Measurements of Impoverishing and Catastrophic Surgical Health Expenditures in Low- and Middle-Income Countries and Reduction Interventions in the Last 30 Years: A Systematic Review.

INTRODUCTION: Approximately 33 million people suffer catastrophic health expenditure (CHE) from surgery and/or anesthesia costs. The aim of this systematic review is to evaluate catastrophic and impoverishing expenditure associated with surgery and anesthesia in low- and middle-income countries (LMICs). METHODS: We performed a systematic review of all studies from 1990 to 2021 that reported CHE in LMICs for treatment of a condition requiring surgical intervention, including cesarean section, trauma care, and other surgery. RESULTS: 77 studies met inclusion criteria. Tertiary facilities (23.4%) were the most frequently studied facility type. Only 11.7% of studies were conducted in exclusively rural health-care settings. Almost 60% of studies were retrospective in nature. The cost of procedures ranged widely, from $26 USD for a cesarean section in Mauritania in 2020 to $74,420 for a pancreaticoduodenectomy in India in 2018. GDP per capita had a narrower range from $315 USD in Malawi in 2019 to $9955 USD in Malaysia in 2015 (Median = $1605.50, interquartile range = $1208.74). 35 studies discussed interventions to reduce cost and catastrophic expenditure. Four of those studies stated that their intervention was not successful, 18 had an unknown or equivocal effect on cost and CHE, and 13 concluded that their intervention did help reduce cost and CHE. CONCLUSIONS: CHE from surgery is a worldwide problem that most acutely affects vulnerable patients in LMICs. Existing efforts are insufficient to meet the true need for affordable surgical care unless assistance for ancillary costs is given to patients and families most at risk from CHE.

Defining the shelf-life of calcium sulfate beads embedded with tobramycin and vancomycin.

Background: Antibiotic-laden calcium sulfate beads are gaining popularity in the treatment of orthopaedic infections such as fracture-related infection and osteomyelitis. Calcium sulfate beads have several advantages over polymethylmethacrylate (PMMA) beads as they are bioabsorbable, have demonstrated improved elution characteristics, and have lower peak polymerization temperatures than seen in PMMA. The ability to make and store antibiotic beads for later use has the potential to standardize dosing and decrease operating room times and healthcare costs. This study aims to determine the antibiotic efficacy of premade, antibiotic-laden calcium sulfate beads. Methods: Calcium sulfate beads containing vancomycin or tobramycin were molded to 4.8 mm in diameter and stored for shelf-life durations of three and six months at 20 °C. A subset of beads was tested immediately after creation. At the designated time points, beads were placed into a buffer solution and incubated at 37 °C with agitation. Antibiotic eluent was collected at 1-hour, 4-hour, 24-hour, and 48-hour timepoints. Eluent concentrations were inferred from a prior study implementing the same calcium sulfate bead model. Eluent was used in microbroth dilution assays to determine its minimum inhibitory concentration (MIC) against methicillin-sensitive Staphylococcus aureus. Results: MIC assays for tobramycin and vancomycin against S. aureus yielded concentrations consistent with previously reported ranges. MIC results across different bead shelf lives also remained consistent without an increase in MIC with increasing shelf life for either antibiotic. Conclusions: Shelf life up to six months does not impact the efficacy of tobramycin or vancomycin eluent from calcium sulfate beads in vitro compared to beads made and tested immediately. These results provide preliminary evidence that tobramycin and vancomycin retain their antimicrobial activity in calcium sulfate beads for at least six months stored at room temperature. Additional studies on sterilization techniques are necessary prior to considering use of prefabricated antibiotic-loaded calcium sulfate beads in clinical practice.

Isolation and characterization of Streptomyces bacteriophages and Streptomyces strains encoding biosynthetic arsenals.

The threat to public health posed by drug-resistant bacteria is rapidly increasing, as some of healthcare's most potent antibiotics are becoming obsolete. Approximately two-thirds of the world's antibiotics are derived from natural products produced by Streptomyces encoded biosynthetic gene clusters. Thus, to identify novel gene clusters, we sequenced the genomes of four bioactive Streptomyces strains isolated from the soil in San Diego County and used Bacterial Cytological Profiling adapted for agar plate culturing in order to examine the mechanisms of bacterial inhibition exhibited by these strains. In the four strains, we identified 104 biosynthetic gene clusters. Some of these clusters were predicted to produce previously studied antibiotics; however, the known mechanisms of these molecules could not fully account for the antibacterial activity exhibited by the strains, suggesting that novel clusters might encode antibiotics. When assessed for their ability to inhibit the growth of clinically isolated pathogens, three Streptomyces strains demonstrated activity against methicillin-resistant Staphylococcus aureus. Additionally, due to the utility of bacteriophages for genetically manipulating bacterial strains via transduction, we also isolated four new phages (BartholomewSD, IceWarrior, Shawty, and TrvxScott) against S. platensis. A genomic analysis of our phages revealed nearly 200 uncharacterized proteins, including a new site-specific serine integrase that could prove to be a useful genetic tool. Sequence analysis of the Streptomyces strains identified CRISPR-Cas systems and specific spacer sequences that allowed us to predict phage host ranges. Ultimately, this study identified Streptomyces strains with the potential to produce novel chemical matter as well as integrase-encoding phages that could potentially be used to manipulate these strains.

Evaluating Organism-Wide Changes in the Metabolome and Microbiome following a Single Dose of Antibiotic.

Antibiotics are a mainstay of modern medicine, but as they kill their target pathogen(s), they often affect the commensal microbiota. Antibiotic-induced microbiome dysbiosis is a growing research focus and health concern, often assessed via analysis of fecal samples. However, such analysis does not inform how antibiotics influence the microbiome across the whole host or how such changes subsequently alter host chemistry. In this study, we investigated the acute (1 day postadministration) and delayed (6 days postadministration) effects of a single parenteral dose of two common antibiotics, ampicillin or vancomycin, on the global metabolome and microbiome of mice across 77 different body sites from 25 different organs. The broader-spectrum agent ampicillin had the greatest impact on the microbiota in the lower gastrointestinal tract (cecum and colon), where microbial diversity is highest. In the metabolome, the greatest effects were seen 1 day posttreatment, and changes in metabolite abundances were not confined to the gut. The local abundance of ampicillin and its metabolites correlated with increased metabolome effect size and a loss of alpha diversity versus control mice. Additionally, small peptides were elevated in the lower gastrointestinal tract of mice 1 day after antibiotic treatment. While a single parenteral dose of antibiotic did not drastically alter the microbiome, nevertheless, changes in the metabolome were observed both within and outside the gut. This study provides a framework for how whole-organism -omics approaches can be employed to understand the impact of antibiotics on the entire host.IMPORTANCE We are just beginning to understand the unintended effects of antibiotics on our microbiomes and health. In this study, we aimed to define an approach by which one could obtain a comprehensive picture of (i) how antibiotics spatiotemporally impact commensal microbes throughout the gut and (ii) how these changes influence host chemistry throughout the body. We found that just a single dose of antibiotic altered host chemistry in a variety of organs and that microbiome alterations were not uniform throughout the gut. As technological advances increase the feasibility of whole-organism studies, we argue that using these approaches can provide further insight on both the wide-ranging effects of antibiotics on health and how to restore microbial communities to mitigate these effects.

Host Cathelicidin Exacerbates Group B Streptococcus Urinary Tract Infection.

Group B Streptococcus (GBS) causes frequent urinary tract infection (UTI) in susceptible populations, including individuals with type 2 diabetes and pregnant women; however, specific host factors responsible for increased GBS susceptibility in these populations are not well characterized. Here, we investigate cathelicidin, a cationic antimicrobial peptide, known to be critical for defense during UTI with uropathogenic Escherichia coli (UPEC). We observed a loss of antimicrobial activity of human and mouse cathelicidins against GBS and UPEC in synthetic urine and no evidence for increased cathelicidin resistance in GBS urinary isolates. Furthermore, we found that GBS degrades cathelicidin in a protease-dependent manner. Surprisingly, in a UTI model, cathelicidin-deficient (Camp-/-) mice showed decreased GBS burdens and mast cell recruitment in the bladder compared to levels in wild-type (WT) mice. Pharmacologic inhibition of mast cells reduced GBS burdens and histamine release in WT but not Camp-/- mice. Streptozotocin-induced diabetic mice had increased bladder cathelicidin production and mast cell recruitment at 24 h postinfection with GBS compared to levels in nondiabetic controls. We propose that cathelicidin is an important immune regulator but ineffective antimicrobial peptide against GBS in urine. Combined, our findings may in part explain the increased frequency of GBS UTI in diabetic and pregnant individuals.IMPORTANCE Certain populations such as diabetic individuals are at increased risk for developing urinary tract infections (UTI), although the underlying reasons for this susceptibility are not fully known. Additionally, diabetics are more likely to become infected with certain types of bacteria, such as group B Streptococcus (GBS). In this study, we find that an antimicrobial peptide called cathelicidin, which is thought to protect the bladder from infection, is ineffective in controlling GBS and alters the type of immune cells that migrate to the bladder during infection. Using a mouse model of diabetes, we observe that diabetic mice are more susceptible to GBS infection even though they also have more infiltrating immune cells and increased production of cathelicidin. Taken together, our findings identify this antimicrobial peptide as a potential contributor to increased susceptibility of diabetic individuals to GBS UTI.

The Fungal Pathogen Candida albicans Promotes Bladder Colonization of Group B Streptococcus.

Group B Streptococcus (GBS) is a common cause of bacterial urinary tract infections (UTI) in susceptible populations, including pregnant women and the elderly. However, the factors that govern GBS persistence and disease severity in this niche are not fully understood. Here, we report that the presence of the fungus Candida albicans, a common urogenital colonizer, can promote GBS UTI. Co-inoculation of GBS with C. albicans increased bacterial adherence to bladder epithelium and promoted GBS colonization in vivo in a C. albicans adhesin-dependent manner. This study demonstrates that fungal colonization of the urogenital tract may be an important determinant of bacterial pathogenesis during UTI.