Endemic, epidemic and pandemic infections: the roles of natural and acquired herd immunity.

PURPOSE OF REVIEW: This review summarizes the general concepts of innate and acquired immunity, including vaccine use and hesitancy, as they relate to reduction of the global burden of highly communicable infectious diseases. RECENT FINDINGS: Vaccination to increase herd immunity remains the cornerstone of disease prevention worldwide yet global vaccination goals are not being met. Modern obstacles to vaccine acceptance include hesitancy, reduced altruistic intentions, impact of COVID-19, distrust of science and governmental agencies as well as recent geopolitical and environmental disasters. Together, such barriers have negatively impacted immunization rates worldwide, resulting in epidemics and pandemics of serious life-threatening infections from vaccine-preventable diseases, especially those affecting children. In addition, pathogens thought to be controlled or eradicated are reemerging with new genetic traits, making them more able to evade natural and acquired immunity, including that induced by available vaccines. Lastly, many serious and widespread infectious diseases await development and utilization of efficacious vaccines. SUMMARY: The global burden of communicable diseases remains high, necessitating continued pathogen surveillance as well as vaccine development, deployment and continued efficacy testing. Equally important is the need to educate aggressively the people and their leaders on the benefits of vaccination to the individual, local community and the human population as a whole.

Investigating the immunomodulatory activities of omadacycline.

BACKGROUND: Apart from their antimicrobial activities, some antibiotics have immunomodulatory effects on host cells, particularly monocytes. Because hyperactivation of the pro-inflammatory cytokine response contributes to acute lung injury in patients with bacterial pneumonia and other lung diseases, antimicrobial agents with immunomodulatory activity can reduce cytokine-mediated tissue injury and improve outcomes. OBJECTIVES: Omadacycline has been recently FDA-approved for community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. The present study investigated omadacycline's ability to modulate LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-1ß), acute-phase reactants (IL-6) and anti-inflammatory cytokines (IL-4, IL-10) by human monocytes in vitro. METHODS: Isolated human monocytes from healthy consenting adults were cultured in RPMI with 1% pooled human serum. Cells were pre-exposed to omadacycline (0.5-64 µg/mL), minocycline (25, 50 or 25 µg/mL) or azithromycin (20, 40 or 80 µg/mL) for 2 h, followed by stimulation with Escherichia coli LPS for 24 h. Cytokines elaborated in the culture supernatant were quantitated by multiplex immunoassay. RESULTS: Omadacycline dose-dependently suppressed LPS-induced production of all cytokines tested. Only high-dose minocycline (100 µg/mL) modestly suppressed TNF-α whereas minocycline significantly increased LPS-induced IL-1ß production. Lower concentrations of minocycline were also stimulatory for IFN-γ, IL-6 and IL-4. Except for suppression of IL-6, azithromycin was largely without effect. CONCLUSIONS: Omadacycline has unique and broad immunomodulatory properties. Such activity supports its use in settings where hyperactivation of the immune response contributes to tissue injury and poor outcomes, especially at sites where pro-inflammatory M-type 1 macrophages dominate the cellular immune response.

Characterization of Paeniclostridium sordellii Metalloproteinase-1 in vitro and in an experimental model of infection.

OBJECTIVE: Paeniclostridium sordellii is a pathogen that causes rapidly fatal infections characterized by severe edema, extreme leukemoid reaction and lack of an innate immune response. We recently identified a metalloproteinase of P. sordellii-1 (Mcs1) that cleaves human vascular cell adhesion molecule 1, an adhesion molecule important to hematopoietic precursor retention and leukocyte diapedesis. In the current study, we further characterize Mcs1 activity and investigate its role in pathogenesis. METHODS: Mcs1 peptide cleavage sequence and activity conditions were identified using a semi-quantitative fluorescence-based reporter assay. Additional host targets for Mcs1 protease activity were tested and confirmed by gel electrophoreses and western blots. Finally, Mcs1 knock out (ΔMcs1) and complemented (cMcs1) strains were developed for assessment in our animal model of myonecrosis. RESULTS: Data show that Mcs1 prefers aliphatic amino acid residues, I or L, especially when adjacent to negatively charged or noncharged-polar residues. In vitro, Mcs1 cleaved or partially cleaved human cell adhesion molecules, E-selectin and intracellular adhesion molecule-1 (ICAM-1), and mediators of innate immune infection defense, complement protein-3 and antimicrobial peptide LL-37. In vivo, infection with the ΔMcs1 P. sordellii strain had little effect on animal survival, tissue destruction or circulating white blood cell counts compared to wild type and cMcs1 strains. CONCLUSIONS: Similar to proteolytic virulence factors from other pathogens, Mcs1 is a promiscuous protease that cleaves multiple human-host factors. Despite minimal impact of Mcs1 on the murine model of P. sordellii infection, it is worth considering its role in humans and other animal models.

Screening for Impaired Glucose Tolerance (Prediabetes) and Prevention of Type 2 Diabetes.

The enormous implications caused by type 2 diabetes on patients, families and health systems in the U.S. require health care providers to apply measures that reduce its burden. Scientific evidence clearly shows that proper screening of populations at risk, implementation of interventions proven beneficial in preventing type 2 diabetes and the use of modern technology in educating patients to adopt a healthier lifestyle are paramount in decreasing the incidence of type 2 diabetes. In this article, we try to answer some of the questions raised by both patients and health care providers about how lifestyle modifications can play a key role in ameliorating and reversing impaired glucose tolerance and type 2 diabetes.

Safe and Effective Triglyceride-Lowering Therapy for Hypertriglyceridemia Associated Pancreatitis: Insulin Mono-therapy in a Non-Diabetic Patient.

This report was prepared to describe a case in which insulin monotherapy was efficacious for the management of hypertriglyceridemia-associated pancreatitis (HGTP) in a patient who was not diabetic. Currently, there are no definite clinical guidelines or standards of practice for nondiabetic HGTP. Apart from insulin infusion, other regimens include plasmapheresis and heparin administration, both of which carry significant risks. We reported a case of a non-diabetic male with HTGP (triglyceride greater than 3,000 mg/dL) who was successfully managed with an insulin infusion. This resulted in achieving a level below 1,000 mg/dL within 28 hours of the initiation of therapy. The patient was discharged without additional incident in 72 hours. We believe that insulin monotherapy for HGTP is efficacious in non-diabetic patients and should be the regimen of choice.

Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus In Vitro.

This study investigated the effects of subinhibitory doses of the lipoglycopeptide antibiotic dalbavancin on Staphylococcus aureus toxin production in vitroS. aureus toxin production levels were compared to those seen with the natural glycopeptide antibiotic vancomycin and with representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely affected toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production at subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections.

Spontaneous C. septicum gas gangrene: A literature review.

As the infectious disease paradigm undergoes a subtle shift, unusual infections associated with malignancy and immunosuppression are being increasingly reported. Spontaneous or non-traumatic Clostridium septicum infection is one such unusual infection which has gained prominence. This article aims to understand the pathophysiology, clinical manifestations and current trends in diagnosing and treating this rare but deadly infection. To understand the multifactorial causation of this infection a review of published cases of spontaneous C. septicum gas gangrene was performed and a total of 94 such cases were identified. Several factors were analyzed for each case: age, infection location and underlying illness, presenting signs and symptoms, neutropenia, gross pathology of the colon, antibiotic use, surgical intervention, and survival. A known or occult malignancy was present in 71% patients and an overall mortality of 67% was observed.

The Impact of Maternal Diabetes, Obesity and Race on Infant Birth Weights in South Dakota.

INTRODUCTION: Maternal obesity, high gestational weight gain and diabetes mellitus during pregnancy are known risk factors that correlate with high infant birth weight and the mother's race. Previous studies have focused on low birth weight, prematurity and infant mortality. This study examined the interaction between race, maternal risk factors and high infant birth weights at the population level in South Dakota to identify factors contributing to the high Native American infant birth weights. We hypothesized that high infant birth weights were associated with maternal diabetes, obesity and high gestational weight gain, and that Native American infants' higher birth weights were related to the prevalence of diabetes and obesity. MATERIALS AND METHODS: De-identified birth certificate data was provided by the South Dakota Department of Health. We used data for live infant births to South Dakota resident mothers from 2006 through 2011. The mothers were categorized as Native American or white by the mother's self-reported primary race. Infants were excluded from the study population for missing data, birth weight less than 350 g or gestational age less than 24 weeks or greater than 45 weeks. The study population included 11,416 Native American infants and 59,263 white infants for a total study population of 70,679 infants. Maternal variables (race, pre-pregnancy weight and body mass index [BMI], gestational weight gain, pre-pregnancy diabetes mellitus [DM], gestational diabetes [GDM] and delivery BMI) and infant variables (gestational age and birth weight) were analyzed using SPSS software. RESULTS: The mean birth weight (BW) of Native American (NA) infants (3377 g) was significantly greater than the mean BW of white (W) infants (3315 g) even though NA infants had a younger mean gestational age (p = 0.006). More NA infants were categorized as high birth weight (HBW) (11.8 percent) than W infants (8.5 percent). Both DM and GDM were significantly more common among NA mothers. Infants of NA mothers with GDM had a higher mean BW than infants of W mothers with GDM. There were more overweight and obese NA mothers (p = 0.006). In each maternal BMI category, NA infants had a higher mean BW. Mean BW was even higher for infants born to mothers with excessive gestational weight gain (GWG) for their BMI. The infants with the highest mean BW were born to obese NA mothers with GDM and excessive GWG (3680 g). Multivariable linear regression showed that race was the most significant variable affecting infant BW (R2 = 0.57, F = 692). Pre-pregnancy BMI, GWG and excessive GWG were also significant. The most significant interaction variables were race and GDM and race and BMI. CONCLUSIONS: Native American race, gestational diabetes mellitus, overweight and obese BMI, and excessive gestational weight gain for BMI were the most significant maternal factors associated with high infant birth weight. Mothers with any one risk factor gave birth to heavier infants. Mothers with all risk factors had infants with the highest mean birth weights in South Dakota. This large population-based study provides evidence that Native American mothers in South Dakota with GDM, overweight or obese BMI and excessive GWG are more likely to give birth to high birth weight infants. At-risk mothers should be educated regarding the risks and potential complications of high birth weight infants.

A novel murine model of Clostridium sordellii myonecrosis: Insights into the pathogenesis of disease.

Clostridium sordellii infections have been reported in women following natural childbirth and spontaneous or medically-induced abortion, injection drug users and patients with trauma. Death is rapid and mortality ranges from 70 to 100%. Clinical features include an extreme leukemoid reaction, the absence of fever, and only minimal pain or erythema at the infected site. In the current study, we developed a murine model of C. sordellii soft tissue infection to elucidate the pathogenic mechanisms. Mice received 0.5, 1.0 or 2.0 × 10(6) CFU C. sordellii (ATCC 9714 type strain) in the right thigh muscle. All doses caused fatal infection characterized by intense swelling of the infected limb but no erythema or visible perfusion deficits. Survival rates and time to death were inoculum dose-dependent. Mice developed a granulocytic leukocytosis with left shift, the onset of which directly correlated with disease severity. Histopathology of infected tissue showed widespread edema, moderate muscle damage and minimal neutrophil infiltration. Circulating levels of granulocyte colony-stimulating factor (G-CSF), soluble tumor necrosis factor receptor I (sTNF-RI) and interlukin-6 (IL-6) were significantly increased in infected animals, while TNF-α, and IL-1ß levels were only mildly elevated, suggesting these host factors likely mediate the leukocytosis and innate immune dysfunction characteristic of this infection. Thus, this model mimics many of the salient features of this infection in humans and has allowed us to identify novel targets for intervention.

The roles of injury and nonsteroidal anti-inflammatory drugs in the development and outcomes of severe group A streptococcal soft tissue infections.

PURPOSE OF REVIEW: This review summarizes clinical and basic science evidence linking trauma and nonsteroidal anti-inflammatory drug (NSAID) use to initiation and progression of severe group A streptococcal (GAS) soft tissue infection. RECENT FINDINGS: New evidence includes recent clinical series and controlled studies that lend support to an NSAID/GAS association, basic science studies that demonstrate unique roles for nonpenetrating injury and NSAID administration in initiation of cryptogenic GAS infection and experimental studies showing that nonselective NSAIDs accelerate disease progression and limit antibiotic efficacy in established GAS soft tissue infections. Potential mechanisms for these processes are discussed. SUMMARY: NSAIDs are important anti-inflammatory and analgesic drugs; however, new experimental data suggest that nonselective NSAIDs do more than simply mask the signs and symptoms of developing GAS infection. A more thorough understanding of the triadic interplay of injury-triggered immune signaling, GAS soft tissue infection and NSAIDs is of significant clinical importance and could shift the current paradigm of pain management to avert the consequences of such devastating infections.

Tigecycline suppresses toxin A and B production and sporulation in Clostridium difficile.

BACKGROUND: Clostridium difficile infection (CDI) is mediated by potent extracellular toxins and is spread largely via bacterial spores. We and others have shown that some antibiotics stimulate C. difficile toxin production in a strain-specific manner; however, the effects of newer anti-C. difficile antibiotics on this process remain to be investigated. METHODS: The effects of the protein synthesis inhibitor tigecycline on sporulation and toxin A and toxin B production were compared in historical (strain 9689) and hypervirulent BI/NAP1/027 (strain 5325) isolates of C. difficile in vitro. RESULTS: Tigecycline at 1/4× MIC stimulated an increased and earlier toxin A and/or B gene expression in both the historical and the hypervirulent strains, although a commensurate increase in toxin protein production was observed only in the 9689 strain. In fact, in the hypervirulent 5325 strain, toxin production was dramatically suppressed. By comparison, subinhibitory concentrations of vancomycin and metronidazole also stimulated increased protein toxin production by the historical, but not the hypervirulent, strain. In addition, tigecycline dose-dependently reduced viable spore production by both the 9689 and 5325 strains. Vancomycin treatment also suppressed spore formation in both C. difficile strains; however, metronidazole, while reducing spore formation in the 9689 strain, stimulated a near 2 log increase in spore production by the 5325 isolate. CONCLUSIONS: In summary, these findings suggest that the treatment of CDI patients with tigecycline could effectively both control disease progression and limit its spread by disrupting sporulation.

Effects of selective and nonselective nonsteroidal anti-inflammatory drugs on antibiotic efficacy of experimental group A streptococcal myonecrosis.

BACKGROUND: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) contribute to more severe group A streptococcal (GAS) infections, yet a beneficial role for NSAIDs has been demonstrated in other experimental bacterial infections. METHODS: Nonselective (ketorolac tromethamine, ibuprofen, indomethacin), COX-1-selective (SC-560), or COX-2-selective (SC-236) NSAIDs ± antibiotics (penicillin, clindamycin) were given to mice challenged intramuscularly with M-type 3 GAS and disease course was followed for 14 days. RESULTS. All nonselective NSAIDs significantly accelerated mortality and reduced antibiotic efficacy; COX-selective NSAIDs had no significant effects. CONCLUSIONS: Use of nonselective NSAIDs, either alone or as adjuncts to antibiotic therapy, for GAS soft tissue infection may contribute to worse outcomes.

Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.