Using Decision Analysis to Improve Malaria Control Policy Making

Malaria and other vector-borne diseases represent a significant and growing burden in many tropical countries. Successfully addressing these threats will require policies that expand access to and use of existing control methods, such as insecticide-treated bed nets (ITNs) and artemesinin combination therapies (ACTs) for malaria, while weighing the costs and benefits of alternative approaches over time. This paper argues that decision analysis provides a valuable framework for formulating such policies and combating the emergence and re-emergence of malaria and other diseases. We outline five challenges that policy makers and practitioners face in the struggle against malaria, and demonstrate how decision analysis can help to address and overcome these challenges. A prototype decision analysis framework for malaria control in Tanzania is presented, highlighting the key components that a decision support tool should include. Developing and applying such a framework can promote stronger and more effective linkages between research and policy, ultimately helping to reduce the burden of malaria and other vector-borne diseases

Incidence and outcome of Staphylococcus aureus bacteremia in hemodialysis patients

Incidence and outcome of Staphylococcus aureus bacteremia in hemodialysis patients.Background. Staphylococcus aureusbacteremia is frequently associated with metastatic complications and infective endocarditis (IE). The Duke criteria for the diagnosis of IE utilize echocardiographic techniques and are more sensitive than previous criteria. The documentation of IE in patients undergoing hemodialysis (HD) has become increasingly important in order to avoid the overuse of empiric vancomycin and the emergence of antibiotic resistance.MethodsPatients who developed S. aureus bacteremia while undergoing HD at a tertiary medical center or one of four affiliated outpatient HD units were identified. Clinical outcome (death, metastatic complications, IE, and microbiologic recurrence) was assessed during hospitalization and at three months after discharge. Transthoracic and transesophageal echocardiograms were performed and the Duke criteria were used to diagnose IE. Pulse field gel electrophoresis was performed to confirm genetic similarity of recurrent isolates.ResultsFour hundred and forty-five patients underwent hemodialysis for 5431.8 patient-months. Sixty-two developed 65 episodes of S. aureus bacteremia (1.2 episodes/100 patient-months). Complications occurred in 27 (44%) patients. Bacteremia recurred in patients who dialyzed through polytetrafluorethylene grafts (44.4% vs. 7.1%, P = 0.0.01), and there was a trend to increased recurrence in patients who received only vancomycin (19.5% vs. 7.1%, P = 0.4). IE was diagnosed in 8 patients (12%), six of whom had normal transthoracic echocardiograms.ConclusionsSensitive echocardiographic techniques and the Duke criteria for the diagnosis of IE should be used to determine the proper duration of antibiotic therapy in hemodialysis patients with S. aureus bacteremia. This diagnostic approach, coupled with early removal of hardware, may assist in improving outcomes

Results from a 13-Year Prospective Cohort Study Show Increased Mortality Associated with Bloodstream Infections Caused by Pseudomonas aeruginosa Compared to Other Bacteria

ABSTRACT The impact of bacterial species on outcome in bloodstream infections (BSI) is incompletely understood. We evaluated the impact of bacterial species on BSI mortality, with adjustment for patient, bacterial, and treatment factors. From 2002 to 2015, all adult inpatients with monomicrobial BSI caused by Staphylococcus aureus or Gram-negative bacteria at Duke University Medical Center were prospectively enrolled. Kaplan-Meier curves and multivariable Cox regression with propensity score models were used to examine species-specific bacterial BSI mortality. Of the 2,659 enrolled patients, 999 (38%) were infected with S. aureus , and 1,660 (62%) were infected with Gram-negative bacteria. Among patients with Gram-negative BSI, Enterobacteriaceae (81% [1,343/1,660]) were most commonly isolated, followed by non-lactose-fermenting Gram-negative bacteria (16% [262/1,660]). Of the 999 S. aureus BSI isolates, 507 (51%) were methicillin resistant. Of the 1,660 Gram-negative BSI isolates, 500 (30%) were multidrug resistant. The unadjusted time-to-mortality among patients with Gram-negative BSI was shorter than that of patients with S. aureus BSI ( P = 0.003), due to increased mortality in patients with non-lactose-fermenting Gram-negative BSI generally ( P < 0.0001) and Pseudomonas aeruginosa BSI ( n = 158) in particular ( P < 0.0001). After adjustment for patient demographics, medical comorbidities, bacterial antibiotic resistance, timing of appropriate antibiotic therapy, and source control in patients with line-associated BSI, P. aeruginosa BSI remained significantly associated with increased mortality (hazard ratio = 1.435; 95% confidence interval = 1.043 to 1.933; P = 0.02). P. aeruginosa BSI was associated with increased mortality relative to S. aureus or other Gram-negative BSI. This effect persisted after adjustment for patient, bacterial, and treatment factors

Scope and Predictive Genetic/Phenotypic Signatures of Bicarbonate (NaHCO3) Responsiveness and β-Lactam Sensitization in Methicillin-Resistant Staphylococcus aureus.

Addition of sodium bicarbonate (NaHCO3) to standard antimicrobial susceptibility testing medium reveals certain methicillin-resistant Staphylococcus aureus (MRSA) strains to be highly susceptible to β-lactams. We investigated the prevalence of this phenotype (NaHCO3 responsiveness) to two β-lactams among 58 clinical MRSA bloodstream isolates. Of note, ∼75% and ∼36% of isolates displayed the NaHCO3 responsiveness phenotype to cefazolin (CFZ) and oxacillin (OXA), respectively. Neither intrinsic β-lactam MICs in standard Mueller-Hinton broth (MHB) nor population analysis profiles were predictive of this phenotype. Several genotypic markers (clonal complex 8 [CC8]; agr I and spa t008) were associated with NaHCO3 responsiveness for OXA

Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment

Methicillin-resistant Staphylococcus aureus (MRSA) is a devastating pathogen responsible for a variety of life-threatening infections. A distinctive characteristic of this pathogen is its ability to persist in the bloodstream for several days despite seemingly appropriate antibiotics. Persistent MRSA bacteremia is common and is associated with poor clinical outcomes. The etiology of persistent MRSA bacteremia is a result of the complex interplay between the host, the pathogen, and the antibiotic used to treat the infection. In this review, we explore the factors related to each component of the host–pathogen interaction and discuss the clinical relevance of each element. Next, we discuss the treatment options and diagnostic approaches for the management of persistent MRSA bacteremia

Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus

Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus

Whole Genome Sequencing of a Methicillin-Resistant Staphylococcus aureus Pseudo-Outbreak in a Professional Football Team.

Two American football players on the same team were diagnosed with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections on the same day. Our investigation, including whole genome sequencing, confirmed that players did not transmit MRSA to one another nor did they acquire the MRSA from a single source within the training facility

Coagulase-Negative Staphylococcal Infections in the Neonatal Intensive Care Unit

Background. Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity, including neurodevelopmental impairment. Objective. To describe the epidemiology of CoNS infections in the NICU. To determine mortality among infants with definite, probable, or possible CoNS infections. Methods. We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from samples obtained from infants aged &lt;121 postnatal days. Setting. A total of 248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009. Results. We identified 16,629 infants with 17,624 episodes of CoNS infection: 1,734 (10%) definite, 3,093 (17%) probable, and 12,797 (73%) possible infections. Infants with a lower gestational age and birth weight had a higher incidence of CoNS infection. When controlling for gestational age, birth weight, and 5-minute Apgar score, we found that infants with definite, probable, or possible CoNS infection had lower mortality (odds ratio [OR], 0.74 [95% confidence interval {CI}: 0.61, 0.89], 0.68 [95% CI, 0.59, 0.79], and 0.69 [95% CI, 0.63, 0.76], respectively) compared with infants who had negative culture results ( P &lt;.001). No significant difference in overall mortality was found in infants who had definite CoNS infection compared with those who had probable or possible CoNS infection (OR, 0.93 [95% CI, 0.75, 1.16] and 0.85 [95% CI, 0.70, 1.03], respectively). Conclusions. CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants with a diagnosis of definite, probable, or possible CoNS infection was observed

Exebacase for Staphylococcus aureus bloodstream infection and endocarditis

BACKGROUND: Novel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSI), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics. METHODS: In this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) at Day 14. RESULTS: Clinical responder rates at Day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics alone groups, respectively (difference=10.4, 90% CI [-6.3, 27.2], p-value=0.31), and were 42.8 percentage points higher in the pre-specified exploratory MRSA subgroup (74.1% vs. 31.3%, difference=42.8, 90% CI [14.3, 71.4], ad hoc p value=0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics alone groups, respectively, with a notable difference in MRSA (3.7% vs. 25.0%, difference= -21.3, 90% CI [-45.1, 2.5], ad hoc p-value=0.06). Among MRSA patients in the United States, median length-of-stay was 4-days shorter and 30-day hospital readmission rates were 48 percentage points lower in the exebacase-treated group compared with antibiotics alone. CONCLUSIONS: This study establishes proof-of-concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSI