Thomas W. Hennessy

Practice Guidelines for the Management of Infectious Diarrhea

The widening array of recognized enteric pathogens and the increasing demand for cost-containment sharpen the need for careful clinical and public health guidelines based on the best evidence currently available. Adequate fluid and electrolyte replacement and maintenance are key to managing diarrheal illnesses. Thorough clinical and epidemiological evaluation must define the severity and type of illness (e.g., febrile, hemorrhagic, nosocomial, persistent, or inflammatory), exposures (e.g., travel, ingestion of raw or undercooked meat, seafood, or milk products, contacts who are ill, day care or institutional exposure, recent antibiotic use), and whether the patient is immunocompromised, in order to direct the performance of selective diagnostic cultures, toxin testing, parasite studies, and the administration of antimicrobial therapy (the latter as for travelers diarrhea, shigellosis, and possibly Campylobacter jejuni enteritis). Increasing numbers of isolates resistant to antimicrobial agents and the risk of worsened illness (such as hemolytic uremic syndrome with Shiga toxin-producing Escherichia coli O157:H7) further complicate antimicrobial and antimotility drug use. Thus, prevention by avoidance of undercooked meat or seafood, avoidance of unpasteurized milk or soft cheese, and selected use of available typhoid vaccines for travelers to areas where typhoid is endemic are key to the control of infectious diarrhea.

A National Outbreak of Salmonella enteritidis Infections from Ice Cream

BACKGROUND In September 1994, the Minnesota Department of Health detected an increase in the number of reports of Salmonella enteritidis infections. After a case-control study implicated a nationally distributed brand of ice cream (Schwans) in the outbreak, the product was recalled and further epidemiologic and microbiologic investigations were conducted. METHODS We defined an outbreak-associated case of S. enteritidis infection as one in which S. enteritidis was cultured from a person who became ill in September or October 1994. We established national surveillance and surveyed customers of the implicated manufacturer. The steps involved in the manufacture of ice cream associated with cases of S. enteritidis infection were compared with those of products not known to be associated with infection matched for the date of manufacture. Cultures for bacteria were obtained from ice cream samples, the ice cream plant, and tanker trailers that had transported the ice cream base (premix) to the plant. RESULTS We estimate that S. enteritidis gastroenteritis developed in 224,000 persons in the United States after they ate Schwans ice cream. The attack rate for consumers was 6.6 percent. Ice cream associated with infection contained a higher percentage of premix that had been transported by tanker that had carried nonpasteurized eggs immediately before (P = 0.02). S. enteritidis was isolated from 8 of 226 ice cream products (3 percent), but not from environmental samples obtained from the ice cream plant (n = 157) or tanker trailers (n = 204). CONCLUSIONS This nationwide outbreak of salmonellosis was most likely the result of contamination of pasteurized ice cream premix during transport in tanker trailers that had previously carried nonpasteurized liquid eggs containing S. enteritidis. To prevent further outbreaks, food products not destined for repasteurization should be transported in dedicated containers.

Community-Onset Methicillin-Resistant Staphylococcus aureus Associated with Antibiotic Use and the Cytotoxin Panton-Valentine Leukocidin during a Furunculosis Outbreak in Rural Alaska

BACKGROUND Community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) reports are increasing, and infections often involve soft tissue. During a CO-MRSA skin infection outbreak in Alaska, we assessed risk factors for disease and whether a virulence factor, Panton-Valentine leukocidin (PVL), could account for the high rates of MRSA skin infection in this region. METHODS We conducted S. aureus surveillance in the outbreak region and a case-control study in 1 community, comparing 34 case patients with MRSA skin infection with 94 control subjects. An assessment of traditional saunas was performed. S. aureus isolates from regional surveillance were screened for PVL genes by use of polymerase chain reaction, and isolate relatedness was determined by use of pulsed-field gel electrophoresis (PFGE). RESULTS Case patients received more antibiotic courses during the 12 months before the outbreak than did control subjects (median, 4 vs. 2 courses; P=.01) and were more likely to use MRSA-colonized saunas than were control subjects (44% vs. 13%; age-adjusted odds ratio, 4.6; 95% confidence interval, 1.7-12). The PVL genes were present in 110 (97%) of 113 MRSA isolates, compared with 0 of 81 methicillin-susceptible S. aureus isolates (P<.001). The majority of MRSA isolates were closely related by PFGE. CONCLUSION Selective antibiotic pressure for drug-resistant strains carrying PVL may have led to the emergence and spread of CO-MRSA in rural Alaska.

Indirect Effect of Conjugate Vaccine on Adult Carriage of Streptococcus pneumoniae: An Explanation of Trends in Invasive Pneumococcal Disease

BACKGROUND Use of heptavalent protein-polysaccharide pneumococcal conjugate vaccine (PCV7) has been associated with decreases in PCV7-type invasive pneumococcal disease and nasopharyngeal (NP) carriage in children. Vaccine use has also indirectly decreased the rate of invasive disease in adults, presumably through decreased transmission of pneumococci from vaccinated children to adults. METHODS We conducted NP carriage surveys in 8 villages in Alaska in 1998-2004. Streptococcus pneumoniae isolates were characterized by serotype and antimicrobial susceptibility. We analyzed trends in serotype distribution, antibiotic resistance, and factors associated with adult carriage of PCV7-serotype pneumococci before and after the introduction of PCV7 in 2001. RESULTS We collected 15,598 NP swabs; overall, 52% of adults living in the villages surveyed participated in the colonization study. The proportion of adult carriers with PCV7-type pneumococcal carriage decreased from 28% of carriers in 1998-2000 to 4.5% of carriers in 2004 (P<.0001). Among adults, the proportion of colonizing isolates that were resistant to penicillin decreased from 13% in 1998-2000 to 6% in 2004 (P=.05), whereas the percentage of isolates with intermediate susceptibility to penicillin increased from 12% in 1998-2000 to 19% in 2004 (P<.01). Adults were more likely to carry PCV7-type pneumococci if they lived with a child <5 years old or if they lived with a child who had not been age-appropriately vaccinated with PCV7. CONCLUSIONS Pediatric vaccination with PCV7 has resulted in decreased PCV7-type pneumococcal carriage among adults and helps to explain recent decreases in the rate of PCV7-type invasive pneumococcal disease among adults.

Antibody Levels and Protection after Hepatitis B Vaccine: Results of a 22-Year Follow-Up Study and Response to a Booster Dose

BACKGROUND The duration of protection in children and adults (including health care workers) resulting from the hepatitis B vaccine primary series is unknown. METHODS To determine the protection afforded by hepatitis B vaccine, Alaska Native persons who had received plasma-derived hepatitis B vaccine when they were >6 months of age were tested for antibody to hepatitis B surface antigen (anti-HBs) 22 years later. Those with levels <10 mIU/mL received 1 dose of recombinant hepatitis B vaccine and were evaluated on the basis of anti-HBs measurements at 10-14 days, 30-60 days, and 1 year. RESULTS Of 493 participants, 60% (298) had an anti-HBs level >or=10 mIU/mL. A booster dose was administered to 164 persons, and 77% responded with an anti-HBs level >or=10 mIU/mL at 10-14 days, reaching 81% by 60 days. Response to a booster dose was positively correlated with younger age, peak anti-HBs response after primary vaccination, and the presence of detectable anti-HBs before boosting. Considering persons with an anti-HBs level >or=10 mIU/mL at 22 years and those who responded to the booster dose, protection was demonstrated in 87% of the participants. No new acute or chronic hepatitis B virus infections were identified. CONCLUSIONS The protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 22 years. Booster doses are not needed.

The relationship among previous antimicrobial use, antimicrobial resistance, and treatment outcomes for Helicobacter pylori infections

Context Adverse effects of previous antibiotic use in patients with Helicobacter pylori infections are unclear. Contribution This retrospective study examined relationships between resistant H. pylori infections and past antibiotic use in 125 Alaskan Native adults. Clarithromycin-resistant H. pylori isolates were common (prevalence, 30%) and were associated in a dose-response manner with previous use of macrolide antibiotics. Of patients with these resistant isolates, 77% had treatment failure with clarithromycin-based regimens. Implications Previous use of macrolide antibiotics is associated with increased risk for infection with clarithromycin-resistant H. pylori and increased risk for treatment failure with that antibiotic. The Editors Helicobacter pylori is a common pathogen of the gastric mucosa, infecting up to 40% of persons in developed countries and up to 90% of individuals living in developing nations (1, 2). Infection with H. pylori has been shown to be a major cause of gastric and duodenal ulcers and is also associated with chronic gastritis, mucosa-associated lymphoid tissue lymphoma, and adenocarcinoma of the stomach (3-6). Eradication of H. pylori has been reported in up to 95% of patients treated with a combination of antimicrobial agents (7-9). In the United States and elsewhere, antimicrobial resistance to metronidazole and clarithromycin is increasing; resistance to amoxicillin and tetracycline remains uncommon (10-12). Compared with persons with susceptible isolates, persons infected with clarithromycin- or metronidazole-resistant H. pylori have lower cure rates when treated with regimens containing these antimicrobial agents (12-15). In studies that have addressed risk factors associated with resistant H. pylori infection, none to our knowledge have evaluated prediagnosis antimicrobial use as a risk factor for resistance or treatment failure (16, 17). Alaska Nativespersons of Eskimo, Indian, and Aleut descenthave high rates of H. pylori infection, with an overall seroprevalence of 75% for specific antibodies (18). We are conducting a study in urban Alaska Native, rural Alaska Native, and urban non-Native adults to determine and compare reinfection rates after successful eradication of H. pylori. The study in urban Alaska Native adults is completed, and in this group, we sought to determine whether past antimicrobial use was associated with antimicrobial resistance among H. pylori isolates obtained through diagnostic endoscopy. We then determined whether H. pylori antimicrobial resistance affected the outcome of H. pylori treatment. Methods From September 1998 through June 2002, the Arctic Investigations Program of the U.S. Centers for Disease Control and Prevention and the Alaska Native Medical Center (ANMC) conducted a study to determine reinfection rates after successful eradication of H. pylori infection among Alaska Natives living in Anchorage. The ANMC is a 150-bed referral hospital that provides outpatient primary care services for Alaska Natives living in the Anchorage area. The institutional review boards of the Centers for Disease Control and Prevention, the Alaska Area Tribal Health Consortium, and the Indian Health Service approved the study, as did the Alaska Native Health Board. Written informed consent was obtained from all participants. Patients and Data Collection From September 1998 through June 2002, we attempted to recruit all Alaska Natives 18 years of age or older from the Anchorage area who had no history of an immunodeficiency condition or were not taking immunosuppressive medications (such as corticosteroids or cancer chemotherapeutic agents) and were scheduled for esophagogastroduodenoscopy. Alaska Natives who use ANMC for surgical procedures are very likely to receive most of their care from this facility, since no copayment is assessed to persons eligible for care at ANMC. A study nurse recruited 293 persons during the study period, 149 of whom had a positive culture for H. pylori. Since 27 September 1990, patient care information from all outpatient health care visits and outpatient pharmacy encounters at ANMC has been entered into a computerized records system. For this analysis, we recorded all antimicrobial prescriptions for 10 years before diagnosis of H. pylori infection by consulting outpatient records of study participants for whom at least 8 years of pharmacy records were available. We also recorded antimicrobial use during all hospitalizations and emergency department visits at ANMC for each participant in the same 10-year period. An antimicrobial course was defined as a prescription for an antimicrobial drug regardless of dose, duration, and frequency. Biopsy and Culture All participants had up to 3 gastric biopsy specimens taken for culture, antimicrobial susceptibility testing, and histologic examination for H. pylori. Gastric biopsy specimens stored in cysteine freeze medium at 80 C were ground in a sterile tissue grinder with heat-inactivated fetal bovine serum and inoculated to 3 types of solid media: blood agar (tryptic soy agar with 5% sheep blood); chocolate agar; and brucella agar containing 10% horse blood, trimethoprim, vancomycin, and polymyxin B. All cultures were incubated at 37 C under microaerophilic conditions and high humidity (12% CO2, 98% humidity) for up to 10 days. Positive cultures were usually identified after 3 to 5 days of incubation. Isolates were identified as H. pylori on the basis of positive catalase, oxidase, and urease reactions; typical uniform, small, translucent colonies; curved gram-negative bacilli on Gram-stained smears; susceptibility to cephalothin (30 g); and resistance to nalidixic acid (30 g). Minimum inhibitory concentrations (MICs) for clarithromycin, amoxicillin, metronidazole, and tetracycline were determined by using agar dilution. Helicobacter pylori isolates were defined as susceptible if the MIC was within the following limits: less than or equal to 0.25 g/mL for clarithromycin, less than or equal to 0.25 g/mL for amoxicillin, less than 8 g/mL for metronidazole, and less than 2 g/mL for tetracycline. Helicobacter pylori isolates with MICs above these limits were classified as resistant (19). In participants who had many cultures of their H. pylori isolates, the highest MIC determined from all of the cultures was used for analysis. Culture results were not available to providers before initiation of treatment. Treatment and Follow-up Each participants attending physician decided whether to initiate treatment and selected the treatment regimen. Patients who were treated received a 2-week course of a combination of 2 or 3 antibiotics plus lansoprazole. A study nurse called each patient approximately every 3 days to document adherence. Successful eradication of H. pylori was defined as negative results on a urea breath test (BreathTek UBT, Meretek Diagnostics, Inc., Nashville, Tennessee) 8 weeks after initiation of treatment. Statistical Analysis Statistical analysis was performed by using StatXact 5 (Cytel Software Corp., Cambridge, Massachusetts) and SAS software (SAS Institute, Inc., Cary, North Carolina). Confidence intervals for binomial proportions were computed by using the Casella procedure (20). Bivariate associations were examined by using the chi-square test or the Fisher exact test for dichotomous variables. The Wilcoxon rank-sum test was used for comparisons of continuous variables. Logistic regression was used to test univariable dose-response relationships and multivariable associations with antimicrobial resistance. Variables were considered for the multivariable models if their univariable P value was less than 0.25, with the exception of sex, which was included in all models. The numbers of courses of macrolides, clarithromycin, erythromycin, azithromycin, and metronidazole were entered into the multivariable models as indicator variables ( 1 course or 0 courses), while the number of all other courses of antibiotics was entered as an interval variable. Variables were considered confounders and remained in the model if their exclusion changed the value of the coefficients of interest by more than 15%. All P values are two-sided, and confidence intervals are exact when appropriate. Results One hundred forty-nine persons with culture-confirmed H. pylori infection were enrolled in the study. Of these, 125 who had documented health encounters for at least 8 years before enrollment (84%) were included for analysis. The median age of participants was 46.5 years (range, 22.2 to 88.7 years). Eighty-two (66%) were women, and all were Alaska Natives. Pharmacy records were available for a median of 8.6 years (range, 8.0 to 9.6 years). A median of 11 (range, 0 to 68) antimicrobial courses was prescribed during the 8 to 10 years before enrollment (mean, 1.52 courses per year). For -lactam antimicrobial agents and macrolide antimicrobial agents, the median number of courses prescribed was 5 (range, 0 to 31) and 1 (range, 0 to 11), respectively. The median number of courses for all other classes of antimicrobial agents prescribed (including metronidazole) was 3 (range, 0 to 30). Thirteen patients (10%) had received previous treatment for H. pylori infection in the 10 years before enrollment. Clinical symptoms included heartburn (75%), nausea (72%), vomiting (40%), and hematemesis (11%). Endoscopic findings included hemorrhagic or superficial ulcerations of the gastric mucosa in 56 patients (45%), duodenal ulcers in 4 (3%), and gastric ulcers in 8 (6%). Two specimens of the gastric mucosa were obtained for culture from 105 participants (84%) at the time of diagnosis. Seventeen patients (14%) had a single specimen submitted for culture, and 3 (2%) had 3 or more specimens. Among the 125 participants, 83 (66%) were found to have H. pylori isolates resistant to metronidazole, 37 (30%) were found to have H. pylori isolates resistant to clarithromycin, 7 (6%) were found to have H. pylori isolates resistant t

Pneumococcal vaccination in developing countries

WHO estimates that about 1·6 million people, including up to 1 million children under 5 years old, die every year of pneumococcal pneumonia, meningitis, and sepsis.1 In populations with high child-mortality rates, pneumonia is the leading infectious cause of mortality and accounts for about 20–25% of all child deaths.2 In these populations, Streptococcus pneumoniae is identified consistently as the leading cause of bacterial pneumonia, and pneumococcal bacteraemia is an important cause of child mortality. 3, 4 and 5 HIV infection increases risk for pneumococcal disease 20–40-fold, and antibiotic resistance makes treatment difficult and expensive. 6 Thus pneumococcal disease is a major global-health issue.

An outbreak of community-onset methicillin-resistant Staphylococcus aureus skin infections in southwestern Alaska.

OBJECTIVE We investigated a large outbreak of community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in southwestern Alaska to determine the extent of these infections and whether MRSA isolates were likely community acquired. DESIGN Retrospective cohort study. SETTING Rural southwestern Alaska. PATIENTS All patients with a history of culture-confirmed S. aureus infection from March 1, 1999, through August 10, 2000. RESULTS More than 80% of culture-confirmed S. aureus infections were methicillin resistant, and 84% of MRSA infections involved skin or soft tissue; invasive disease was rare. Most (77%) of the patients with MRSA skin infections had community-acquired MRSA (no hospitalization, surgery, dialysis, indwelling line or catheter, or admission to a long-term-care facility in the 12 months before infection). Patients with MRSA skin infections were more likely to have received a prescription for an antimicrobial agent in the 180 days before infection than were patients with methicillin-susceptible S. aureus skin infections. CONCLUSIONS Our findings indicate that the epidemiology of MRSA in rural southwestern Alaska has changed and suggest that the emergence of community-onset MRSA in this region was not related to spread of a hospital organism. Treatment guidelines were developed recommending that beta-lactam antimicrobial agents not be used as a first-line therapy for suspected S. aureus infections.

The Relationship Between In-Home Water Service and the Risk of Respiratory Tract, Skin, and Gastrointestinal Tract Infections Among Rural Alaska Natives

OBJECTIVES We investigated the relationship between the presence of in-home piped water and wastewater services and hospitalization rates for respiratory tract, skin, and gastrointestinal tract infections in rural Alaska. METHODS We determined in-home water service and hospitalizations for selected infectious diseases among Alaska Natives by region during 2000 to 2004. Within 1 region, infant respiratory hospitalizations and skin infections for all ages were compared by village-level water services. RESULTS Regions with a lower proportion of home water service had significantly higher hospitalization rates for pneumonia and influenza (rate ratio [RR] = 2.5), skin or soft tissue infection (RR = 1.9), and respiratory syncytial virus (RR = 3.4 among those younger than 5 years) than did higher-service regions. Within 1 region, infants from villages with less than 10% of homes served had higher hospitalization rates for pneumonia (RR = 1.3) and respiratory syncytial virus (RR = 1.2) than did infants from villages with more than 80% served. Outpatient Staphylococcus aureus infections (RR = 5.1, all ages) and skin infection hospitalizations (RR = 2.7, all ages) were higher in low-service than in high-service villages. CONCLUSIONS Higher respiratory and skin infection rates were associated with a lack of in-home water service. This disparity should be addressed through sanitation infrastructure improvements.

Viral respiratory infections in hospitalized and community control children in Alaska

Respiratory syncytial virus (RSV) in Alaska Native children from the Yukon Kuskokwim (YK) Delta is associated with a hospitalization rate five times higher than that reported for the general US child population. The role of other viral respiratory pathogens has not been studied in this population. YK Delta children <3 years of age hospitalized with respiratory infections and same aged community control children were prospectively enrolled between October 2005 and September 2007. Polymerase chain reaction detection of viruses was performed on nasopharyngeal samples. Characteristics of hospitalized and asymptomatic control children were analyzed. From October 2005 to September 2007, 440 hospitalized and 425 control children were analyzed. Respiratory viruses were detected in 90% (395) of hospitalized children: 194 (44%) rhinovirus, 131 (30%) adenovirus, 102 (23%) RSV, 77 (18%) para influenza viruses (PIV), 66 (15%) human metapneumovirus (hMPV), 23 (5%) influenza, and 25 (6%) coronavirus. Fifty‐two percent (221) of control children had a virus detected, most commonly rhinovirus (33%), and adenovirus (16%). RSV, PIV, hMPV, and influenza were significantly more common in hospitalized cases than control children, but rhinovirus, adenovirus, and coronavirus were not. RSV and hMPV were associated with higher severity of illness. In this study, RSV remains the most important virus associated with respiratory hospitalization, although hMPV and PIV were also common. RSV and hMPV were associated with more severe illness. Rhinovirus and adenovirus were detected in two‐thirds of hospitalized children, but their frequent detection in control children made their role in respiratory hospitalization uncertain. J. Med. Virol. 82:1282–1290, 2010.