Debby Hurlburt

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.

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

Changes in Antibiotic-Prescribing Practices and Carriage of Penicillin-Resistant Streptococcus pneumoniae: A Controlled Intervention Trial in Rural Alaska

From 1998 to 2000, 13 rural Alaskan villages (population, 3326) were surveyed annually by nasopharyngeal cultures for Streptococcus pneumoniae carriage. Data regarding antibiotic use for the entire population was abstracted from clinic records. In 1999, education of medical providers and the community about appropriate antibiotic use began in 4 villages; this program was expanded to include all villages in 2000. Antibiotic courses per person decreased by 31% in the initial intervention villages and by 35% in the remaining villages after education (P<.01 for each). Samples were obtained for culture from a mean of 31% of the population each year; 31% carried pneumococcus. No sustained decrease in carriage of penicillin-nonsusceptible strains was observed. When linear regression was used, serotype accounted for 81% of the variance in pneumococcal minimum inhibitory concentrations after the intervention, compared with 7% for antibiotic use. This suggests that reducing the carriage of serotypes associated with antibiotic resistance by use of pneumococcal conjugate vaccines may have a greater short-term impact than does decreasing antibiotic use.

Invasive Pneumococcal Disease in Alaskan Children: Impact of the Seven-Valent Pneumococcal Conjugate Vaccine and the Role of Water Supply

Background: Alaska Native (AN) children, especially those in the Yukon-Kuskokwim region (YK-AN children), suffer some of the highest rates of invasive pneumococcal disease (IPD) in the world. Rates of IPD declined after statewide introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2001, but increased in subsequent years. Methods: Population-based laboratory surveillance data (1986–2007) for invasive Streptococcus pneumoniae infection in Alaskan children <5 years old were used to evaluate the association of IPD rates and serotype distribution with immunization, socioeconomic status, and in-home water service. Results: Introduction of PCV7 vaccine resulted in elimination of IPD caused by vaccine serotypes, but was followed by increasing rates of IPD caused by nonvaccine serotypes. Among YK-AN children IPD rates dropped by 60%, but then rose due to non-PCV7 serotypes to levels 5- to 10-fold higher than rates in non-YK-AN children and non-AN children. IPD rates in YK-AN children were twice as high in villages where <10% of houses had in-home piped water compared with villages where more than 80% of houses had in-home piped water (390 cases/100,000 vs. 146 cases/100,000, P = 0.008). Conclusions: High IPD rates in Alaska are associated with lack of in-home piped water (controlling for household crowding and per capita income). The effect of in-home piped water is most likely mediated through reduced water supply leading to limitations on handwashing.

The Relationship between Previous Fluoroquinolone Use and Levofloxacin Resistance in Helicobacter pylori Infection

The relationship between prior fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection is unknown. Among 125 enrolled patients, 8.8% had H. pylori isolates that were resistant to levofloxacin. Levofloxacin resistance was associated with any prior fluoroquinolone use over the previous 10 years and with the total number of fluoroquinolone courses prescribed (P<.001).

Impact of conjugate vaccine on transmission of antimicrobial-resistant Streptococcus pneumoniae among Alaskan children.

Background: The impact of heptavalent pneumococcal conjugate vaccine (PCV7) on transmission of antimicrobial-resistant Streptococcus pneumoniae is an important concern for countries considering PCV7 introduction. Methods: Every winter from 2000 to 2004, as PCV7 was routinely introduced, we obtained nasopharyngeal swabs for pneumococcal culture, serotyping, and susceptibility testing from 150 children aged 3–59 months at each of 3 Anchorage, Alaska clinics. We assessed risk factors for pneumococcal carriage, including vaccination status and antimicrobial use. Results: Between 2000 and 2004, 2250 nasopharyngeal swabs from 2061 infants and children were collected. The proportion of children receiving ≥1 PCV7 vaccination increased from 0 to 89%, whereas overall pneumococcal carriage remained stable (38% versus 41%, respectively). Among S. pneumoniae carriers, we observed declines in carriage of PCV7 serotypes (from 54% to 10%, P < 0.01) and trimethoprim-sulfamethoxazole nonsusceptible strains (44% to 16%, P < 0.01), but not in PCN-nonsusceptible strains (36% versus 37%). Among PCN-nonsusceptible types, the proportion of serotype 19A strains increased from 10% to 32% (P = 0.0002). Recent β-lactam use was stable throughout the period (29% overall), whereas trimethoprim-sulfamethoxazole use declined from 6% to 2% (P = 0.02). Conclusions: PCV7 vaccination in the first 5 years did not affect overall pneumococcal carriage, but was associated with a shift in serotype distribution from PCV7 types to non-PCV7 types. With persistent pressure of some antimicrobials, reductions in carriage of antimicrobial nonsusceptible PCV7 types may be offset by increases in carriage of nonsusceptible non-PCV7 types.

Alaska Sentinel Surveillance for Antimicrobial Resistance in Helicobacter pylori Isolates from Alaska Native Persons, 1999–2003

Background:  Previous studies in Alaska have demonstrated elevated proportions of antimicrobial resistance among Helicobacter pylori isolates.

Effect of the 13-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae—Alaska, 2008–2012

BACKGROUND In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced a 7-valent vaccine (PCV7) that contained all PCV7 serotypes plus 6 additional serotypes (PCV6+). We conducted annual surveys from 2008 to 2012 to determine the effect of PCV13 on colonization by pneumococcal serotypes. METHODS We obtained nasopharyngeal swabs for pneumococcal identification and serotyping from residents of all ages at 8 rural villages and children age <60 months at 2 urban clinics. We conducted interviews/medical records review for all participants. RESULTS A total of 18 207 nasopharyngeal swabs (rural = 16 098; urban = 2109) were collected. From 2008 to 2012, 84% of rural and 90% of urban children age <5 years were age-appropriately vaccinated with a PCV. Overall pneumococcal colonization prevalence remained stable among rural (66%) and urban (35%) children age <5 years, and adults age ≥18 years (14%). Colonization by PCV6+ serotypes declined significantly among rural children age <5 years, urban children age <5, and adults age ≥18 over the course of the study (25%-5%, 22%-9%, 22%-6%, respectively). CONCLUSIONS PCV13 was rapidly introduced into the Alaska childhood immunization schedule and reduced colonization by PCV6+ serotypes among children. Unvaccinated adults also experienced comparable reductions in vaccine serotype colonization indicating substantial indirect protection from PCV13.

Characterization of Helicobacter pylori cagA and vacA Genotypes among Alaskans and Their Correlation with Clinical Disease

ABSTRACT Helicobacter pylori infection is common in Alaska. The development of severe H. pylori disease is partially determined by the virulence of the infecting strain. Here we present vacA and cagA genotype data for H. pylori strains isolated from Alaskans and their correlation with clinical disease. We enrolled patients scheduled for esophagogastroduodenoscopy and positive for H. pylori infection. Gastric biopsy specimens from the stomach antrum and fundus were cultured. We performed PCR analysis of the H. pylori vacA gene and for the presence of the cagA gene and cagA empty site. We genotyped 515 H. pylori samples from 220 Native and 66 non-Native Alaskans. We detected the cagA gene in 242/286 (85%) persons; of 222 strains that could be subtyped, 95% (212) were non-Asian cagA and 3% (6) were East Asian cagA. After removing mixed infections (n = 17), 83% of H. pylori strains had either the vacA s1m1 (120/269) or s2m2 (103/269) genotype. Sixty-six percent (68/103) of H. pylori strains with the vacA s2m2 genotype also contained the cagA gene. Infection with an H. pylori strain having the cagA gene or vacA s1m1 genotype (compared with s1m2 and s2m2) was associated with a decreased risk of esophagitis (P = 0.003 and 0.0003, respectively). Infection with an H. pylori strain having the vacA s1m1 genotype (compared with s1m2 and s2m2) was associated with an increased risk of peptic ulcer disease (PUD) (P = 0.003). The majority of H. pylori strains in this study carried the non-Asian cagA gene and either the vacA s1m1 or s2m2 genotype. A majority of H. pylori strains with the vacA s2m2 genotype also contained the cagA gene. There was an association of H. pylori genotype with esophagitis and PUD.

Haemophilus influenzae serotype a invasive disease, Alaska, USA, 1983-2011.

Before introduction of Haemophilus influenzae type b (Hib) vaccines, rates of Hib disease in Alaska’s indigenous people were among the highest in the world. Vaccination reduced rates dramatically; however, invasive H. influenzae type a (Hia) disease has emerged. Cases of invasive disease were identified through Alaska statewide surveillance during1983–2011. Of 866 isolates analyzed for serotype, 32 (4%) were Hia. No Hia disease was identified before 2002; 32 cases occurred during 2002–2011 (p<0.001). Median age of case-patients was 0.7 years; 3 infants died. Incidence of Hia infection (2002–2011) among children <5 years was 5.4/100,000; 27 cases occurred in Alaska Native children (18/100,000) versus 2 cases in non-Native children (0.5/100,000) (risk ratio = 36, p<0.001). From 12/2009 to 12/2011, 15 cases of Hia disease occurred in southwestern Alaska (in children <5 years, rate = 204/100,000). Since introduction of the Hib conjugate vaccine, Hia infection has become a major invasive bacterial disease in Alaska Native children.