureus (MSSA). The concern for resistance influences clinicians to escalate therapy. This practice increases cost and length of therapy, and possi- bly even toxicity. Antibiotics can cause a number of unwanted side effects that are more severe in the elderly (e.g., delirium and prolongation of the QTc interval on electrocardiogram with certain quinolones, nephrotoxicity and ototoxicity with aminoglycosides). Hence, in many ways, antibiotic resistance is as important as the potential virulence of the infecting pathogen.
366 Bonomo C. Basic Microbiological Principles Certain microbiological and pharmacological principles are essential to the un- derstanding of antibiotic resistance (26,27). These will be introduced here to en- sure a complete understanding of the discussion to follow. 1. Minimum Inhibitory Concentration and Minimum Bactericidal Concentration Minimum inhibitory concentration (MIC) is the lowest concentration of antibiotic that inhibits growth of an organism after 18 to 24 hour of incubation. This is a quantitative endpoint. Factors such as pH, oxygen, cations, composition of media (liquid or solid), inoculum size, drug stability, and others, can influence the MIC. Two methods are used to determine bacterial susceptibility to antibacterial agents: disk diffusion and agar or broth dilution. Disk diffusion is performed by applying commercially available filter paper disks impregnated with specific quantities of the drug on the surface of agar plates in which a specific amount of the bacteria has been streaked. After 18 to 24 hours, the size of the clear zone of inhibition around the disc is determined. The size of the zone is related to the activity of the drug against the test strain and the size of the inoculum tested. Standards for sen- sitivity vary for each test organism and they are based on the concentration of the drug that can be achieved safely in the plasma. Dilution tests (agar or broth) use serially diluted concentrations. The lowest concentration of the antibiotic that pre- vents (i.e., inhibits) visible growth is the MIC. The value that kills 99.9% of the bacterial numbers is the minimum bactericidal concentration (MBC). In many ref- erence laboratories, these assessments have been automated. Often a test strain may appear susceptible at a low inoculum but become re- sistant at a large inoculum. This is most commonly observed when E. coli or Kleb- siellae spp possessing extended spectrum -lactamases are tested (see below). As an example, susceptibility to ceftazidime is observed at a concentration of 104 or- ganisms, but resistance is seen at a higher inoculum of 106 organisms. 2. Pharmacological Principles After an antibiotic (like any other drug) has been administered by the oral, intra- venous, or intramuscular route, it is absorbed and has a peak serum concentration (C max), volume of distribution (VD), and serum half-life (T1/2). The combination of these considerations and the immune status of the host are important in eradi- cation of the organism. A critical factor is the site of infection and how well the antibiotic penetrates that site. For example, when treating infections in the cham- ber of the eye, low concentrations are usually achieved. In treating UTIs, high con- centrations of antibiotic are obtained in the urine. The postantibiotic effect is suppression of bacterial growth despite the pres- ence of subinhibitory drug concentrations (after removal of the antibiotic). Many
Antibiotic Resistance 367 antibiotics are advertised as having this property, but its effectiveness is unclear. Certain antibiotics’ killing properties are dependent on concentrations of the drug that are achieved above the MIC levels. The efficacy of -lactam antibiotics de- pends on the length of time the drug is above the MIC. Dose-dependent toxicities usually limit the amount of quinolones or aminoglycosides that are administered. D. Resistance to -Lactams The safety and therapeutic efficacy of -lactams have made them the most fre- quently prescribed antibiotics in LTCFs. Resistance to -lactams occurs by three mechanisms: alteration in the target protein (penicillin-binding protein), produc- tion of inactivating enzymes (-lactamases), and impaired entry into bacterial cells (loss of the channels that permit the ingress of antibiotics into bacteria or ac- tive efflux). The most important mechanism is production of -lactamases. Clin- ically important -lactam-resistant pathogens are: ceftazidime-resistant gram- negative bacilli, gram-negative bacilli producing inhibitor-resistant -lactamases, MRSA, and penicillin-resistant pneumococci (Table 1). 1. Ceftazidime-Resistant Gram-Negative Bacilli -Lactamases are bacterial enzymes that inactivate -lactams. Certain -lacta- mases prefer penicillin (penicillinases), whereas other -lactamases hydrolyze cephalosporins more readily (cephalosporinases) (28,29). These inactivating en- zymes may be encoded by genes on plasmids, transposons, or in the bacterial chromosome. The most concerning -lactamases are those that inactivate potent broad-spectrum penicillins (e.g., piperacillin) and third-generation cepha- Table 1 Resistant Pathogens Found in Long-Term Care Facilities Multiresistant gram-negative bacilli Extended spectrum -lactamase-producing gram-negative bacilli (Escherichia coli and Klebsiella pneumoniae) Inhibitor-resistant -lactamase producing E. coli, Klebsiella spp, or Proteus spp Plasmid-mediated third-generation cephalosporin-resistant Klebsiella pneumoniae and E. coli Third-generation cephalosporin-resistant Enterobacter and Citrobacter spp Quinolone-resistant Pseudomonas aeruginosa Trimethoprim-sulfamethoxazole-resistant E. Coli Resistant gram-positive bacteria Methicillin-resistant Staphylococcus aureus Vancomycin-resistant enterococci Penicillin-resistant Streptococcus pneumoniae (resistant also to macrolides, clindamycin, sulfamethoxazole, and tetracyclines)
368 Bonomo losporins. In this group are the inducible chromosomal cephalosporinases (AmpC -lactamases) and the extended-spectrum -lactamases (ESBLs). The latter are so named because they “extended the hydrolytic spectum” of penicillinases and cephalosporinases to include ceftazidime, cefotaxime, ceftriaxone, and aztre- onam. Most ESBLs are of the TEM and SHV variety (see www.lahey.org). An in- creasing number are also being discovered that are of the non-TEM and non-SHV variety (CTX-M, OXA, BES-1, and GES-1, and others). Extended-spectrum -lactamases are readily inhibited by -lactamase inhibitors (clavulanic acid, tazobactam, or sulbactam). Chromosomal cephalosporinases are able to hydrolyze third-generation cephalosporins but are not readily inhibited by -lactamase in- hibitors. Extended-spectrum -lactamases are the primary threats to the efficacy of cephalosporins in LTCFs (16,18,28,30). The widespread use of third-generation cephalosporins and the emergence of ESBLs in LTCFs have been well docu- mented. In one study, 31 of 35 selected residents from eight nursing homes in Chicago harbored an ESBL on admission to the hospital (16). These organisms (E. coli and Klebsiella spp) were multiresistant (resistant to ceftazidime, aminogly- cosides, TMP-SMX, and ciprofloxacin) and harbored a common plasmid encod- ing TEM-10 -lactamase. AmpC -lactamases are found in Enterobacter, Citrobacter, Serratia, and Pseudomonas aeruginosa. Exposure of these bacteria to agents such as cefoxitin, clavulanic acid, or imipenem induces production of AmpC -lactamases. More recently, transferable plasmids have been reported that possess AmpC -lacta- mases. The transferability of some of these plasmids suggests a significant poten- tial for spread under the appropriate selective conditions (28,31). 2. Inhibitor-Resistant -Lactamases Resistance to amoxacillin-clavulanic acid, ampicillin-sulbactam, and piperacillin- tazobactam) in E. coli or Klebsiella pneumoniae should raise concern (32). In the LTCF, clinicians have used -lactam -lactamase inhibitor combinations to treat infection caused by enteric bacilli and anaerobes (infected pressure ulcers and as- piration pneumonia). -Lactamases resistant to inactivation by -lactamase in- hibitors have evolved (33–35). Most inhibitor-resistant -lactamases are variants of the TEM-1 enzyme. To date, there has only been one description of a clinical isolate possessing SHV resistant to inhibitors (SHV-10) (35). Piperacillin- tazobactam, in particular, may still be effective for the treatment of E. coli pos- sessing certain inhibitor resistant TEM -lactamases (36). It is possible that the frequency of inhibitor-resistant -lactamases is under- estimated in LTCFs. Inhibitor-resistant clinical strains of K. pneumoniae have been discovered in a nursing home in France (37). Many laboratories in the United States do not identify these strains. Clinicians are unaware of the significance of
Antibiotic Resistance 369 resistance to amoxacillin-clavulanic acid, especially when they can use a first- generation cephalosporin. 3. MRSA Methicillin-resistant Staphylococcus aureus (MRSA) is a true “persistent pathogen” in LTCFs (38–44) (see Chapter 22). The molecular basis of resistance to methicillin is the expression of low-affinity penicillin-binding protein (PBP) PBP2a, encoded by the mecA gene (45). The mecA gene resides in the staphylo- coccal chromosome within a complex 30 to 50 kilobase genetic region that fre- quently encodes resistance to other antibiotics. Hence, MRSA is resistant to mul- tiple antibiotics. Vancomycin, quinupristin-dalfopristin (Synercid™), and linezolid (Zyvox™) are the only effective agents against MRSA. Fortunately, re- duced vancomycin susceptibility among S. aureus remains extremely rare. 4. Penicillin-Resistant Pneumococci Streptococcus pneumoniae remains one of the most frequent causes of pneumo- nia. Significant outbreaks of penicillin-resistant pneumococci (PRP) have oc- curred in LTCFs (46,47). Remodeling of pneumococcal PBPs is responsible for the reduction in the affinity for penicillins, carbapenems, and certain cepha- losporins (48). Pneumococci susceptible to penicillin have MICs less than 0.1 g/ml. Those with MICs higher than 0.1 but less than 2 g/ml are considered in- termediate in their resistance. Those with penicillin MICs greater than 2 g/ml are high-level resistant. Retrospective studies suggest that penicillin is effective therapy for pul- monary infections caused by pneumococci with intermediate resistance to peni- cillin (49). High-level resistance compromises the utility of -lactams antibiotics in the intravenous therapy of meningitis. The reduced activity of the penicillins against high-level PRP has focused attention on the use of the newer (antipneu- mococcal) fluoroquinolones for the treatment of respiratory infections, as these agents retain excellent activity against S. pneumoniae regardless of the level of penicillin resistance. How effective fluoroquinolone antibiotics will be in the treatment of penicillin-resistant pneumococci in LTCFs remains to be seen. An- tibiotic potency cannot compensate for a debilitated host. E. Resistance to Macrolides Erythromycin (the first macrolide) was initially isolated from Streptomyces ery- therus, which are soil organisms found in the Philippines. It is so named because it contains a many-member lactone ring to which are attached one or more deoxy sugars (26,27). There are currently three macrolides in common use: ery- thromycin, clarithromycin, and azithromycin. Clarithromycin differs from ery-
370 Bonomo thromycin only by methylation of the hydroxy group at the 6 position and azithromycin differs by the addition of a methyl-substituted nitrogen atom in the lactone ring. These structural modifications improve acid stability and broaden spectrum of activity. Macrolides are concentrated within neutrophils and macrophages by an energy-dependent process. Concentration in alveolar macrophages and neutrophils are up to 23 times and 10 to 13 times greater, re- spectively, than the levels in extracellular fluid. This is a property of all macrolide antibiotics and is a key factor in why these drugs are used in the treatment of cer- tain types of intracellular pathogens (see below). 1. Mechanism of Action Erythromycin (and all macrolides) inhibits protein synthesis in susceptible organ- isms by binding reversibly to a single high-affinity site of the 50S subunit of the 70S bacterial ribosome. The antimicrobial binding site is located in the peptidyl- tRNA binding region of the 50S-ribosome subunit. Erythromycin inhibits translo- cation wherein a newly synthesized peptidyl tRNA molecule moves from the ac- ceptor site on the ribosome to the peptidyl (or donor site). Erythromycin does not bind to mammalian ribosomes. Gram-negative organisms are resistant to ery- thromycin because erythromycin cannot enter the gram-negative cell. Organisms rendered cell-wall-deficient are susceptible to erythromycin (50–52). 2. Mechanism of Resistance (Table 2) Resistance to macrolides has been described in many common pathogens (50–54). A major mechanism for resistance to macrolide antibiotics (e.g., in S. pneumo- niae) is MLS B (macrolide, lincosamide, and streptogramin B) resistance, mani- fested when the 23S rRNA is methylated by the product of an erm gene. This mod- ification results in the decreased binding of all known macrolide, lincosamide, and streptogramin B antibiotics to the ribosome. Several mechanisms of bacterial re- sistance to erythromycin have also evolved over the years. These include imper- meability of the bacterial cell wall, altered intracellular targets, and drug inactiva- tion. A number of interesting inactivating enzymes exist. These include methy- lases that modify the ribosomal target leading to decrease in drug binding (ermB gene) and esterases that hydrolyze the antibiotics. Chromosomal mutations that al- ter the 50S ribosome also confer resistance. Macrolides can also be pumped out of cells (mefE gene) in an energy-dependent manner. Regulation and expression of erm methylases are complex and apparently species dependent. Erythromycin-re- sistant strains can be assigned to the constitutive resistance (cMLS) phenotype or the inducible resistance (iMLS) phenotype. Clarithromycin and azithromycin offer the following advantages when compared with erythromycin: reduced gastrointestinal toxicity, increased tissue
Antibiotic Resistance 371 Table 2 Mechanisms of Resistance Mechanism Site Example Altered target Penicillin-binding protein Methicillin-resistant Staphylococcus aures, Ligase Streptococcus pneumoniae Ribosome Vancomycin-resistant Inactivating enzyme DNA gyrase enterococci Topoisomerase IV Dihydrofolate reductase Erythromycin-resistant S. pneumoniae and dihydropteric acid synthesis Clindamycin-resistant S. -lactamase pneumoniae Penetration Aminoglycoside modifying Escherichia coli enzyme Quinolone-resistant S. aureus Trimethoprim-sulfamethoxazole- Tetracycline efflux pump Porin mutation resistant S. pneumoniae E. coli Klebsiella pneumoniae Enterobacter Citrobacter Pseudomonas aeruginosa Proteus S. pneumoniae P. aeruginosa absorption, and easier dosing. To date, they have not proved more effective. How- ever, the ease of dosing and the diminished side effect profile make these newer macrolides very popular. The enhanced tissue penetration also has made these drugs the mainstays of treating nontuberculosis mycobacterial infections (My- cobacterium avium complex [MAC]) in acquired immunodeficiency syndrome (AIDS) patients. At present, physicians are using the newer macrolides (clar- ithromycin and azithromycin) almost exclusively. Clarithromycin is degraded to 14-OH-clarithromycin that has enhanced activity against Haemophilus influen- zae, Legionella, and Helicobacter pylori. 3. Ketolides Ketolides belong to a new class of semisynthetic 14-membered-ring macrolides, which differ from erythromycin by having a 3-keto group instead of the neutral sugar L-cladinose. These are being developed in the search for more active agents against penicillin-resistant pneumococci and erythromycin-resistant H. influen- zae. Some intriguing data suggest these also act as immunomodulators. Teli-
372 Bonomo thromycin, a ketolide, is active against streptococcal and pneumococcal strains exhibiting erythromycin-inducible resistance and resistance by active efflux (53). In addition, ketolides are highly active against other bacteria causing respiratory tract infections (Moraxella and H. influenzae), anaerobic, and intracellular pathogens (Legionella). The principal advantage of ketolides is their activity against pneumococci and macrolide-resistant streptococci while preserving the re- mainder of the macrolide spectrum of activity, particularly for intracellular pathogens. The recommended dose is 800 mg once a day. The safety of this dose has been validated for patients treated for 7 to 10 days for community-acquired pneumonia. Telithromycin is uniformly and highly active against pneumococci (regard- less of their susceptibility or resistance to erythromycin, penicillin, or both), ery- thromycin-susceptible S. pyogenes and erythromycin-resistant S. pyogenes strains of the M phenotype (in which resistance is mediated by an efflux system) or iMLS-B or -C phenotype (in which resistance is mediated by a methylase encoded by the ermTR gene). Ketolides are less active against erythromycin-resistant S. pyogenes strains with the cMLS phenotype or the iMLS-A subtype (where resis- tance is mediated by a methylase encoded by the ermAM gene), these strains rang- ing in phenotype from the upper limits of susceptibility to low-level resistant. F. Resistance to TMP-SMX 1. Mechanism of Action Trimethoprim-sulfamethoxazole is a fixed-dose combination chemotherapeutic agent first introduced in Europe in 1968. It subsequently became available in the United States in 1973. It possesses a fixed ratio of one part TMP to five parts SMX. The relative amount of each drug varies with the preparation. Standard- dose oral tablets have 80 mg TMP and 400 mg SMX. Double-strength tablets con- tain twice this amount. The two components of the drug provide sequential inhibition of enzyme systems involved in bacterial synthesis of tetrahydrofolic acid, and thereby disrupt nucleic acid synthesis. These agents selectively attack bacterial nucleic acid syn- thesis because bacteria (in contrast to humans) cannot use exogenous folate to me- tabolize proteins. Sulfonamides inhibit synthesis of dihydrofolic acid (para- aminobenzoic acid into folic acid) and bind to bacterial dihydrofolate reductase in preference to human dihydrofolate reductase, which prevents the formation of the active metabolite tetrahydrofolic acid. Trimethoprim inhibits the reduction of di- hydrofolate into tetrahydrofolate. The latter is the form necessary for one-carbon transfer reactions, for example, the synthesis of thymidylate from deoxyuridylate. The combination of TMP and SMX provides inhibitory and even synergistic ac- tivity against bacteria. Trimethoprim is usually 20 to 100 times more potent than SMX.
Antibiotic Resistance 373 2. Mechanism of Resistance Resistance to TMP-SMX has become a major problem in the United States and the rest of the world (55,56). The biggest impact on resistance to these agents has been seen when treating pneumococci (otitis media, bronchitis, and pneumonia) and E. coli (UTIs). Trimethoprim-sulfamethoxazole-resistant organisms may arise by point mutations in the genes encoding these enzymes. Resistance in gram- negative bacteria is often common in LTCFs and is associated with the acquisition of a plasmid that codes for an altered dihydrofolate reductase enzyme (57). G. Resistance to Tetracyclines Tetracycline antibiotics were one of the first broad-spectrum antibiotics effective against a wide range of microorganisms. Chlortetracycline was first introduced in 1948 because of screening of natural products from the soil. Tetracyclines are now less generally used, owing in part to the evolution of other antimicrobial drugs as well as antimicrobial resistance. There are three categories of tetracyclines: the short-acting compounds chlortetracycline, oxytetracycline, and tetracycline; an intermediate group consisting of demeclocycline and methacycline; and long-act- ing compounds such as doxycycline and minocycline. The basic structure of tetra- cycline consists of a hydroxynapthacene nucleus containing, as the name implies, four fused benzene rings. Chlortetracycline was first isolated from Streptomyces aureofaciens in 1947, and oxytetracycline was isolated from Streptomyces rimo- sus in 1950. Doxycycline and minocycline are semisynthetic derivatives discov- ered in 1966 and 1972, respectively. 1. Mechanism of Action Tetracyclines are bacteriostatic drugs and act on the bacterial ribosome. Penetra- tion of the bacterial cell wall by tetracycline occurs as the result of both passive diffusion and an active transport system. Once the drug is within the bacterial cell, inhibition of protein synthesis occurs by binding to the 30S-ribosome subunit to block the binding of aminoacyl-tRNA to the acceptor site on the mRNA ribosome complex. This prevents the addition of new amino acids to the growing peptide chain. 2. Mechanism of Resistance The mechanism of resistance has been shown to be acquisition of a resistance de- terminant known as tetM, a transposon-borne determinant found initially in the gene of Streptococcus and more recently Mycoplasma that has migrated into other gram-negative organisms. The major ways bacteria become resistant to tetracy- clines is by decreased accumulation (blocked entry or efflux pumps), decreased access to the ribosome by protection proteins, and by enzymatic inactivation.
374 Bonomo 3. Glycylcyclines New tetracyclines are on the horizon! Glycylcyclines are tetracycline antibiotic derivatives. Tigilcycline, formerly known as GAR-936, is novel, semisynthetic tetracycline with broad-spectrum activity. Currently, tigilcycline is in three phase II clinical trials for complicated UTIs, intra-abdominal infections, and skin struc- ture infections. Efficacy and tolerability are becoming established. Their spectrum of activity is similar to tetracycline and includes gram positives, gram negatives, and anaerobes. In general, glycyclines are more active than minocycline and ap- pear to be more active against MRSA, penicillin-resistant pneumococci, and van- comycin-resistant enterococci (VRE). H. Resistance to Quinolones The history of the newer 4-quinolone antibacterial agents began with the intro- duction of nalidixic acid in 1962. The importance of the quinolone agents is de- rived from broad antibacterial spectrum, unique mechanism of action, absorption in the gastrointestinal tract (bioavailability) after oral administration, excellent tis- sue distribution, bactericidal activity, and low incidence of adverse reactions. The quinolone agents are all structurally similar compounds. They are di- vided into four general groups. These are naphthyridines, cinnolines, pyridopy- rimidines, and quinolones. These are all dual ring structures. 1. Mechanism of Action The molecular bases for the potent antibacterial effects of the newer quinolone agents have not been determined definitively (58–62). Previous studies indicated that the mechanism of action of nalidixic acid and the newer quinolones is inhi- bition of DNA topoisomerases (gyrases) of which four subunits (two A and two B monomers) have been identified. The topoisomerases supercoil strands of bac- terial DNA into the bacterial cell. Each chromosomal domain is transiently nicked during supercoiling, which results in single-stranded DNA. When super- coiling is completed, the single-stranded DNA state is abolished by an enzyme that seals the nicked DNA. The enzyme, termed gyrase or topoisomerase II (nicking-closing enzyme), nicks double-stranded chromosomal DNA, introduces supercoils, and seals the nicked DNA (58). The A and B subunits are thought to introduce the nicks, the B subunits supercoil, and the A subunits seal the nick they produce initially. Quinolones trap or stabilize the enzyme DNA complex after strand breakage or resealing of DNA. This trapped complex functions as a cellular poison, possibly by generating a DNA break that the cell is unable to repair. Quinolones also inhibit topoisomerase IV that is structurally similar to DNA gyrase. It has been observed that inhibitors of RNA and protein synthesis reduce
Antibiotic Resistance 375 the bactericidal activity of some quinolones, but they do not effect their ability to inhibit bacterial synthesis of DNA. Thus, inhibition of bacterial DNA synthesis is not sufficient to account for bacterial killing and, possibly, newly synthesized gene products may be necessary. The nature of the gene products is yet to be de- fined. The gene products in the RecA-SOS DNA repair and recombination sys- tem, the expression which is known to be induced by damage to bacterial DNA caused by quinolones, appears to function, at least in part, to repair quinolone-in- duced DNA damage. Rec mutants with deficient function are hypersusceptible to quinolones. Many more genes or gene products are also suspected to be important. 2. Mechanism of Resistance There are two mechanisms of resistance: altered gyrase or altered drug permeation through the bacterial membrane (60,61). Alterations in the bacterial subunit A of gyrase (point mutations) have been identified in numerous gram-positive and gram-negative strains. Single amino acid changes in the subunit B have also been identified. The resistance caused by movement of quinolones in and out of bacte- rial cells involves energy-dependent processes that depend on proton motive force, carrier-mediated drug efflux pumps, porin mutations, and others. The se- lection in vitro of both gram-positive and gram-negative bacterial variants with re- duced susceptibility to the quinolones has occurred after serial exposure of bacte- ria to subinhibitory drug concentrations. The resulting strains exhibit cross- resistance to all quinolones. I. Resistance to Aminoglycosides The aminoglycosides are bactericidal drugs that have been in clinical use since the 1940s. Currently the most important and widely used members of this antibiotic family are gentamicin, tobramycin, and amikacin. The principal use of the amino- glycosides is against aerobic and facultative gram-negative bacilli. They fre- quently are used in combination with -lactam agents against life-threatening gram-negative infections, gram-negative infections in the immunocompromised host, and in Pseudomonas spp infections. They do not possess clinically useful ac- tivity against gram-positive organisms when used alone; however, these antibi- otics act synergistically with a number of cell wall-active antibiotics (the peni- cillins, cephalosporins, and glycopeptides) against a number of gram-positive bacteria such as S. aureus, coagulase-negative staphylococci, group B strepto- cocci, enterococci, and Listeria monocytogenes. The aminoglycosides must be administered parenterally. They are usually given intravenously, but absorption after intramuscular injection is excellent. Ab- sorption through the gastrointestinal tract is minimal, although toxicity may occur if oral dosing is continued over a long period. The drugs have low protein binding
376 Bonomo (approximately 10%), but are charged at physiologic pH and are water soluble. As such, they distribute primarily to the intravascular and interstitial spaces and cross biological membranes poorly, with a volume of distribution of 0.2 to 0.3 L/kg. This distribution has clinically relevant ramifications. For example, the drugs pen- etrate poorly in bronchial secretions, and some have advocated the use of aerosolized aminoglycosides in the setting of severe pneumonia. The drug is ex- creted by the kidneys and concentrations in the urine exceed peak serum concen- trations by 25- to 100-fold. 1. Mechanism of Action All aminoglycosides possess a six-member ring with an amino-group substituent (called aminocyclitol). The drugs bind to the bacterial surface, and their entry into the microorganisms results in some disruption of the lipopolysaccharide in the cell wall. However, the principal mechanism of antibiotic activity is the binding to the interface of the 30S and 50S ribosomal subunits. This binding leads to instability of the polysome and subsequent interruption in translation of messenger RNA. 2. Mechanism of Resistance Resistance to aminoglycosides is a well-established, worldwide phenomenon. Al- most all resistant clinical isolates elaborate one of three enzymes, namely, amino- glycoside acetyltransferase, adenlytransferase, or phosphorylase (63). Each en- zyme results in a modification of the aminoglycoside resulting in poor ribosomal binding. Some resistant clinical isolates have been identified that have decreased aminoglycoside uptake (63). Virtually all aminoglycosides share the same pattern of toxicity, namely, renal toxicity and ototoxicity. Renal toxicity usually is manifested as an eleva- tion in serum creatinine, but acute oliguric renal failure can occur. Nephrotoxi- city among children and young, healthy adults is uncommon. However, older patients, particularly those with underlying renal disease, and those given other nephrotoxic drugs concomitantly, are particularly predisposed to aminoglyco- side nephrotoxicity. With regard to ototoxicity, both cochlear and vestibular tox- icity occur and may be irreversible. Rarely, aminoglycosides administration can result in neuromuscular blockade from inhibition of presynaptic release of acetylcholine; the incidence of this complication is increased in intensely ill pa- tients receiving neuromuscular blocking agents, such as pancuronium. J. Resistance to Glycopeptides The glycopeptide family is composed of two antibiotics, namely, vancomycin and teicoplanin. In the United States, currently only vancomycin is available.
Antibiotic Resistance 377 Vancomycin is bactericidal against a very broad variety of gram-positive organisms: gram-positive cocci and bacilli, and both aerobes and anaerobes. The drug is particularly useful in the treatment of MRSA and in gram-positive infections in which the organism has acquired resistance to the -lactam agents. Like the -lactam antibiotics, vancomycin exerts its effect by interrupting peptidoglycan synthesis, but at a step proximate to that involved with the peni- cillins and cephalosporins. The drug binds to a peptidoglycan precursor during an early reaction, leading to poor integrity of the cell wall and ultimately to bacterial swelling and breakdown. Until recently, acquired resistance to vancomycin was rare. Resistance to vancomycin by enterococci in LTCFs has emerged (64–67). This resistant phenotype is carried on a transposon containing multiple genes; to- gether, these genes enable the organism to produce a peptidoglycan of altered bio- chemical structure, which is sufficient to maintain the bacteria, but which binds poorly to vancomycin. III. CONCLUSIONS AND PROSPECTS FOR NOVEL DRUGS New antibiotics are being developed. The problem of resistant gram-positive in- fections (VRE, MRSA, PRP) in hospitals is accelerating the pace of new drug dis- covery. To that end, the newest antimicrobials being use are streptogramins, gly- cylcyclines (see above), and oxazolidinones (see Chapter 11) Streptogramins are members of the MLS group of antibiotics (see macrolides-lincosamides-streptogramins, above). Streptogramins act on the ribo- somal level to inhibit protein synthesis. The most recent MLS released is Syner- cid® (combination drug, quinupristin and dalfopristin in a 30:70 tratio). Dalfo- pristin binds to the 50S ribosome causing a persistent conformational change. It also increases the binding affinity for quinupristin. Quinupristin prevents the ex- tension of the peptide chain and causes incomplete chains to be released. It also inhibits peptide bond elongation. Together, there is a dual block in protein syn- thesis. Synercid is active against gram-positive bacteria. It is targeted against VRE, specifically vancomycin-resistant E. faecium. Resistance to Synercid has occurred by modifying the ribosomal binding site, enzymatic inactivation, and adenosine triphosphate (ATP)-driven efflux pump. Linezolid, an oxazolidinone, is also targeted against VRE. It is bacterio- static against MRSA, penicillin-resistant pneumococci, and VRE. Site of action is the ribosome, inhibiting the formation of a functional initiation complex. This drug can be administered orally and by the intravenous route and is highly effec- tive against VRE and other resistant gram positives. Multiple drug-drug interac- tions are possible, but the drug has been used safely. Unfortunately, resistance to linezolid has emerged (65).
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22 Methicillin-Resistant Staphylococcus aureus Larry J. Strausbaugh Portland VA Medical Center, and Oregon Health Sciences University School of Medicine, Portland, Oregon I. INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) is defined by minimum in- hibitory concentrations (MIC) of methicillin of 16 g/ml or more or oxacillin 4 g/ml or more (1). Strains of MRSA possess the mecA gene (1,2). This chromo- somal gene encodes an altered enzyme, termed penicillin-binding protein 2a (or PBP 2Ј), which has a low affinity for all beta-lactam antibiotics. This feature, pre- sumably, allows the enzyme to perform essential functions in construction of the gram-positive cell wall, even in the presence of methicillin and other beta-lactam antibiotics. As a rule, strains of MRSA also possess resistance determinants for many other antimicrobial agents; in fact, until recently, only vancomycin provided reliable therapy for serious infections caused by this organism. This extraordinary level of resistance combined with the inherent virulence of S. aureus accounts for the level of interest and concern generated by MRSA. Strains of MRSA emerged soon after methicillin became commercially available in the early 1960s (2,3). They became increasingly prevalent in the United States in the late 1970s, appearing initially in tertiary care hospitals and disseminating subsequently to smaller facilities and other settings (2,4). By the year 2000, MRSA strains accounted for 53% of all S. aureus clinical isolates ob- tained from patients with nosocomial infections that were acquired in U.S. inten- sive care units (5). As MRSA became more prevalent in acute care settings, the continual interchange of patients between hospitals and long-term care facilities (LTCFs) ensured their spread into the latter. The first report of MRSA in a U.S. 383
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