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April 2016
Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.
Low Numbers, Big Impact: A Look at the Effectiveness of HPV Vaccination
Reviewed by Terri Stillwell, MD 
The quadrivalent human papillomavirus (4vHPV) vaccine was licensed in 2006. Soon after, it was routinely recommended for females aged 11 to 26 years old. Recommendations for routine HPV vaccination in males 11 to 21 years old followed in 2011. Despite these recommendations, vaccine uptake remains low. A recent Pediatrics article assessed vaccine effectiveness, comparing HPV prevalence in pre- and post-vaccine time periods using data from the National Health and Nutrition Examination Survey (NHANES). 
NHANES performs cross-sectional surveys every year, using both a household interview and a physical exam. The survey collects various health information, including vaccine history, sexual history, and self-collected cervicovaginal swabs. During the pre-vaccine years (2003-2006), 2,587 females age 14 to 34 were interviewed and had swabs available for HPV typing; in the post-vaccine years (2009-2012), 2,061 female survey participants were available for this study. Post-vaccine data revealed receipt of at least one dose of HPV vaccine to be 51.4 percent among 14 to 19 year old females, 32.6 percent among 20 to 24 year olds, 14.7 percent among 25 to 29 year olds, and only 3.3 percent among 30 to 34 year olds. 
When comparing pre- and post-vaccine prevalence for HPV types found in the 4vHPV vaccine, there was a significant decrease in prevalence in females aged 14 to 19 and in those aged 20 to 24 (11.5 percent to 4.3 percent, 18.5 percent to 12.1 percent, respectively); there was no significant difference found in the later age groups. These findings held true when limiting the comparison to females who were sexually active, with an even greater prevalence decrease in sexually active, vaccinated females (18.6 percent to 2.1 percent). There was no significant change in non-4vPHV types; vaccination does not appear to provide cross-protection. 
This study affirms the effectiveness of HPV vaccination, despite continued low uptake in the U.S. Efforts to increase vaccination rates should continue. 
Using Social Norms to Reduce Unnecessary Antibiotic Prescriptions
Reviewed by Michael T. Melia, MD

Alarms regarding inappropriate antibiotic use continue to sound. Because up to 90 percent of antibiotic prescriptions are written by general practitioners (GPs), targeting these providers to reduce inappropriate antibiotic use may be worthwhile. 
A recent article in the Lancet describes the use of publicly available United Kingdom prescribing data in concert with “social norm feedback,” the presentation of information showing that individuals are behavioral outliers in order to prompt them to adjust their behaviors to the social norm. The 1,581 GP practices in England that were within the top quintile of antibiotic prescriptions were randomized to two sequential interventions: (1) sending (or not) clinician-focused letters from England’s Chief Medical Officer to GPs informing them that their practice prescribed more antibiotics than 80 percent of neighboring practices, and offering behavioral science-based strategies to reduce prescribing, and (2) delivery (or not) of patient-focused educational posters and leaflets to the practice manager. 
The clinician letters reduced antibiotic prescribing by 4.27 prescriptions per 1,000 population (3.3 percent relative reduction), or an estimated 73,406 prescriptions. The effect was significant only for penicillins and macrolides. The cost to print and mail the provider intervention was estimated at 8 cents (U.S.) per prescription prevented. Patient-focused materials did not impact antibiotic prescribing rates. 
This study serves as a nice companion to articles described in last month’s Journal Club. Given that the intervention group provided nearly 2.2 million prescriptions during the six months of the first intervention, the reduction by 73,406 prescriptions is modest but notable, particularly given the low cost and scalability of the intervention. While an accompanying editorial mentions several caveats—the intervention requires access to prescribing data, information on individual antibiotic appropriateness and patient outcomes were not captured, and factors affecting antibiotic prescribing are complex—this effort indicates that social norm feedback may be a useful arrow in the quiver of antimicrobial stewardship. 
When Is a Narrow-Spectrum Antibiotic OK? Predicting Resistance in Pediatric UTIs
Reviewed by Terri Stillwell, MD 
Daily, physicians must decide which antimicrobial treatment is optimal, one that is narrow with a beneficial side-effect profile, yet likely covers the organisms of concern. With rising antimicrobial resistance, this is an increasing challenge. A recent article in The Journal of Pediatrics looked at patient characteristics in relation to antimicrobial resistance of uropathogens in pediatric patients and whether certain characteristics can predict resistance. 
Using data from two previous multicenter studies, this study analyzed 769 children, less than 6 years old, presenting with their first or second urinary tract infection (UTI). This cohort was 91 percent female; 49 percent were less than a year of age. Urine cultures were positive for E. coli 91 percent of the time. 
Interestingly, amoxicillin sensitivity was low for both E. coli and non-E. coli isolates at 55 and 61 percent, respectively. While sensitivity to a first generation cephalosporin and nitrofurantoin remained high for E. coli isolates (93 and 99 percent), sensitivity of non-E. coli isolates was less, at 72 and 40 percent. Finally, trimethoprim-sulfamethoxazole sensitivities were lower in E. coli compared to non-E. coli isolates (81 and 98 percent). Sensitivity to the boarder antibiotics was greater than 90 percent for all pathogens. 
When analyzing patient characteristics, uncircumcised males, those with history of bowel/bladder dysfunction, and those who had received a dose of antibiotic within the last six months had increased likelihood of having uropathogens resistant to narrow-spectrum antibiotics. Presence of vesicoureteral reflux (VUR) only impacted nitrofurantoin resistance, with higher grades of VUR having higher resistance rates; presence of VUR did not influence resistance rates of the other antimicrobials. Interestingly, Hispanic children more often presented with trimethoprim-sulfamethoxazole-resistant organisms. 
While this study’s patient population may not be directly generalizable to all settings, it shows that some narrow-spectrum antibiotics may still suffice as treatment for lower risk patients, though local epidemiology and antibiograms should always be taken into consideration. 
Can Multiplex PCR Testing Improve the Diagnosis and Treatment of Community-Acquired Pneumonia?
Reviewed by Jennifer Brown, MD 
Community-acquired pneumonia (CAP) is one of the commonest infectious diseases, yet determining the etiology of CAP is an ongoing challenge. In the April 1 issue of Clinical Infectious Diseases, investigators described the results of their study in which respiratory tract specimens from adults with clinical and radiological evidence of CAP were tested by multiplex polymerase chain reaction (PCR) assays for 26 different bacterial and viral pathogens. The PCR results were compared to those of standard culturing methods. 
Of the 323 specimens tested, 310 (96 percent) were sputa and 13 (4 percent) were endotracheal aspirates. Overall, PCR testing identified a bacterial or viral pathogen in 280 (87 percent) of specimens. Bacteria were detected in 81 percent of specimens, with Haemophilus influenzae and Streptococcus pneumoniae identified most commonly. Thirty-two percent of specimens had more than one bacteria identified; H. influenza or S. pneumoniae were present in 92 percent of these co-detections. Viruses were detected in 30 percent of specimens, with rhinovirus and influenza A/B prevailing. Bacteria were detected in 82 percent of the specimens in which viruses were detected. In contrast to PCR testing, cultures identified a pathogen in only 127/323 (39 percent) of specimens. When a reasonable cutoff of >105 colony-forming units was used, bacteria were still detected in almost twice the number of specimens by PCR as compared to culture. Among the 268 patients who had received antimicrobials prior to specimen collection, PCR testing detected bacteria in more specimens than did culturing methods (78 vs. 32 percent, P < .0001). 
The investigators suggest that the enhanced sensitivity of multiplex PCR testing for detecting potential CAP pathogens can facilitate antimicrobial de-escalation. However, the lack of a control patient cohort and the possibility that positive PCR results represented oropharyngeal contamination or residual genetic material rather than active infection limit this assessment and will require further study. 

An Update on Dengue Vaccine Development

Reviewed by Sheila Mitsuma, MD 
With over 350 million dengue infections estimated to occur annually, and up to 3 billion people now at risk for infection worldwide, vaccine development efforts are actively underway. 
Last fall, in The Journal of Infectious Diseases (JID), investigators reported the results of a randomized, placebo-controlled trial evaluating the safety and immunogenicity of two live attenuated tetravalent dengue vaccines, TV003 and TV005, developed by the National Institute of Allergy and Infectious Diseases. The latter, TV005, was formulated with an enhanced dengue serotype 2 component. In this trial of 168 flavivirus-naïve adults, 60 patients received TV003, 60 patients received TV005, and 48 patients received placebo. 
Single doses of either vaccine induced antibody responses to dengue serotypes 1, 3, and 4 in 92 percent to 100 percent of vaccine recipients on day 90. No statistically significant difference in response was detected between vaccine formulations for these three serotypes. A higher frequency of seroconversion for dengue virus serotype 2 was observed for TV005 compared to TV003, with a detectable response at day 90 reported in 97 percent vs. 76 percent of recipients, respectively (p = 0.007). No serious adverse vaccine-related events were reported. No significant boost in antibody response was observed after a second dose at 6 months. 
To determine whether delaying a second dose of TV003 would increase the frequency of seroconversion or augment the magnitude of antibody responses, the same research group performed a second randomized trial, also recently reported in JID. Forty patients were randomized to TV003 at zero and 12 months; eight controls received placebo. A high frequency of seroconversion was seen for all four viral serotypes following the first dose: 89 percent for serotype 1, 95 percent for serotype 2, and 100 percent for both serotypes 3 and 4. Rates of seroconversion and multivalence of the antibody response were not augmented by a second dose. Mean antibody titers before and after the second dose increased less than the boost threshold (four-fold) in the great majority of patients across serotypes. These studies suggest that a single dose of either vaccine is highly immunogenic and that the neutralizing antibody response remains stable at 12 months without the need for booster dosing. As we do not yet know what titer of neutralizing antibody is required for protection against dengue, we anxiously await results evaluating vaccine effectiveness now underway in endemic areas. 

For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases:

April 15
  • The Gut–Vascular Barrier
  • Cellulitis or Pseudocellulitis?
  • Bacterial Evolution Continues, Even in the Absence of Environmental Influences
April 1
  • Uncontacted Amerindians: Highly Diverse Microbiomes but With a Reservoir of Antibiotic Resistance Genes
  • Plasmid-Mediated Resistance to Colistin: Present in at Least 3 Continents

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