To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

https://link.springer.com/content/pdf/10.1007%2Fs00134-017-4683-6.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.

/pdf/bad-bugs-no-drugs-no-eskape-an-update-from-the-infectious-5dylylu5f3.pdf

Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America

Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which have been used extensively in the prophlylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The first tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing number of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are associated with mobile plasmids or transposons and can be distinguished from each other using molecular methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited number of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivatives are being examined, although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food production is needed if we are to continue to use this class of broad-spectrum antimicrobials through the present century.

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

3D
: three-dimensional
AIDS
: acquired immune deficiency syndrome
b.i.d.
: bis in die (twice daily)
BCNIE
: blood culture-negative infective endocarditis
CDRIE
: cardiac device-related infective endocarditis
CHD
: congenital heart disease
CIED
: cardiac implantable electronic device

/pdf/2015-esc-guidelines-for-the-management-of-infective-2z2r1c1flx.pdf

2015 ESC Guidelines for the management of infective endocarditis

Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

/pdf/clinical-practice-guidelines-by-the-infectious-diseases-3wgg73ktjz.pdf

Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children

The in vitro activity of biapenem, a new carbapenem previously designated L-627, was compared with those of imipenem and several other antimicrobial agents against 771 clinical bacterial isolates. Against gram-positive organisms, biapenem was found to be approximately as active as imipenem, inhibiting 90% of isolates of most species at concentrations within one dilution of the MIC of imipenem for 90% of the isolates. Against gram-negative organisms and Bacteroides fragilis, biapenem was at least as active as and often more active than imipenem, with MICs for 90% of the isolates two- to eightfold lower than those of imipenem.

In vitro activity of biapenem against clinical isolates of gram-positive and gram-negative bacteria.

https://www.amjmed.com/article/0002-9343(85)90207-4/pdf

Antimicrobial combinations in the therapy of infections due to gram-negative bacilli.

Combinations of cephalothin and aminoglycoside antibiotics are not currently used in the therapy of serious enterococcal infections, because clinical trials of these combinations have been unsuccessful. Studies of 28 enterococci isolated from patients with enterococcal bacteremia suggested three possible mechanisms for this in vivo antibiotic failure: (i) a relatively high level of resistance to cephalothin among all enterococci and especially those characterized as Streptococcus faecium , (ii) a significant incidence of high-level resistance to the aminoglycosides among certain strains of enterococci, and (iii) a failure of synergism to occur when cephalothin concentrations fall below the minimal inhibitory concentration of the enterococcus, as occurs during the in vivo metabolism and excretion of this antibiotic when given in standard doses for endocarditis.

https://aac.asm.org/content/aac/7/5/522.full.pdf

Studies of Cephalothin: Aminoglycoside Synergism Against Enterococci

With newer forms of therapy, such as the use of cytotoxic agents and immunosuppression, and with the placement for extended periods of time of long intravenous lines utilized for hyperalimentation and antibiotic administration, the incidence of isolations of Candida species from blood cultures has increased. Previous reports have emphasized the local and systemic complications of intravenous lines, 1-4 the seriousness of candidemia, 5 and the relation of candidemia to antibiotic therapy. 6,7 Recently, six patients with candidemia and Candida endophthalmitis have been described. 8 All six had received antibiotics systemically and had indwelling intravenous catheters for prolonged periods of time. We describe two additional patients who had a similar complication of the use of systemic antibiotics and intravenous catheters. We emphasize the importance of prompt detection of the lesions and the early institution of therapy with amphotericin B. Both patients demonstrated marked improvement in conjunction with systemic antifungal therapy. Materials

Candida endophthalmitis. A complication of candidemia.

The comparative in-vitro activity of A-56268 (TE-031), a new semisynthetic macrolide antibiotic, was assessed against approximately 400 bacterial isolates. The new drug demonstrated excellent activity against penicillin-susceptible streptococci (MIC90s less than or equal to 0.06 mg/l) and methicillin-susceptible staphylococci (MIC90 = 0.25 mg/l). Among other Gram-positive organisms tested, a significant number were resistant to A-56268 as well as to erythromycin and clindamycin. A-56268 was at least as active as erythromycin against Pasteurella multocida and Campylobacter jejuni, but was more active than erythromycin against Legionella spp. (MIC90 less than or equal to 0.06 mg/l), Bacteroides fragilis (MIC90 = 4 mg/l) and Bact. melaninogenicus (MIC90 less than or equal to 0.125 mg/l). Activity of A-56268 was pH dependent (more active at pH 7 than at pH 6) and was moderately affected by inoculum size. The drug was bactericidal against two strains of Streptococcus pyogenes tested, but exerted a bacteriostatic effect against Staphylococcus aureus and Str. faecalis.

Robert C. Moellering

Papers

In vitro activity of biapenem against clinical isolates of gram-positive and gram-negative bacteria.

Antimicrobial combinations in the therapy of infections due to gram-negative bacilli.

Studies of Cephalothin: Aminoglycoside Synergism Against Enterococci

Candida endophthalmitis. A complication of candidemia.

Comparative in-vitro activity of A-56268 (TE-031), a new macrolide antibiotic