Systematic review of household transmission of Strep A: A potential site for prevention that has eluded attention.

BACKGROUND: Despite being the sixth most common infectious disease globally, transmission of Streptococcus pyogenes (Strep A) within the household remains an understudied driver of infection. We undertook a systematic review to better understand the transmission of Strep A between people within the home while highlighting opportunities for prevention. METHODS: A search strategy was applied to five databases between September 2022 and March 2023. Results were limited to those published between January 2000 and March 2023. Texts were reviewed by two authors and the following data extracted: article details (title, author, year), study type, transmission year, country, participant age/s, infection status, molecular testing, and transmission mode. Funding was provided by the Australian National Health and Medical Research Council (NHMRC, grant number GNT2010716). RESULTS: The final analysis comprised 28 texts. Only seven studies (25.0%) provided sufficient detail to identify the Strep A transmission mode. These were contact (4), vehicle (bedding; clothing; other fabric, and medical equipment, [2]), and contact with animals (1). All others were classified as household (specific mode unascertainable). Most articles reported outbreaks involving invasive Strep A infections. CONCLUSIONS: There is limited literature regarding household transmission of Strep A. Understanding transmission in this setting remains imperative to guide control methods.

Standardization of Epidemiological Surveillance of Group A Streptococcal Cellulitis.

Cellulitis is an acute bacterial infection of the dermis and subcutaneous tissue usually found complicating a wound, ulcer, or dermatosis. This article provides guidelines for the surveillance of cellulitis. The primary objectives of cellulitis surveillance are to (1) monitor trends in rates of infection, (2) describe the demographic and clinical characteristics of patients with cellulitis, (3) estimate the frequency of complications, and (4) describe the risk factors associated with primary and recurrent cellulitis. This article includes case definitions for clinical cellulitis and group A streptococcal cellulitis, based on clinical and laboratory evidence, and case classifications for an initial and recurrent case. It is expected that surveillance for cellulitis will be for all-cause cellulitis, rather than specifically for Strep A cellulitis. Considerations of the type of surveillance are also presented, including identification of data sources and surveillance type. Minimal surveillance necessary for cellulitis is facility-based, passive surveillance. Prospective, active, facility-based surveillance is recommended for estimates of pathogen-specific cellulitis burden. Participant eligibility, surveillance population, and additional surveillance considerations such as active follow-up of cases, the use of International Classification of Disease diagnosis codes, and microbiological sampling of cases are discussed. Finally, the core data elements to be collected on case report forms are presented.

The global burden of sore throat and group A Streptococcus pharyngitis: A systematic review and meta-analysis.

Background: Contemporary data for the global burden of sore throat and group A Streptococcus (Strep A) pharyngitis are required to understand the frequency of disease and develop value propositions for Strep A vaccines. Methods: We used Clarivate Analytics' Web of Science platform to search WoS core collection, PubMed, Medline, data citation index, KCI-Korean Journal Database, Russian Science Citation Index, and the SciELO Citation Index for articles published between Jan 1, 2000, and Feb 15, 2021, from any country and in any language. The risk of bias was assessed using the JBI critical appraisal checklist. We used random-effects meta-analyses to pool sore throat and Strep A sore throat incidence rates from community-based studies. Our study was registered with PROSPERO (CRD42020181103). Findings: Of 5,529 articles identified by the search strategy, 26 studies met the inclusion criteria, but only two included data to determine incidence among adults. The pooled incidence rate, calculated for children only, was 82.2 episodes per 100 child-years (95% CI 25.2-286.3, I2 = 100%) for sore throat (7 studies; 7,964 person years) and 22.1 episodes per 100 child-years (95% CI 14.7-33.1, I2 = 98%) for Strep A sore throat (9 studies; 15,696 person years). The pooled cumulative incidence rate of sore throat from five studies was 31.9 per 100 children. There was significant methodological and statistical heterogeneity among studies, and five of 26 studies had a risk of bias score less than five (range: nine [maximum score] to one). Interpretation: Strep A sore throat has a considerable global burden. However, methodologically standardised studies are required to quantify that burden, analyse differences in rates between populations, and evaluate the likely impact of future Strep A vaccines. Funding: This study was funded by Wellcome Trust 215,490/Z/19/Z.

Modes of transmission and attack rates of group A Streptococcal infection: a protocol for a systematic review and meta-analysis.

BACKGROUND: Group A Streptococcus (Strep A) is an important cause of mortality and morbidity globally. This bacterium is responsible for a range of different infections and post-infectious sequelae. Summarising the current knowledge of Strep A transmission to humans will address gaps in the evidence and inform prevention and control strategies. The objective of this study is to evaluate the modes of transmission and attack rates of group A streptococcal infection in human populations. METHODS: This systematic review protocol was prepared according to the Preferred Reporting Items for Systematic reviews and Meta-analysis Protocols (PRISMA-P) 2015 Statement. Using a comprehensive search strategy to identify any transmission studies that have been published in English since 1980, full-text articles will be identified and considered for inclusion against predefined criteria. We will include all studies reporting on Strep A transmission, who have identified a mode of transmission, and who reported attack rates. Risk of bias will be appraised using an appropriate tool. Our results will be described narratively and where feasible and appropriate, a meta-analysis utilizing the random-effects model will be used to aggregate the incidence proportions (attack rates) for each mode of transmission. In addition, we will also evaluate the emm genotype variants of the M protein causing Strep A infection and the association with transmission routes and attack rates, if any, by setting, socioeconomic background and geographical regions. DISCUSSION: We anticipate that this review will contribute to elucidating Strep A modes of transmission which in turn, will serve to inform evidence-based strategies including environmental health activities to reduce the transmission of Strep A in populations at risk of severe disease. TRIAL REGISTRATION: Systematic review registration: PROSPERO ( CRD42019138472 ).

Topical versus systemic antibiotics for chronic suppurative otitis media.

BACKGROUND: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and often polymicrobial infection (involving more than one micro-organism) of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Antibiotics are the most common treatment for CSOM, which act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be administered both topically and systemically, and can be used alone or in addition to other treatments for CSOM such as ear cleaning (aural toileting). OBJECTIVES: To assess the effects of topical versus systemic antibiotics for people with CSOM. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving patients (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. The studies compared topical antibiotics against systemic (oral, injection) antibiotics. We separated studies according to whether they compared the same type of antibiotic in both treatment groups, or different types of antibiotics. For each comparison we considered whether there was background treatment for both treatment groups, for example aural toileting (ear cleaning). DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not, measured at between one week and up to two weeks, two weeks up to four weeks, and after four weeks), health-related quality of life using a validated instrument, ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways. MAIN RESULTS: Six studies (445 participants), all with high risk of bias, were included. All but two studies included patients with confirmed CSOM, where perforation of the ear drum was clearly documented. None of the studies reported results for resolution of ear discharge after four weeks or health-related quality of life. 1. Topical versus systemic administration of the same type of antibiotics (quinolones) Four studies (325 participants) compared topical versus systemic (oral) administration of ciprofloxacin. Three studies reported resolution of ear discharge at one to two weeks and found that the topical administration may slightly increase resolution (risk ratio (RR) 1.48, 95% confidence interval (CI) 1.24 to 1.76; 285 participants; 3 studies; I2 = 0%; low-certainty evidence). In these studies, aural toileting was either not mentioned, or limited to the first visit. Three studies (265 participants) reported that they did not suspect ototoxicity in any participants, but it is unclear how this was measured (very low-certainty evidence). No studies reported the outcomes of ear pain or serious complications. No studies reported results for hearing, despite it being measured in three studies. 2. Topical versus systemic administration of different types of antibiotics (quinolones versus aminoglycosides) One study (60 participants) compared topical ciprofloxacin versus gentamicin injected intramuscularly. No aural toileting was reported. Resolution of ear discharge was not measured at one to two weeks. The study did not report any 'side effects' from which we assumed that no ear pain, suspected ototoxicity or serious complications occurred (very low-certainty evidence). The study stated that "no worsening of the audiometric function related to local or parenteral therapy was observed". 3. Topical versus systemic administration of different types of antibiotics (quinolones versus amoxicillin-clavulanic acid) One study compared topical ofloxacin with amoxicillin-clavulanic acid with all participants receiving suction ear cleaning at the first visit. It is uncertain if there is a difference between the two groups in resolution of ear discharge at one to two weeks due to study limitations and the very small sample size (RR 2.93, 95% CI 1.50 to 5.72; 56 participants; very low-certainty evidence). It is unclear if there is a difference between topical quinolone compared with oral amoxicillin-clavulanic acid with regards to ear pain, hearing or suspected ototoxicity (very low-certainty evidence). No studies reported the outcome of serious complications. AUTHORS' CONCLUSIONS: There was a limited amount of low-quality evidence available, from studies completed over 15 years ago, to examine whether topical or systemic antibiotics are more effective in achieving resolution of ear discharge for people with CSOM. However, amongst this uncertainty there is some evidence to suggest that the topical administration of antibiotics may be more effective than systemic administration of antibiotics in achieving resolution of ear discharge (dry ear). There is limited evidence available regarding different types of antibiotics. It is not possible to determine with any certainty whether or not topical quinolones are better or worse than systemic aminoglycosides. These two groups of compounds have different adverse effect profiles, but there is insufficient evidence from the included studies to make any comment about these. In general, adverse effects were poorly reported.

Using the Delphi method to identify meaningful and feasible outcomes for pharmaceutical value-based contracting.

In an effort to demonstrate measurable value of pharmaceuticals in the United States, many payers and drug manufacturers have entered into value-based purchasing contracts that link payment for prescription medications to patient outcomes, creating shared risk between the 2 entities. These agreements have emerged as part of a larger movement within the health care landscape to transition away from volume-based payment models and towards value-based designs that promote high-quality and affordable care. Key to the success of pharmaceutical value-based contracting is agreement on meaningful and measurable outcomes that reflect drug performance. Traditional value-based contracts are developed by pharmaceutical companies and payers and may not reflect values of other important stakeholders, such as patients, providers, and employers (when applicable). One approach to more effectively align the interests of all key stakeholders and to maximize the effect and transparency of value-based pharmaceutical contracts is to use the validated Delphi surveying technique, which can gather information and build stakeholder consensus on key elements before contract development. In this Viewpoints article, we describe our experience conducting Delphi studies in 5 disease contexts to inform pharmaceutical value-based contract development, including insights learned and practical considerations for real-world application. In addition, we outline advantages to using this validated consensus-building tool to solicit vital and underrepresented stakeholder input, foster transparency in the contract development process, and promote shared learning for future value-based initiatives. DISCLOSURES: No outside funding supported this project. All authors are or were employed by UPMC Health Plan at the time of this study and have no other disclosures to declare.

Aural toilet (ear cleaning) for chronic suppurative otitis media.

BACKGROUND: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and often polymicrobial infection (involving more than one micro-organism) of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Aural toileting is a term describing a number of processes for manually cleaning the ear. Techniques used may include dry mopping (with cotton wool or tissue paper), suction clearance (typically under a microscope) or irrigation (using manual or automated syringing). Dry mopping may be effective in removing mucopurulent discharge. Compared to irrigation or microsuction it is less effective in removing epithelial debris or thick pus. Aural toileting can be used alone or in addition to other treatments for CSOM, such as antibiotics or topical antiseptics. OBJECTIVES: To assess the effects of aural toilet procedures for people with CSOM. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving people (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. We included any aural toileting method as the intervention, at any frequency and for any duration. The comparisons were aural toileting compared with a) placebo or no intervention, and b) any other aural toileting method. We analysed trials in which background treatments were used in both arms (e.g. topical antiseptics or topical antibiotics) separately. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks; health-related quality of life using a validated instrument; and ear pain (otalgia) or discomfort or local irritation. Secondary outcomes were hearing, serious complications, and the adverse events of ear bleeding and dizziness/vertigo/balance problems. MAIN RESULTS: We included three studies with a total of 431 participants (465 ears), reporting on two comparisons. Two studies included only children with CSOM in the community (351 participants) and the other study (80 participants) included children and adults with chronic ear discharge for at least six weeks. None of the included studies reported the outcomes of health-related quality of life, ear pain or the adverse event of ear bleeding. Daily aural toileting (dry mopping) versus no treatment Two studies (351 children; 370 ears) compared daily dry mopping with no treatment. Neither study presented results for resolution of ear discharge at between one and up to two weeks or between two to four weeks. For resolution of ear discharge after four weeks, one study reported the results per person. We are very uncertain whether there is a difference at 16 weeks (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.60 to 1.72; 1 study; 217 participants) because the certainty of the evidence is very low. No results were reported for the adverse events of dizziness, vertigo or balance problems. Only one study reported serious complications, but it was not clear which group these patients were from, or whether the complications occurred pre- or post-treatment. One study reported hearing, but the results were presented by treatment outcome rather than by treatment group so it is not possible to determine whether there is a difference between the two groups. Daily aural toileting versus single aural toileting on top of topical ciprofloxacin One study (80 participants; 95 ears) compared daily aural toileting (suction) with administration of topical antibiotic (ciprofloxacin) ear drops in a clinic, to a single aural toileting (suction) episode followed by daily self-administered topical antibiotic drops, in participants of all ages. We are unsure whether there is a difference in resolution of ear discharge at between one and up to two weeks (RR 1.09, 95% CI 0.91 to 1.30; 1 study; 80 participants) because the certainty of the evidence is very low. There were no results reported for resolution of ear discharge at between two to four weeks. The results for resolution of ear discharge after four weeks were presented by ear, not person, and could not be adjusted to by person. One patient in the group with single aural toileting and self administration of topical antibiotic ear drops reported the adverse event of dizziness, which the authors attributed to the use of cold topical ciprofloxacin. It is very uncertain whether there is a difference between the groups (RR 0.33, 95% CI 0.01 to 7.95; 1 study; 80 participants, very low-certainty). No results were reported for the other adverse events of vertigo or balance problems, or for serious complications. The authors only reported qualitatively that there was no difference between the two groups in hearing results (very low-certainty). AUTHORS' CONCLUSIONS: We are very uncertain whether or not treatment with aural toileting is effective in resolving ear discharge in people with CSOM, due to a lack of data and the poor quality of the available evidence. We also remain uncertain about other outcomes, including adverse events, as these were not well reported. Similarly, we are very uncertain whether daily suction clearance, followed by antibiotic ear drops administered at a clinic, is better than a single episode of suction clearance followed by self-administration of topical antibiotic ear drops.

Genetic Manipulation of Group A Streptococcus-Gene Deletion by Allelic Replacement.

Genetic manipulation of Streptococcus pyogenes (Group A Streptococcus, GAS) has historically been a challenging process, with considerable variation in efficiency between different strains. Here, we outline an optimized, rapid method for creating markerless isogenic mutations that combines Gibson assembly cloning with a new temperature-sensitive plasmid, pLZts. This method is highly efficient and reduces the time needed to create GAS mutants to ~2-3 weeks, with the ability to prepare multiple mutants simultaneously.

Indirect treatment comparison/network meta-analysis study questionnaire to assess relevance and credibility to inform health care decision making: an ISPOR-AMCP-NPC Good Practice Task Force report.

Despite the great realized or potential value of network meta-analysis of randomized controlled trial evidence to inform health care decision making, many decision makers might not be familiar with these techniques. The Task Force developed a consensus-based 26-item questionnaire to help decision makers assess the relevance and credibility of indirect treatment comparisons and network meta-analysis to help inform health care decision making. The relevance domain of the questionnaire (4 questions) calls for assessments about the applicability of network meta-analysis results to the setting of interest to the decision maker. The remaining 22 questions belong to an overall credibility domain and pertain to assessments about whether the network meta-analysis results provide a valid answer to the question they are designed to answer by examining 1) the used evidence base, 2) analysis methods, 3) reporting quality and transparency, 4) interpretation of findings, and 5) conflicts of interest. The questionnaire aims to help readers of network meta-analysis opine about their confidence in the credibility and applicability of the results of a network meta-analysis, and help make decision makers aware of the subtleties involved in the analysis of networks of randomized trial evidence. It is anticipated that user feedback will permit periodic evaluation and modification of the questionnaire.

Medical utilization associated with palivizumab compliance in a commercial and managed medicaid health plan.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections and hospitalization in infants. Palivizumab is currently the only available agent for prevention of RSV infection in high-risk infants. This high-cost injectable requires monthly dosing during the RSV season. Compliance with the injection schedule is important in the prevention of RSV infection and respiratory complications. Managed care organizations have an interest in the relationship between compliance with the palivizumab dosing schedule and respiratory-related medical outcomes such as emergency room (ER) visits, physician office visits, and hospitalizations. OBJECTIVE: To evaluate respiratory-related medical outcomes and cost for infants who were prescribed and received palivizumab in accordance with the dosing schedule recommended by the American Academy of Pediatrics (AAP) in 2006 versus those who did not. METHODS: A retrospective claims analysis was conducted to assess the relationship between compliance with the palivizumab dosing schedule and respiratory-related medical visits and costs in a western Pennsylvania managed care organization composed of approximately 307,000 commercial and 92,000 Medicaid members. De-identified pharmacy and medical claims data were extracted for infants (0-24 months) who met prior authorization criteria and who received at least 1 dose of palivizumab during the 2006-2007 RSV season (October 15, 2006, to April 15, 2007). Patient compliance was based on (a) starting palivizumab on time, (b) receiving the expected number of injections, and (c) no more than a 37-day gap between palivizumab claims. Medical utilization (physician office visits, ER visits, and hospital admissions) was analyzed by comparing medical services (with respiratory-related ICD-9-CM codes) for the compliant versus noncompliant groups. Net health plan costs (after subtraction of member cost share) were compared for compliant versus noncompliant groups for (a) palivizumab-only pharmacy cost; (b) the cost of RSV-related medical services; and (c) the cost of all respiratory-related medical services, excluding those provided during the inpatient newborn stay. The associations between compliance and other patient variables were assessed using the Mann-Whitney U test for nonparametric data and Pearson chi-square or Fisher's Exact tests for categorical data. RESULTS: Of the 245 infants who received palivizumab during the 2006- 2007 RSV season, 151 (61.6%) were first-season recipients of palivizumab, and 131 (53.5%) were male; 145 (59.2%) belonged to a Medicaid benefit plan, and 100 (40.8%) belonged to a commercial benefit plan; and 73 (29.8%) were deemed to be compliant with the 2006 AAP recommended palivizumab dosing schedule. Fourteen (19.2%) of compliant infants had at least 1 respiratory-related hospital admission compared with 37 (21.5%) of noncompliant infants (P = 0.734). The proportions of infants with at least 1 respiratory-related physician office visit were also similar for the 2 groups, 60.3% (n = 44) for compliant infants versus 64.5% (n = 111) for noncompliant infants (P = 0.564). There was a significant difference in the proportion of infants with at least 1 respiratory-related ER visit, 15.1% (n = 11) of compliant infants versus 28.5% (n = 49) of noncompliant infants (P = 0.034), but there were no RSV-related ER visits in either group and no significant differences between the groups in the proportion with at least 1 RSV-related office visit (9.6% for compliant infants vs. 5.8% for noncompliant infants, P = 0.284). RSV-related hospitalization occurred in 0 (0.0%) compliant and 2 (1.2%) noncompliant infants (P = 1.000). Compliant infants had significantly higher median per patient palivizumab pharmacy costs ($10,416) compared with noncompliant infants ($7,605, P = 0.011). However, median total (palivizumab and respiratory-related medical) costs for the 2 groups did not significantly differ (P = 0.189). CONCLUSION: About 30% of the infants who received palivizumab during the 2006-2007 RSV season were compliant with dosing recommendations. Compliance was associated with a lower proportion of infants with at least 1 respiratory-related ER visit but not with any other study outcome, including the proportion of infants with at least 1 hospital admission or physician visit or any measure of RSV-related use. Median palivizumab per patient costs were higher for the compliant group, but there was no significant between-group difference in total median per patient cost (palivizumab drug plus respiratory-related medical cost).