Infection Management for Geriatrics in Long Term Care Facilities

184 Nicolle have an unpleasant odor. This “symptom” is more appropriately addressed through improved continence management rather than antimicrobial treatment. D. Long-Term Indwelling Catheters For microbiologic diagnosis of urinary infection in the resident with a chronic in- dwelling catheter, a specimen must be collected aseptically from the catheter port or by aspiration through the catheter tubing. Catheters that have been in situ for several days will have biofilm formation, primarily on the inner surface of the catheter. A urine specimen obtained from the catheter or tubing provides samples of the bacteriology of this biofilm rather than bladder urine. The microbiologic findings in a specimen obtained from the catheter differ quantitatively and quali- tatively when compared with bladder urine (66,67). A higher number of bacteria and higher quantitative counts of organisms in the urine are isolated from a biofilm-laden catheter. Thus, where a urine specimen for culture is obtained to identify infecting organisms and susceptibilities, the indwelling catheter should be replaced, and a urine specimen obtained from the newly inserted catheter before antimicrobial therapy begins. The most common clinical presentation of symptomatic urinary infection in the catheterized patient is fever without localizing findings. At least 30% to 50% of such episodes in residents with an indwelling catheter have a urinary source (21). Thus, a diagnosis of symptomatic urinary infection with this clinical presen- tation is appropriate in the catheterized resident. Localizing findings, including hematuria, an obstructed catheter, suprapubic tenderness, or costovertebral angle pain or tenderness should be sought, as these increase the probability of a urinary source. V. THERAPEUTIC INTERVENTIONS A. Asymptomatic Bacteriuria Asymptomatic bacteriuria in residents of LTCFs should not be treated. Prospec- tive, randomized, comparative trials have repeatedly shown no decrease in mor- bidity or mortality with antimicrobial treatment of asymptomatic bacteriuria (9,11,24,68). Specifically, there is no decrease in acute episodes of symptomatic urinary infection, no change in chronic genitourinary symptoms, and no decreased mortality with treatment of asymptomatic bacteriuria (Table 5). Some studies have, in fact, reported a trend towards increased mortality with intensive antimi- crobial therapy to attempt to maintain sterile urine (9,11). Treatment of asymp- tomatic bacteriuria does result in an increased incidence of new infection in treated residents, increased adverse effects from antimicrobial therapy, increased cost, and increased reinfection with more resistant organisms. Thus, studies are

Urinary Tract Infection 185 Table 5 Randomized Clinical Trials of Therapy and No Therapy for Management of Asymptomatic Bacteriuria in Long-Term Care Facility Residents Population Number Follow-up Outcomes of therapy and no therapy Men (9) 36 2 years • Similar for symptomatic Women (11) 50 episodes 12 months Women (23) 358 • Similar for mortality Men and women (68) 191 8.5 years • ↑ infection, ↑ adverse effects, 3 days Long-term catheter (82) 35 mean 29.2 ↑ resistance with antimicrobial therapy weeks • Similar symptomatic episodes and mortality • No difference in mortality • Treatment had no effect on chronic incontinence • No difference: bacteriuria, fever, catheter obstruction • ↑ Resistant bacteria with cephalexin consistent in reporting no benefit with treatment of asymptomatic bacteriuria, and several harmful outcomes. It follows that routine screening of asymptomatic res- idents of LTCFs for the presence of asymptomatic bacteriuria is not indicated. B. Antimicrobial Treatment Antimicrobial therapy is certainly indicated for the treatment of symptomatic in- fection. Many different antimicrobials are effective for treatment of urinary infec- tion (Table 6). Selection of a specific agent for treatment of an episode is directed by the known or presumed susceptibilities of the infecting organism, patient tol- erance, evidence of prior efficacy of the antimicrobial in the management of uri- nary infection, and facility formulary. Antimicrobial selection is not altered on the basis of age alone (69). In every case, a urine specimen for culture should be ob- tained before instituting antimicrobial therapy. If possible, empirical treatment should be avoided. For individuals with mild lower tract symptoms or only low- grade fever, institution of antimicrobial therapy should be delayed pending results of the urine culture. When the resident’s clinical status is severe enough to war- rant empiric therapy, such as a resident with acute confusion, high fever, or hemo- dynamic instability, empirical antimicrobial therapy is indicated. The empirical regimen should be reassessed once the urine culture result is available, usually at 48 to 72 hours after start of treatment, and the initial clinical course and response to antimicrobial therapy can be reviewed.

186 Nicolle Table 6 Antimicrobials for Treatment of Urinary Tract Infection in Long-Term Care Facility Residents Regimen Oral Parenteral Penicillins 500 mg tid 1–2q 6h Ampicillin 500 mg tid Amoxicillin 3g q 4h Amoxicillin/clavulanic acid 500 mg qid 3.375g q 6h Piperacillin 125–250 mg bid Piperacillin/tazobactam 400 mg od 1.0g q 8h 750 mg q 8h Cephalosporins 400 mg bid 1.0g q 8–12h Cephalexin 250–750 mg bid 1.0g q 24h Cefazolin 200–400 mg bid 1.0g q 8h Cefuroxime (axetil) 250–500 mg od 1–1.5 mg/kg q 8h or 3–4 mg/kg q 24h Cefixime 400 mg od 1–1.5 mg/kg q 8h or 3–4 mg/kg q 24h Cefotaxime 400 mg od 3–5 mg/kg q 8h or 15 mg/kg q 24h Ceftriaxone 100 mg bid Ceftazidime 160/800 mg bid 400 mg q 12h 100 mg bid 500 mg od Aminoglycosides Gentamicin 1.0g q 8h Tobramycin 500 mg q 6h Amikacin 500 mg q 8h 1.0g q 12h Fluoroquinolones Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Gatifloxacin Moxifloxacin Other Trimethoprim Trimethoprim/sulfamethoxazole Nitrofurantoin Aztreonam Imipenem/cilastatin Meropenem Vancomycin* * Gram positive infections only. Abbreviations: OD, once daily; bid, twice daily; tid, three times daily; qid, four times daily.

Urinary Tract Infection 187 Few studies address the question of the optimal antimicrobial regimen for treatment of symptomatic urinary infection in residents of LTCFs. Thus, the rela- tive efficacy of different antimicrobials and optimal duration of therapy are not known. For oral therapy, trimethoprim/sulfamethoxazole or trimethoprim alone may be preferred as initial therapy (2). If resistant organisms are known or thought to be causing infection, a quinolone antimicrobial may be appropriate, and for gram-positive infections, amoxicillin is usually preferred. Quinolone antimicro- bials should be reserved for therapy when other oral options are not available, to limit emergence of resistance to this class of agents. Nitrofurantoin is useful for episodes of lower tract infection. It also has limited impact on the normal host flora and, on occasion, may be effective therapy for vancomycin-resistant entero- cocci. However, it is not effective for P. mirabilis infection, is not indicated for upper tract infection, and is contraindicated in patients with renal failure. When the resident’s clinical status or infection with antimicrobial-resistant organisms warrants parenteral therapy, an aminoglycoside antimicrobial such as gentamicin may be considered (2). A relatively safe and convenient dosage regi- men for aminogylcosides is once-daily administration (70), which may be feasi- ble in a long-term care setting. Gentamicin or tobramycin may be given intra- muscularly or intravenously in a dose of 3 to 4 mg/kg/day every 24 to 48 hours depending on renal function of the resident (70). Aminoglycosides may be given either intravenously or intramuscularly. Aminoglycoside use avoids the extended- spectrum cephalosporins or quinolones, limiting antimicrobial pressure for emer- gence of extended-spectrum beta-lactamase producing Enterobacteriaceae or quinolone-resistant organisms, both of which have been identified as a concern in LTCF populations. When empirical therapy with an aminoglycoside is initiated, the clinical course and infecting organism should be reassessed after 48 to 72 hours to ensure that the aminoglycoside remains optimal therapy and that par- enteral therapy is still required. In many cases, the aminoglycoside may be changed to an alternative parenteral or oral drug at this time. If a more prolonged course of aminoglycoside therapy is indicated, then aminoglycoside levels and re- nal function should be monitored at least twice weekly. However, in LTCFs, such regular assessments may not be feasible and alternative agents such as quinolones, extended-spectrum cephalosporin, or a carbapenen should be considered. Amino- glycosides are not an appropriate empiric choice for individuals with renal failure and in this setting, a parenteral quinolone antimicrobial or an extended-spectrum cephalosporin would be preferred. C. Duration of Treatment Few studies are available to define the optimal duration of treatment. For minor lower tract symptoms, a 7-day of course of therapy is adequate. Shorter courses of 3 to 5 days are less effective than in younger women with acute cystitis and are

188 Nicolle not recommended for this population. More severe clinical presentations with ev- idence of systemic illness should be treated for 10 to 14 days. In a few selected clinical indications, longer courses of antimicrobial therapy may be necessary. Men with symptomatic relapsing infection from a prostatic source may require 6 or 12 weeks of treatment (71,72). Residents with recurrent episodes of invasive in- fection and an abnormality of the genitourinary tract that promotes infection and cannot be corrected, including infection stones that cannot be removed, may ben- efit from long-term suppressive therapy (73). This is undertaken in only highly se- lected patients, and specific therapy chosen on a case by case basis. Long-term an- timicrobial therapy should always be embarked on with care, as it is likely to promote emergence of resistant organisms. D. Chronic Indwelling Catheters The principles of antimicrobial selection in residents with chronic indwelling catheters are similar to those for residents without indwelling catheters. The catheter should be changed before initiating antimicrobial therapy, so the urine specimen obtained reflects the microbiology of bladder urine rather than biofilm on the catheter. Replacement of the catheter before instituting antimicrobial ther- apy may also lead to improved clinical outcomes, such as more rapid deferves- cence of fever and a decreased occurrence of symptomatic relapse (74). The optimal duration of antimicrobial therapy for treatment of a symp- tomatic episode in a patient with a chronic indwelling catheter is not known. How- ever, the continuing presence of the catheter will result in recurrent urinary infec- tion, and antimicrobial therapy promotes reinfection with organisms of increasing resistance. Thus, the duration of antimicrobial therapy should be as short as pos- sible. In residents with a prompt clinical response and rapid defervescence of fever, a 7-day course of therapy should be sufficient. VI. INFECTION CONTROL MEASURES A. General The goals of infection control measures in the LTCF are to prevent acquisition of infection by residents and prevent transmission of organisms between residents. The most important interventions are appropriate hand washing and glove use by staff members, use of aseptic or clean technique in patient care, and effective cleaning of equipment. A particular concern related to urinary infection in the LTCF is the cleaning and drying of leg bags for individuals using a condom or in- dwelling catheter (75). Surveillance for infection identifies the presence and extent of specific problems and by itself may contribute to decreasing infection rates as staff are made aware of the burden of morbidity. Because of the high prevalence and lack

Urinary Tract Infection 189 of evidence of harm of asymptomatic bacteriuria in this population, routine urine collection for screening cultures is not appropriate. Surveillance should be under- taken for symptomatic urinary infection, including bacteremia from urinary sources (75). Any surveillance strategy must have a capacity for early identifica- tion of potential outbreaks. Antimicrobial use for urinary infection should also be monitored, together with a means of assessing the appropriateness of such use. B. Long-Term Indwelling Catheters The urine from individuals with long-term indwelling catheters is a reservoir for resistant organisms within the long-term care setting. Thus, care must be taken to limit transmission of organisms, through equipment or the hands of staff, between patients with chronic catheters. Urine-measuring devices should not be shared among patients, appropriate glove and hand-washing practices by staff members in catheter care should be maintained, and policies governing catheter care in LTCF patients should be developed and updated regularly. These policies should also specify when long-term indwelling catheters should be used and how catheter use should be monitored to assist in limiting use. Surveillance of long-term indwelling catheter use should include the preva- lence of catheter use, reasons for catheter use, and reasons why the catheter cannot be removed in a given individual. As all residents with chronic indwelling catheters are bacteriuric, there is no indication for routine screening for the presence of bac- teriuria. However, surveillance for symptomatic urinary infection should be per- formed, including surveillance for episodes of catheter obstruction or trauma. VII. PREVENTION A. General Measures The major factors promoting urinary tract infection in elderly residents of LTCFs are associated comorbid diseases leading to a neurogenic bladder. As these are the same comorbidities that lead to admission to the LTCF and, in most cases cannot be altered, it is not clear whether any current interventions can prevent bacteriuria. As a general approach to care, optimizing nutrition, mobility, and medical man- agement of comorbid illnesses is desirable, but the impact of these on the occur- rence of urinary infection is unknown. In fact, one clinical study reported that im- proving nutrition of LTCF residents did not decrease the occurrence of urinary infection (76). B. Specific Measures Several specific interventions may decrease the occurrence of urinary infection. The use of condom catheters is associated with an increased frequency of infec-

190 Nicolle tion, so limiting the use of these devices should decrease the occurrence of bac- teriuria. Whether this would also decrease the occurrence of symptomatic infec- tion is unknown. In many cases, however, patient care requires the use of these de- vices, and it is unrealistic to think use can be entirely avoided. For individuals with voiding managed with intermittent catheterization, the frequency of infection is similar using a clean or sterile catheterization technique (77). Hence, clean, inter- mittent catheterization is appropriate and less costly. Increased intake of cranberry juice has been suggested as an approach to decrease infection. However, increased cranberry juice did not decrease the prevalence of bacteriuria or symptomatic in- fection in a placebo-controlled trial (78). Topical vaginal estrogen therapy de- creased the occurrence of both symptomatic and asymptomatic infection in a group of elderly, institutionalized women with a very high frequency of symp- tomatic infection (79) and may be an approach for some women. Finally, trauma to the mucosa in an infected genitourinary tract is associated with a high risk of bacteremia and sepsis. Prophylactic antimicrobial therapy should be given before any invasive genitourinary procedure is undertaken in a bacteriuric resident, as this is effective in preventing these severe complications (80). C. Long-Term Indwelling Catheters The most effective way to avoid urinary infection associated with a long-term catheter is, of course, not to use the catheter or to limit the duration of use to as short a time as clinically necessary. Otherwise, bacteriuria cannot currently be prevented in a patient with a long-term indwelling catheter. Several specific in- terventions to decrease the frequency of catheter-associated infection have been evaluated, but none have been shown to be effective. For instance, routine daily bladder irrigation with saline does not decrease the incidence of infection (81), an- timicrobial treatment of asymptomatic bacteriuria does not decrease the frequency of asymptomatic or symptomatic infection (82), and different catheter materials, such as latex or silicone, do not alter the rate of infection. Silicone catheters have been reported to have fewer episodes of obstruction and may be useful in patients with a high rate of obstruction. However, they have not been shown to decrease the occurrence of symptomatic infection and, as they are more costly, are recom- mended only for selected patients. Other interventions, such as daily periurethral cleaning with soap and water or with a disinfectant, or placing disinfectant in the drainage bag, do not decrease the frequency of bacteriuria in patients with short- term indwelling catheters and would also be assumed to be ineffective for long- term catheters. Because the frequency of asymptomatic bacteriuria cannot be decreased, the focus of prevention must be to minimize the occurrence of symptomatic episodes. Appropriate catheter care to limit trauma, avoiding contamination with inconti- nent stool (e.g., securing the catheter to the upper thigh of the resident), and

Urinary Tract Infection 191 prompt identification and replacement of an obstructed catheter will prevent some episodes of symptomatic infection. In addition, the use of prophylactic antimicro- bials before an invasive genitourinary procedure will prevent postprocedure sep- sis and bacteremia (80). Prophylactic antimicrobials are not indicated with catheter change, as the risk of infectious complications with this intervention is not sufficient to warrant this intervention (83,84). The problem of urinary infection in the individual with a long-term in- dwelling catheter is a technical issue related to ensuring adequate urinary drainage, and catheter materials to prevent bacterial growth. Further technological develop- ments, then, are necessary to make a substantial impact on the frequency of urinary infection in residents with long-term indwelling catheters. Current studies of dif- ferent drainage devices, such as intraurethral catheters, or catheter materials to pre- vent bacterial growth, may result in improvements in the future. REFERENCES 1. Nicolle LE, Strausbaugh LJ, Garibaldi RA. Infections and antibiotic resistance in nursing homes. Clin Microbiol Rev 1996; 9:1–17. 2. Nicolle LE, Bentley D, Garibaldi R, Neuhaus E, Smith P, SHEA Long Term Care Committee. Antimicrobial use in long-term care facilities. Infect Control Hosp Epi- demiol 2000; 21:537–545. 3. Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti- infective drugs for the treatment of urinary tract infection. Clin Infect Dis 1992; 15(Suppl 1):S216–S227. 4. Nicolle LE. Asymptomatic bacteriuria in the elderly. Infect Dis Clin North Am 1997; 11:647–662. 5. Warren JW. Catheter-associated bacteriuria. Clin Geriatr Med 1992; 8:805–819. 6. Ouslander JG, Schapira M, Finegold S, Schnelle J. Accuracy of rapid urine screening tests among incontinent nursing home residents with asymptomatic bacteriuria. J Am Geriatr Soc 1995; 43:772–775. 7. Kasviki-Charvati P, Drolette-Kefakis B, Papanayiotou PC, Dontas AS. Turnover of bacteriuria in old age. Age Ageing 1982; 11:169–174. 8. Bentzen A, Vejlsgaard R. Asymptomatic bacteriuria in elderly subjects. Dan Med Bull 1980; 27:101–106. 9. Nicolle LE, Bjornson J, Harding GKM, MacDonell JA. Bacteriuria in elderly institu- tionalized men. N Engl J Med 1983; 309:1420–1425. 10. Ouslander JG, Schapira M, Schnelle JF. Urine specimen collection from incontinent female nursing home residents. J Am Geriatr Soc 1995; 43:279–281. 11. Nicolle LE, Mayhew WJ, Bryan L. Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women. Am J Med 1987; 83:27–33. 12. Abrutyn E, Mossey J, Levison M, Boscia J, Pitsakis P, Kaye D. Epidemiology of asymptomatic bacteriuria in elderly women. J Am Geriatr Soc 1991; 39:388–393.

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13 Influenza and Other Respiratory Viruses Ghinwa Dumyati and Ann R. Falsey University of Rochester School of Medicine, and Rochester General Hospital, Rochester, New York I. INTRODUCTION Viral respiratory infections are extremely common during childhood but decrease in frequency with increasing age. In general, older adults experience approxi- mately one upper respiratory infection (URI) per year (1,2). The incidence of in- fection is lower, but the morbidity of these respiratory viruses is significantly greater in the elderly compared with the young. The reasons for more severe dis- ease are multifactorial and include an aging lung, the presence of comorbid con- ditions, and age-related immune dysfunction. In long-term care facilities (LTCFs) the rates of acute respiratory tract infection vary, depending on the season studied and the methods used for diagnosis. Several studies estimate the rate of URI to be one to three per resident per year (3–5). Acute respiratory tract infection was re- ported at a rate of 6.3/100 person-months in a study conducted during the winter at a 590-bed LTCF in Rochester, New York (6). Forty-two percent of these infec- tions were proven to be caused by viruses. The devastating effect of influenza out- breaks is well defined in the nursing home population, but the impact of other viruses is less well known. More recently, respiratory syncytial virus (RSV) in- fection has emerged as an important pathogen causing significant morbidity and mortality approaching that of influenza infection. Less data are available, but other viruses, such as parainfluenza, coronavirus, and rhinoviruses, have also been described as pathogens in elderly adults and may contribute to increased mortal- ity (7). Control of viral respiratory infections in LTCFs can be challenging be- cause specific diagnosis is often difficult. Congregate settings, hands-on attention 197

198 Dumyati and Falsey required by staff and residents, and cognitive deficits that hamper disease recog- nition all contribute to the spread of viruses and the development of outbreaks. In this chapter, the clinical presentation and impact of influenza, RSV, coronavirus, parainfluenza, and rhinovirus infections in residents of LTCFs will be reviewed. The mode of transmission and methods for prevention of these viruses will also be discussed. II. INFLUENZA A. Epidemiology and Clinical Relevance 1. Viral Characteristics Influenza virus is well known to cause worldwide pandemic and epidemic disease. Three types exist: A, B, and C, which are classified based on antigenic differences between the internal proteins. Both A and B cause severe disease, whereas type C has been reported to cause milder upper respiratory tract infection. Immunity to influenza infection is both humoral and cell mediated. Protective antibodies are produced against the viral envelope proteins, haemagglutinin (H) and the neu- raminidase (N). Repeated infections can occur because of yearly antigenic varia- tions in these envelope proteins. Such variations are caused by point mutations in the envelope protein genes. This process, referred to as “antigenic drift,” leads to annual epidemics and is the reason for yearly changes in the components of the in- fluenza vaccine. A major change due to an introduction of a completely new H or N gene, referred to as “antigenic shift,” leads to influenza pandemics. Pandemics occur because all members of the community are susceptible to infection by the new strain of influenza virus. Antigenic shift only occurs in influenza A viruses. In recent years, influenza A (H3N2 and H1N1) and influenza B have been cocir- culating (8). H1N1 viruses are uncommon causes of infection in the elderly nurs- ing home resident, possibly because of immunity acquired in younger life (9–11). 2. Attack Rate, Morbidity, and Mortality Influenza is an important viral pathogen in the elderly population, as approxi- mately 80% to 90% of the deaths attributable to influenza occur in persons aged 65 or older. Death is caused by pneumonia or exacerbation of cardiopulmonary diseases and other underlying diseases (12–15). The estimated death rate in the United States varies between 20,000 to 40,000 deaths per season and excess hos- pitalizations resulting from influenza or complications average from 200 to 1,000 per 100,000 population (16). Conditions that predispose to complicated influenza include cardiovascular diseases, pulmonary diseases, and metabolic diseases, such as diabetes mellitus, renal dysfunction, anemia, and immunosuppression. The presence of any of these high-risk conditions in adults older than age 45 has

Influenza and Other Respiratory Viruses 199 been estimated to increase the death rate from influenza by 39-fold (15). The es- timated death rates are 104 and 240 per 100,000 for persons with cardiovascular and chronic pulmonary diseases, respectively. The presence of both pulmonary and cardiovascular diseases results in the highest mortality at 870 per 100,000 deaths. In addition to causing excess mortality, influenza infection also causes sig- nificant morbidity in the elderly. Approximately 10% of older persons who are hospitalized are discharged to a higher level of care, even though many were in- dependent before admission (17,18). Frail nursing home residents have been noted to have a decline in functional status after influenza infection (19). Influenza is an important pathogen in LTCFs because of the propensity to cause explosive outbreaks of severe illness. Attack rates vary between 20% to 40%, with a re- ported mortality of 15% to 30% during influenza A outbreaks and 10% during in- fluenza B outbreaks (20–23). Risk factors for outbreaks in LTCFs include low res- ident and staff vaccination rates, larger homes, presence of closed wards, and common dining areas (22). Other risk factors also include crowding and poor ven- tilation (24). B. Clinical Manifestations After an incubation period of approximately 1 to 2 days, the classic influenza syn- drome is characterized by the abrupt onset of fever, chills, headache, and myal- gias, accompanied by respiratory symptoms of sore throat, nonproductive cough, and nasal congestion. Ocular symptoms, such as tearing, burning, and pain with movement of the eyes helps to distinguish influenza from other viral illnesses (8). Elderly and debilitated persons may have a less “classic” picture and present with only high fever, lassitude, or confusion and minimal respiratory symptoms. Fever typically lasts for 3 days but can persist as long as 8 days. In the nursing home pop- ulation, it is difficult to clinically differentiate influenza from other respiratory viruses such as RSV because symptoms overlap and, not infrequently, viruses co- circulate. However, the presence of fever, systemic and gastrointestinal com- plaints suggests influenza (Table 1). C. Diagnostic Approach Viral culture from the nasopharynx is the gold standard for the diagnosis of in- fluenza. Virus may also be recovered from sputum. A nasopharyngeal specimen is obtained by swabbing the nose and the throat separately and combining both swabs in the same viral transport media. Nasal washes are difficult to obtain from elderly, debilitated persons and nasopharyngeal swabs are preferred. Viral culture is important for epidemiological purposes and is essential for making decisions re- garding the best antiviral treatment and prophylaxis. However, it takes 3 to 5 days to identify the virus by culture. Time is critical for controlling outbreaks and in-

200 Dumyati and Falsey Table 1 Clinical Manifestation in Elderly Patients with Influenza Virus Versus RSV Infection Clinical manifestations Influenza RSV Upper respiratory symptoms 97% 100% Lower respiratory symptoms 66% 44% Systemic (malaise, myalgias, chills) 84%* 44% Gastrointestinal (anorexia, nausea) 38% Temperature higher than 37.2°C (99°F) 90% 0% 56% *Statistically significant difference. Abbreviation: RSV, Respiratory syncytial virus. Source: Adapted from Ref. 56. stituting appropriate antiviral treatment and, therefore, rapid diagnostic methods such as immunofluorescence assay (IFA) or enzyme immunoassay (EIA) have been developed. These tests detect viral antigens directly from respiratory secre- tions and can be used for influenza A or influenza A and B together (25,26). Re- sults can be obtained within an hour. The sensitivity and specificity for influenza A rapid tests (Directigen Flu A®, Becton Dickinson) approaches those of viral culture under optimal conditions, with a sensitivity varying between 80% to 90% and specificity varying between 90% to 100%. For combination A and B (FLU OIA®, Biostar; QUICKVUE® Influenza Test, Quidel; ZSTATFLU®, ZymeTx) the sensitivities are approximately 60% to 70% and specificities approach 95% to 100% (27). The sensitivity of various tests depends on the quality of the specimen, with better results obtained from nasal washes and swabs compared with pharyn- geal specimens alone (26,28). Other techniques include reverse transcription- polymerase chain reaction (RT-PCR), which although very sensitive, is not widely available. At present, PCR is expensive and requires specimens to be sent to specialized laboratories. Serology using acute and convalescent sera is not help- ful for the acute management of patients but is useful in retrospective analysis of outbreaks. D. Therapeutic Interventions and Infection Control The explosive nature of influenza outbreaks suggests aerosol transmission. How- ever, this has not been as well documented as for tuberculosis or varicella. A large amount of virus is present in the respiratory secretions of infected persons and is dispersed into the air by sneezing, coughing, and talking (29). Virus shedding be- gins approximately 24 hours before onset of symptoms, rapidly increases for the first 24 to 48 hours of illness, and then diminishes to low levels for up to 5 to 10 days (8). Higher rates of transmission occur in crowded and confined settings such

Influenza and Other Respiratory Viruses 201 as in hospitals, nursing homes, and college dormitories. Transmission may also occur through fomites and contaminated hands. Influenza virus can survive up to 24 to 48 hours on hard, nonporous surfaces and on hands for up to 5 minutes (30). 1. Treatment and Chemoprophylaxis Two classes of antiviral agents are available for prophylaxis and treatment of in- fluenza infection. The M2 channel inhibitors, amantadine and rimantadine, and the neuraminidase inhibitors, zanamivir and oseltamivir, have both been proven efficacious. a. Amantadine and Rimantadine. Amantadine and rimantadine inhibit growth of influenza A viruses only. They act by blocking the M2 channels that span the viral membrane and result in inhibition of viral uncoating from the host cell (31). Amantadine and rimantadine have been licensed for prophylaxis and treatment of influenza A infection. Efficacy. Both amantadine and rimantadine have similar efficacy in prevention and treatment of influenza A. Most studies that have shown amantadine and ri- mantadine to be effective in preventing influenza have used challenge experi- ments in healthy adults or natural infections in the family setting. These drugs pre- vent 50% of laboratory-documented influenza infections and 70% to 90% of illnesses (32–34). Amantadine and rimantadine are also effective in the treatment of uncomplicated influenza. Treatment of healthy adults and children, when started within the first 2 days of illness, results in a decrease of illness duration by 1 to 2 days (33). A decrease in symptom scores and virus shedding have also been demonstrated (35). One placebo-controlled study, carried out in a nursing home population, showed more rapid reduction in fever and symptoms and less use of antibiotics, antitussives, and antipyretics in the rimantadine-treated group (36). The effectiveness of early therapy in high-risk patients with amantadine and ri- mantadine in reducing frequency of subsequent complications is unknown. A number of observational studies have shown that both amantadine and rimanta- dine are effective in controlling nursing homes outbreaks when prophylaxis and treatment have been started early (37). However, no randomized, placebo-con- trolled studies to assess the effectiveness of widespread chemoprophylaxis with rimantadine or amantadine have been carried out. Dosing. Amantadine and rimantadine have similar mechanisms of action; how- ever, they differ in their pharmacokinetics. Amantadine is excreted unmetabolized in the urine. The half-life is two times longer in elderly compared with young adults and further prolonged in patients with impaired renal function. The recommended dose is 100 mg per day in persons aged 65 and older; the dose should be adjusted for creatinine clearance below 50% (33). Rimantadine is metabolized in the liver with 20% excreted by the kidney. Because a dose of 200 mg per day was associ-

202 Dumyati and Falsey ated with high plasma levels in elderly nursing home residents, the recommended dose for rimantadine is also 100 mg per day. However, modifications are not needed for renal and liver dysfunction (38). The recommended doses of amanta- dine and rimantadine are summarized in Table 2. Treatment duration is 3 to 5 days. Side effects. Amantadine and rimantadine are both known to cause central ner- vous system (CNS) and gastrointestinal effects, but the CNS side effects are more common with amantadine and have been reported in 33% of cases (39). The CNS symptoms include nervousness, anxiety, difficulty concentrating, lightheadedness and seizures. Seizures are more common with amantadine than rimantadine and, therefore, its use is contraindicated in persons with a seizure history. A 4% to 8% increase in the frequency of falls among nursing home residents has been reported during periods of amantadine prophylaxis (40). Both drugs cause nausea and anorexia in 1% to 3% of cases. The highest incidence of adverse effects is associ- ated with high plasma levels seen in renal failure and with the use of 200 mg of amantadine. Resistance. Resistance to both agents occurs rapidly (within 2 to 3 days) in one- third of influenza-infected patients receiving these drugs (41,42). It is recom- mended that treated patients be isolated from patients receiving prophylaxis. Amantadine- and rimantadine-resistant viruses do not demonstrate increased vir- ulence, and they remain sensitive to zanamivir and oseltamivir (34). Table 2 Recommended Treatment and Prophylactic Dosage of Antiviral Drugs for Influenza, in Nursing Home Residents Drug Indication Route Dose Dose in renal failure* Amantadine Prophylaxis and Oral (tablet or 100 mg/day 100 mg every Rimantadine treatment syrup) 48–72 hr Zanamivir influenza A 100 mg/day Oseltamivir Oral (tablet or 100 mg/day Prophylaxis and syrup) 2 inhalations of treatment 5 mg each No change influenza A Oral inhalation twice daily (powder) 75 mg/day Treatment 75 mg/day influenza Oral 75 mg twice A&B daily Influenza A&B Prophylaxis Treatment * Creatinine clearance Ͻ 50 ml/mm. Consult package insert for doses for severe renal insufficiency.

Influenza and Other Respiratory Viruses 203 b. Zanamivir and Oseltamivir. Zanamivir and oseltamivir are neuraminidase inhibitors of both influenza A and B viruses. Neuraminidase is an enzyme that cleaves terminal sialic acid residues from carbohydrate moieties on the surface of host cells and influenza virus envelopes. This process promotes the release of progeny viruses from infected cells, prevents the aggregation of virus, and pos- sibly decreases viral inactivation by respiratory mucus. Inhibition of neu- raminidase results in virus aggregation and a decrease in the amount of infec- tious virus released (43). Both agents have been approved for treatment of influenza A and B infections, but only oseltamivir has been licensed for pro- phylactic use. Dosing. Oseltamivir is administered orally and zanamivir by oral inhalation. Zanamivir requires a cooperative patient who can inspire effectively. Zanamivir deposits primarily in the oropharynx and throat with 20% reaching the lungs. Less than 20% is systemically absorbed. Oseltamivir is excreted unchanged in the urine, and the dose must be reduced in renal failure. The treatment duration is 5 days for both drugs. Recommended doses for both medications are summarized in Table 2. Efficacy. The efficacy of zanamivir and oseltamivir in treatment and prophy- laxis of influenza has been studied primarily in healthy, young adults. Data re- garding the efficacy of these drugs in high-risk patients are limited. Both drugs prevent naturally acquired influenza infection by 30% to 40% and illness by 67% to 84% (44,45). Zanamivir reduced the time to alleviation of influenza illness by 1 day in all subjects and by 3 days in those with febrile illness or those treated within 30 hours after the onset of symptoms (46). In elderly and high-risk subjects, a 2.5 day reduction in symptoms was observed (47). Nonfebrile patients or pa- tients treated after 30 hours derive little or no benefit (46–48). Oseltamivir used in healthy adults showed a reduction in influenza symptoms by 1 to 1.5 days (49). In some studies, oseltamivir reduced the frequency of complications such as oti- tis media, sinusitis, bronchitis, and other infections requiring antibiotics; however, the frequency of pneumonia in these studies was too low to assess its effect on lower respiratory complications (47,49). The experience with prophylactic use of zanamivir and oseltamivir in LTCFs is limited but encouraging. One small, ran- domized, unblinded study in a Wisconsin nursing home population compared zanamivir to rimantadine for prophylaxis against influenza A and placebo against influenza B epidemics (50). Zanamivir was given for 2 weeks, and protection was comparable to rimantadine in influenza A epidemic. No cases of influenza B oc- curred in residents receiving zanamivir prophylaxis. Another randomized, double- blind, placebo-controlled study of oseltamivir used for 6 weeks showed a statisti- cally significant decrease of laboratory-confirmed influenza compared with placebo. The protective efficacy was 92%. This protection was in addition to that provided by influenza vaccination (51a).

204 Dumyati and Falsey Side effects. Both zanamivir and oseltamivir are better tolerated than amanta- dine and rimantadine. Central nervous system side effects have been infrequently reported. Zanamivir can reduce peak expiratory flow rates and should be used cau- tiously in patients with chronic obstructive lung disease (43,52). Oseltamivir use is associated with nausea of mild to moderate intensity with rare vomiting. These symptoms are transient and usually occur after the first dose (45,49). Resistance. The emergence of virus resistant to zanamivir and oseltamivir is un- common. One influenza B strain resistant to zanamivir was isolated from an im- munocompromised child (53). In one study of oseltamivir treatment, only 1% of isolates recovered on day 4 to 6 post treatment were found to be resistant. There was no clinical deterioration and, unlike resistant viruses recovered during M2 channel blocker treatment, neuraminidase-resistant viruses were less virulent in animal models (51b). E. Influenza Control in Long-Term Care Facilities 1. Infection Control Recommendations for influenza control in LCTFs were recently reviewed and the recommendations of the Society for Healthcare Epidemiology of America and Centers for Disease Control and Prevention (CDC) have been published (16,54,55). All emphasize that the best method of influenza control in the nursing home is prevention of infection by yearly immunization of residents and staff. Nursing home residents continue to become infected with influenza despite vac- cination because of suboptimal vaccine response, high frequency of exposure, and ease of transmission of influenza virus in closed, crowded settings. Another con- tributing factor is failure to immunize staff, who are frequently responsible for the introduction of influenza to the nursing home (22). The key to controlling outbreaks is to identify cases rapidly so that isolation and treatment can be initiated promptly. To achieve this goal, a surveillance pro- gram for influenza-like respiratory illnesses (ILI) should be in place during the in- fluenza season. The CDC defines ILI as a temperature of 37.8°C (100°F) or greater accompanied by any symptoms of cough, coryza, or sore throat. However, only 70% of all elderly with influenza will have fever, so some cases will be missed. Another proposed definition includes symptoms of cough, sore throat, nasal congestion, or rhinorrhea with or without fever. However, none of these def- initions have been validated in a large prospective study in nursing homes. Resi- dents exhibiting any of the above symptoms should have a nasopharyngeal swab taken for rapid influenza detection and viral culture. Laboratory documentation of influenza infection is important because other respiratory infections have similar clinical manifestations in the elderly (56). Rapid diagnostic tests are also impor- tant for the purpose of early treatment and prophylaxis. Lower attack rates of in-

Influenza and Other Respiratory Viruses 205 fluenza have been demonstrated in an uncontrolled study in nursing homes that used both rapid influenza tests and culture compared with those that used culture alone (25). The CDC recommends that when institutional outbreaks occur, chemopro- phylaxis should be administered to all residents regardless of their vaccine status. However, the definition of an outbreak remains controversial. Most recommend starting chemoprophylaxis when 10% of residents on a ward have ILI and in- fluenza has been documented. Others define an outbreak as two to three cases of ILI occurring within 48 to 72 hours (57). Once prophylaxis is started, it should be continued for 2 weeks or 1 week after the last documented case of influenza (58). Other measures during an outbreak include vaccination and chemoprophylaxis of unvaccinated staff. Chemoprophylaxis should be continued for 2 weeks after vac- cination of staff members when protective antibodies are generated. In epidemics where the vaccine virus does not match the circulating virus strain, staff members should receive chemoprophylaxis alone (16). The present recommendation is to use either amantadine or rimantadine in influenza A outbreaks. No recommendations have been published regarding the prophylactic use of zanamivir or oseltamivir in nursing homes. Although more expensive, rimantadine is preferable to amantadine for influenza A outbreaks be- cause of fewer side effects. Influenza cases that develop on rimantadine prophy- laxis may be treated with oseltamivir because of the possibility of rimantadine-re- sistant virus. For influenza B outbreaks and patients with seizure disorders, the use of zanamivir or oseltamivir should be considered. Oseltamivir is preferred be- cause of the ease of administration and, at this time, it is the only agent approved for prophylaxis. Another measure to control outbreaks in LTCFs is isolation (Table 3). Be- cause transmission of influenza virus can occur by aerosol and fomites, isolation of ill residents is recommended (55). Patients should be confined to their rooms and centralized activities should be decentralized or postponed. Healthcare work- ers should wear masks when in close contact with ill residents and should wash their hands after contact. The optimal duration of isolation is unclear, but 3 to 5 days is reasonable. The effectiveness of these isolation methods has not been proven in LTCFs but have been useful in hospital-based outbreaks. Other mea- sures include closing the facility or ward to new admissions, restricting visitors, requesting sick personnel remain home, and restricting personnel from floating to other wards. 2. Vaccination The most effective measure to prevent influenza outbreak in nursing homes is an- nual administration of inactivated trivalent influenza vaccine to both staff and res- idents (see Chapter 20). Previous surveys of nursing homes have reported vacci-

Table 3 Control of Nursing Home Nosocomial Viral Respiratory Infections 206 Dumyati and Falsey Virus Influenza RSV Parainfluenza Coronavirus Rhinovirus Mode of spread Unknown Close contact skin, Close contact, aerosol Close contact Close contact Fomite, ?aerosol ?Skin, fomite Skin, fomite Skin, fomite Control measures ϩ ϩϩ ϩ ϩ Hand washing ϩ ϩ/Ϫ Gloves ϩ Masks ϩ ϩϩ Isolation of ill patients in their room ϩ ϩϩ Cohort staff ϩ ϩϩ Limiting group activities ϩ ϩ/Ϫ ϩ/Ϫ Closing facility or ward to new admissions ϩ ϩ/Ϫ ϩ/Ϫ Limit visitors with respiratory illness Abbreviation: RSV, Respiratory syncytial virus. ϩ ϭ Recommended intervention. ϩ/Ϫ ϭ Optional or unclear recommendation. Source: Adapted from Ref. 29.