Donald Kaye

Hospital-acquired Infection with Vancomycin-resistant Enterococcus faecium Transmitted by Electronic Thermometers

OBJECTIVES To describe an epidemic of vancomycin-resistant Enterococcus faecium causing bacteremia and bacteriuria, to identify the source of infection, to delineate risk factors associated with acquisition of the organism, and to determine antibiotic sensitivities for the organism. DESIGN Investigation of an epidemic, including a case-control study. SETTING Medical-surgical intensive care unit and ward in a university medical center. PATIENTS Nine patients infected or colonized with vancomycin-resistant Enterococcus faecium and 20 noninfected controls. MEASUREMENTS Clinical data, environmental surveillance cultures, and in-vitro microbiologic studies. RESULTS Colonization or infection by vancomycin-resistant E. faecium was associated with an increased duration of treatment with ceftazidime, 13.2 compared with 4.6 days, and a greater number of nonisolated days of hospitalization in the intensive care unit, 19.9 compared with 6.4 days for infected and noninfected patients, respectively (P less than 0.05). Environmental surveillance cultures recovered the organism repeatedly from the rectal probe handles of three electronic thermometers used exclusively on nonisolated patients in the intensive care unit. Restriction endonuclease analysis of plasmid DNA showed that all clinical and environmental isolates were identical. Infection control measures, including isolation of colonized or infected patients and removal of the rectal thermometer probes suspected to be responsible for transmission, resulted in termination of the outbreak. In-vitro, time-kill studies showed that the combination of ciprofloxacin, rifampin, and gentamicin resulted in bactericidal activity against the organism. CONCLUSIONS This nosocomial outbreak of infection due to a highly vancomycin-resistant strain of Enterococcus is the first epidemic in which an electronic thermometer has been implicated as the vehicle of transmission for an infectious agent.

Dental and Cardiac Risk Factors for Infective Endocarditis: A Population-Based, Case-Control Study

Infective endocarditis is uncommon but potentially fatal. Administration of antibiotic prophylaxis is conventional [1], but data supporting its effectiveness derive solely from anecdotal reports, studies of bacteremia after dental and other procedures, and animal models. The low incidence of disease [2] has made randomized human trials of antibiotic effectiveness impractical. Even if effective, antibiotic prophylaxis should be reserved for patients at increased risk, such as those with cardiac abnormalities who are undergoing dental procedures. However, controlled human studies of risk factors are lacking. Previous case series indicate that approximately 15% of patients with infective endocarditis caused by mouth organisms had undergone a recent dental procedure [3], but the comparable percentage from a general population is unknown. The single hospital-based casecontrol study did not find an elevated risk associated with dental therapy, except for a borderline increase with dental scaling [4]. We are unaware of controlled human studies that quantify the risk for infective endocarditis associated with cardiac valve abnormalities other than mitral valve prolapse. We therefore conducted a population-based casecontrol study to evaluate and quantify risk factors for infective endocarditis, especially those considered by the American Heart Association (AHA) to be indications for antibiotic prophylaxis [1]. Methods Participants From August 1988 to November 1990, we maintained surveillance for infective endocarditis in 54 hospitals of the Delaware Valley Case-Control Network, a population-based network of hospitals in the eight counties that constitute the Philadelphia Metropolitan Statistical Area and the county of New Castle, Delaware. Patients with a putative diagnosis of infective endocarditis were identified by hospital personnel and were reported to study nurses, who also actively sought cases. To assess the completeness of ascertainment, five high-yield hospitals and three low-yield hospitals were asked to list all patients discharged with a diagnosis of endocarditis over 3 months. These lists were compared with those obtained from our surveillance; charts were reviewed when differences were identified. We obtained informed consent from physicians and case-patients, then used structured forms to abstract medical records, including echocardiographic reports and hospital laboratory information on the infecting organism. We deleted information on purported risk factors for infective endocarditis and submitted these records for review by three of the authors, who are consultants in infectious diseases recognized for their expertise in infective endocarditis [5, 6]. These experts used their own global clinical judgment to classify potential cases as definite, probable, or possible cases or probable noncases. Agreement of two of the three reviewers was required to make the determination of a case or a noncase [6]. One control from the community was selected for each case-patient by using a modification of the Waksberg random-digit dialing method [7]. Controls and case-patients were matched for age (in 5-year strata), sex, and neighborhood of residence (by using area code, telephone exchange, and the first subsequent digit of the case-patients telephone number). We excluded from these analyses patients with infective endocarditis who were younger than 18 years of age, intravenous drug users, and patients who developed endocarditis in the hospital. This study received separate institutional review board approval at the University of Pennsylvania and all 54 participating hospitals. Data Collection Information was obtained from case-patients by conducting a structured telephone interview after hospital discharge. The date of hospital admission served as the study date for case-patients; for controls, the date of the telephone interview was used. Telephone interviewers collected information on demographic characteristics; diagnostic and therapeutic medical and dental procedures in the year before the study date; potential host risk factors, including preexisting cardiac lesions, preexisting local infection, risk factors for oral or dental disease, diabetes mellitus, immune deficiencies, family history of endocarditis, alcoholism, malignant conditions, and autoimmune disease; previous antibiotic use; and other recent illnesses. For each host risk factor, we requested the date of diagnosis, diagnostic method (for example, echocardiography for mitral valve prolapse), and the name of the practitioner who made the diagnosis. For each medical and dental procedure, we sought information about the procedure, the month and year in which it was performed, and the practitioner. We requested medical and dental records describing procedures and validating individual diagnoses. Study Variables Case-patients were considered infected with dental flora if the organism found was viridans streptococci; nutritionally variant streptococci; Actinobacillus species; Cardiobacterium hominis; anaerobes; -hemolytic streptococci (not group D); unspecified streptococci; or Haemophilus, Eikenella, Kingella, or Neisseria species. Because this study focused on indications for antibiotic prophylaxis, we examined host characteristics reported by patients as the primary risk factor variables, reflecting the information that would be available to a practitioner about to perform a procedure for which prophylaxis might be indicated. A variable called any valvular heart abnormality was defined as the presence of any of the following self-reported, preexisting conditions: mitral valve prolapse, congenital heart disease, history of rheumatic fever with heart involvement, prosthetic heart valve, previous episode of endocarditis, or other valvular heart disease. Dental visit information was obtained solely from dental records. Dental hygiene care was defined as preventive oral health services and therapeutic services, including coronal scaling and polishing. Consistent with AHA guidelines, invasive dental procedures were defined to include dental hygiene care, extractions, periodontal treatment (including scaling and root planing), endodontic treatment, mouth or gingival surgery, and treatment of tooth abscess. Noninvasive dental procedures were simple restorations, prosthetic and restorative dentistry, fluoride treatment, and other procedures (prosthetic services, including adjustments and suture removal). Unless otherwise specified, dental treatment refers to all dental treatment and is not limited to invasive procedures. Initial analyses focused on dental procedures performed at any time in the 3 months before the study date. Analyses were then narrowed to 2 months and 1 month before the study date. Time frames are approximate because the onset of infective endocarditis is often difficult to determine with certainty. We therefore chose the date of hospital admission as the study date, collected procedural data based on month rather than on a specific date, and calculated time frames under the assumption that procedures were performed on the 15th of the month. Statistical Analysis Frequencies and cross-tabulations between casecontrol status and potential risk factors were obtained. Conditional logistic regression was used to determine the independent effects of the various potential risk factors and the possibility of any interactions among factors [8]. Variables were included in multiple regression models if they were significant (P < 0.2) in unadjusted (matched) analyses (such as kidney disease and diabetes), if their inclusion had a substantial effect (>15% change) on coefficients for variables already in the model (such as insurance status) [9], or if they were strongly suspected a priori of being confounders (such as ethnicity). For analyses specific to participants with known cardiac valvular abnormalities, odds ratios and CIs were calculated from a model that included main effects for cardiac valvular abnormalities and dental treatment and the interaction between those variables. The odds ratio for various dental therapy variables among participants with cardiac valvular abnormalities was estimated by combining coefficients for the dental therapy variable and the interaction term. The CI for this combination of coefficients was estimated by using the appropriate variance and covariance terms [8]. With the interaction terms, participants with and those without valvular abnormalities were included in these analyses. Exact odds ratios and CIs, stratified on the matching variables, were calculated when data were too sparse for conditional logistic regression [10]. We used SAS statistical software (SAS Institute Inc, Cary, North Carolina) for data management and to obtain frequencies and cross-tabulations. We used EGRET (Epidemiological Graphics, Estimation and Testing software, version 0.25.1, Cytel Software Corp., Cambridge, Massachusetts) for conditional logistic regressions and exact analyses. All CIs are 95%, and all P values are two-sided. The sample size for the study was chosen so that by assuming an level of 0.05 (two-sided) and a power of 80%, we would be able to detect associations with an odds ratio of 2.0 or more for risk factors with a prevalence between 0.1 and 0.8. Results Participants We identified and recruited 416 potential case-patients (Figure 1). Our assessment process confirmed that more than 90% of true cases of infective endocarditis had been identified. The expert panel judged 379 patients to have definite, probable, or possible infective endocarditis; 37 (9%) were judged to be probable noncases and were excluded. Agreement among judgments was high, ranging from 92% to 96% [6]. Figure 1. Enrollment of case-patients. Of these 379 patients, 287 had community-acquired infective endocarditis not associated with intravenous drug use (248 on native valves and 39 on prosthetic valves), 27 had nosocomial infective endocarditis (18 on nativ

Serum Lipids in Infection

Abstract Striking elevations in concentrations of total serum lipids were observed in patients with infection caused by gram-negative bacilli. The elevated levels of total lipid in these patients were due mainly to marked increases in serum concentrations of triglycerides or free fatty acids or both. In contrast, patients with severe infection caused by gram-positive cocci had normal concentrations of total serum lipids. Those with fever but no infection and those with influenza had normal concentrations of total serum lipids and normal levels of the major lipid classes. Patients with infectious or serum hepatitis demonstrated a moderate hyperlipidemia, which resulted from increased concentrations of serum triglycerides and free cholesterol. Lipoprotein electrophoresis demonstrated that the hyperlipidemia in patients with severe infection caused by gram-negative bacilli was related to increased levels of pre-beta-lipoproteins. In patients with hepatitis there were increased levels of pre-beta-lipoproteins...

Epidemiology of bacteriuria in an elderly ambulatory population

This study of bacteriuria in elderly (mean age 85 years, range 68 to 103) Jewish subjects of mostly middle and upper class attempted to determine disease prevalence, define the turnover in infected subjects, and assess the relation between functional status and infection. The prevalence of bacteriuria (midstream clean-catch method) was assessed in 373 women and 150 men. It was higher in women (18.2 percent) than in men (6.0 percent) (p less than 0.001) and was more common in functionally impaired nursing home residents (23.5 percent) than in apartment house dwellers (12.1 percent) (p less than 0.01). In longitudinal studies, 260 subjects (184 women and 76 men) had three urine culture surveys at six-month intervals. The cumulative percent infected on at least one survey was high (women 30.4 percent, men 10.5 percent). However, persistence of the same organism on all three surveys was surprisingly infrequent (women 6.0 percent, men 1.3 percent), and the turnover of infected and noninfected subjects was considerable. Persistence of bacteriuria on all three surveys was significantly more common in nursing home residents (13.9 percent) than in apartment house dwellers (3.1 percent) (p less than 0.01). Thus, bacteriuria is common in the elderly and appears related to functional status. However, the turnover of infected and noninfected subjects was high, and surprisingly, persistence was not found in most. The transient nature of bacteriuria in most provides support against the treatment of asymptomatic bacteriuria in the elderly.

Risk Factors for Infective Endocarditis Oral Hygiene and Nondental Exposures

Background—The risks of infective endocarditis (IE) associated with various conditions and procedures are poorly defined. Methods and Results—This was a population-based case-control study conducted in 54 Philadelphia, Pa–area hospitals from 1988 to 1990. Community-acquired IE cases unassociated with intravenous drug use were compared with matched community residents. Subjects were interviewed for risk factors. Diagnoses were confirmed by expert review of medical record abstracts with risk factor data removed. Cases were more likely than controls to suffer from prior severe kidney disease (adjusted OR [95% CI]=16.9 [1.5 to 193], P =0.02) and diabetes mellitus (adjusted OR [95% CI]=2.7 [1.4 to 5.2], P =0.004). Cases infected with skin flora had received intravenous fluids more often (adjusted OR [95% CI]=6.7 [1.1 to 41], P =0.04) and had more often had a previous skin infection (adjusted OR [95% CI]=3.5 [0.7 to 17], P =0.11). No association was seen with pulmonary, gastrointestinal, cardiac, or genitourinary procedures or with surgery. Edentulous patients had a lower risk of IE from dental flora than patients who had teeth but did not floss. Daily flossing was associated with a borderline decreased IE risk. Conclusions—Within the limits of the available sample size, the data showed that IE patients differ from people without IE with regard to certain important risk factors but not regarding recent procedures.

Does Asymptomatic Bacteriuria Predict Mortality and Does Antimicrobial Treatment Reduce Mortality in Elderly Ambulatory Women

Asymptomatic bacteriuria, a common problem of the elderly, has been associated with increased mortality in the elderly [1-4], although not all studies have confirmed this finding [5-9]. To reconcile these conflicting results, we did a longitudinal study of urinary tract infection in ambulatory elderly women to evaluate the putative relation between asymptomatic bacteriuria and mortality. We considered resolution of this issue to be important because of the implications for clinical practice. If asymptomatic bacteriuria were shown to be an independent risk factor for mortality and if it could also be shown that eradication of the infection by antimicrobial therapy decreased the risk for death, then screening and antimicrobial treatment of elderly ambulatory women with asymptomatic bacteriuria might be warranted and the cost of identifying and treating such infections might be justified. Conversely, failure to confirm a relation would support the view that programs to screen for bacteriuria would not be justified if their goal was to enhance survival. This report summarizes the findings of our 9-year study to determine whether asymptomatic bacteriuria in elderly ambulatory women is a marker of increased mortality and, if so, whether it is because of an association with other determinants of mortality or because asymptomatic bacteriuria is itself an independent cause, the removal of which might improve longevity. The components of the study were a longitudinal study in elderly ambulatory women to compare mortality in those with and without asymptomatic bacteriuria and a double-blind, controlled clinical trial in which antimicrobial therapy was administered for asymptomatic bacteriuria to assess whether treatment decreases mortality. Methods Participant enrollment and the participating institutions have been described previously [10, 11]. Elderly ambulatory residents of the Philadelphia Geriatric Center and of 21 continuing care retirement communities in the greater Philadelphia metropolitan area who gave informed consent were enrolled in this long-term study of urinary tract infection in the elderly. Enrollment continued throughout the course of the study. Philadelphia Geriatric Center houses about 1000 residents who primarily are Jewish; incomes are higher than the maximum Social Security payment; and congregate living is provided either in an apartment house or in a nursing home. In contrast, the continuing care retirement communities are smaller (bed size range, 108 to 675); incomes are higher; residents are primarily not Jewish; and a higher proportion of residents are fully independent. All female residents were eligible to participate except those with indwelling catheters or those incapable of providing midstream clean-catch urine specimens for culture. Specimens were obtained on enrollment and every 6 months thereafter. The protocol was approved by the appropriate institutional review boards, and informed consent was obtained from the participants or their surrogates. Table 1 shows the study periods and chronology of important study events. Throughout the study, urine cultures were obtained at about 6-month intervals. An observational study to compare mortality of bacteriuric and nonbacteriuric volunteers regardless of treatment status was begun in January 1983 and ended in February 1992. Initially, residents with asymptomatic bacteriuria were identified and followed, but treatment was not given. However, on 10 October 1983, a controlled clinical trial was begun to evaluate whether antimicrobial therapy for asymptomatic bacteriuria decreased mortality; every bacteriuric study participant identified after this date was enrolled in the trial. Mortality among residents who were treated with antimicrobial agents for asymptomatic bacteriuria each time it was present was compared with the mortality of those who received no therapy for their episodes of bacteriuria. At enrollment, participants were assigned to the treatment group or to the control group based on the last digit of an identification number unrelated to the conduct of the study. Urine cultures were read by personnel blinded to the study group assignment. When asymptomatic bacteriuria was identified, participants with even numbers were given antimicrobial therapy according to a defined protocol (see below); those with odd numbers served as controls. From 10 October 1983 to 10 December 1987, controls were given no therapy. Thereafter, on the advice of external consultants, the protocol was changed so that participants not assigned to the active treatment group were given placebo pills in place of no treatment. The placebo pills were identical in appearance to each of the antimicrobial agents used. Thus, after 10 December 1987, volunteers with asymptomatic bacteriuria were given therapy in either the form of antimicrobics or placebo after a new consent was obtained; the volunteers and clinical personnel did not know study group assignments. Table 1. Study Design and Enrollment The methods for collecting first-morning urine and for processing the specimens in our research microbiology laboratory have been previously described [10, 11]. Participants were considered to have asymptomatic bacteriuria on a survey if two urine specimens were culture-positive (105 colony-forming units or more per mL of urine) for the same organism within 2 weeks. From 10 October 1983 through 10 December 1987, residents with asymptomatic bacteriuria who were assigned to receive antimicrobial treatment were given short-course therapy (single dose or 3 days) as follows: trimethoprim, 200 mg in one dose; trimethoprim-sulfamethoxazole, 1 double-strength tablet; cefaclor, 500 mg three times a day for 3 days; amoxicillin, 250 mg three times a day for 3 days; carbenicillin indanyl sodium, four times a day for 3 days; or macrodantin, 100 mg twice a day for 3 days, depending on susceptibility of the infecting organism and history of drug allergy. Participants were considered cured if test-of-cure cultures contained less than 104 colony-forming units/mL of the infecting organism on cultures obtained 5 to 10 days after antimicrobial treatment or placebo or on cultures obtained on the next survey in those receiving no therapy. When positive for the same organism, patients were retreated for 14 days with test-of-cure culture afterward. If the organism differed, reinfection was diagnosed and a single dose or 3-day therapy was used; treatment failures were treated as defined above. Test-of-cure cultures were obtained again after therapy and, if positive for the same organism, participants were treated for 14 days. No treatment was given after failure of a 14-day course or two reinfections after short courses. Controls received no therapy during this period. After 10 December 1987, culture-positive patients were assigned to antimicrobial treatment or placebo. Single-dose therapy was given with trimethoprim, 200 mg, or norfloxacin, 400 mg, depending on the susceptibility of the organism; the same drugs (trimethoprim, 100 mg twice daily, and norfloxacin, 400 mg twice daily) were used for 14 days of therapy in patients failing single-dose therapy. Single-dose therapy was used for reinfection. The placebo pills and regimen given to a placebo recipient matched the regimen administered to the participant in the active treatment group who was treated most recently (for example, if the active treatment participant received short-course trimethoprim followed by 14 days of trimethoprim, the next placebo participant received short-course trimethoprim placebo followed by 14 days of trimethoprim placebo). Symptomatic infections were managed by the participants personal physician or by physicians associated with the facility in which the patient lived. Reports were received on an annual or semiannual basis from the participating institutions that detailed changes in their census. All deaths were noted, and registry coordinators reviewed available documents to confirm each death. After 1 September 1987, detailed functional and mental status assessments were done when persons were newly enrolled into the study or were seen for an annual follow-up visit using techniques previously described [11, 12]. Self-care activities of daily living were assessed by a modification of the Multilevel Assessment Instrument [13], and mental status was assessed using a modified version of the Kahn and Goldfarb questionnaire [14]. A subjective measure of global health status (scale, 1 to 4) was based on responses to the question: How do you rate your health: excellent (score 1), good, fair, and bad or poor (score 4)? Diagnoses recorded in the persons medical record were extracted and provided a more objective measure of health status; they were coded according to the ICD-9-CM three-digit codes [15]. The Geriatric Depression Scale [16] was used to assess depressive symptoms, and walking ability was assessed on a scale of 1 (specialized help needed) to 3 (help not needed) [11]. Statistical Analysis Observational Study These analyses compared residents with asymptomatic bacteriuria with residents who did not have asymptomatic bacteriuria on any of the urine culture surveys done during the period of their participation. For the purposes of the survival analyses in the observational study, the results of urine cultures were considered a time-dependent covariate. Accordingly, participants were considered in the ever-positive group once asymptomatic bacteriuria was identified, and all subsequent time on study was contributed to the group with positive cultures regardless of urine culture results on subsequent surveys. Persons entering the study with a negative urine culture were considered in the never-positive group until asymptomatic bacteriuria was identified. Thus, a person who entered the study with negative cultures and who later became culture-positive would have contributed person-time to the follow-up of those in the categ

A lack of association between bacteriuria and symptoms in the elderly

In a study of bacteriuria in elderly (mean age 85 years, range 69 to 101), mostly middle- and upper-class Jewish subjects, attempts were made to determine if bacteriuria without dysuria is otherwise asymptomatic. Seventy-two subjects (59 women and 13 men) without dysuria were questioned about other urinary symptoms (incontinence, frequency, urgency, suprapubic pain, flank pain, fever) and symptoms indicating a lack of well-being (anorexia, difficulty in falling asleep, difficulty in staying asleep, fatigue, malaise, weakness) when they were with and without bacteriuria. Twenty-two subjects had bacteriuria that resolved spontaneously; bacteriuria subsequently developed in 24 nonbacteriuric subjects; and 26 subjects had bacteriuria that resolved with antimicrobial therapy. Subjects occasionally reported urinary symptoms (especially incontinence) and commonly reported symptoms indicating a lack of well-being when they were with and/or without bacteriuria. However, no differences in symptoms were found when bacteriuric subjects were compared with themselves when they were nonbacteriuric. Thus, bacteriuria without dysuria in the elderly appears to be asymptomatic.

Immunologic response in an elderly population with a mean age of 85

Previous studies of changes in immune responses in the elderly have been limited in both number and age of elderly subjects and have produced conflicting results. Using 260 subjects, mean age 84.6, the present study conclusively demonstrates that T cell response is decreased in the elderly. Decreases in response to phytohemagglutinin and concanavalin A were demonstrated in groups aged 70 to 79, 80 to 84, and 85 to 89, although a group 90 to 106 years old showed a decreased response only to phytohemagglutinin. None of the groups had a decreased response to pokeweed mitogen. No response to all three mitogens was observed in 13 percent of the group aged 70 to 89, but in none of the group aged 90 to 106 or in the young groups. No differences in natural killer cell cytotoxicity were observed among the elderly groups. In contrast to previous studies, these results suggest that: the decreased immune response of the elderly is not directly related to age, over age 70; and there may be a selection process in which subjects who live to the age of 90 are those in whom the least decrease in immune response is demonstrated.

Prophylaxis for Infective Endocarditis: An Update.

The American Heart Association has updated its recommendations for prevention of bacterial endocarditis. The major changes are less emphasis on administration of parenteral agents and a reduction of the period of prophylaxis. The simplified new recommendations should make compliance easier and should be assiduously implemented by dental and medical practitioners. However, several changes are suggested for possible consideration: Because of the relatively low risk, prophylaxis may not be needed for persons with mitral valve prolapse (unless there is a holosystolic murmur) or for most gastrointestinal endoscopic procedures. Consideration should be given to using a single oral 3-g dose of amoxicillin for dental procedures in all patients at risk and for genitourinary and gastrointestinal tract procedures in patients at risk who have natural cardiac valves. Vancomycin should probably be the agent of choice for prophylaxis in cardiac valve surgery.

Special Problems of Urinary Tract Infection in the Elderly

Bacteriuria is much more common among elderly than among younger populations, and is most often asymptomatic. Asymptomatic bacteriuria in the elderly is a benign condition in the vast majority of cases and does not require therapy. When symptomatic lower UTI occurs, short-course (3-day) therapy with any of several agents is indicated, and is usually effective. Women with frequently recurrent symptomatic UTI may benefit from estrogen therapy. Fourteen days of therapy is indicated in patients with upper UTI. The typical signs and symptoms of pyelonephritis may be altered or absent in elderly patients.