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

A B S T R A C T The mechanism by which agents that inhibit bacterial cell wall synthesis produce a synergistic effect against enterococci when combined with aminoglycoside antibiotics has not been elucidated. Using 'Clabeled streptomycin, it could be shown that uptake of this aminoglycoside antibiotic was markedly enhanced in enterococci growing in the presence of penicillin or other agents which inhibit the synthesis of bacterial cell walls. There was no enhancement of streptomycin uptake when the cells were incubated with antibiotics which primarily affect the bacterial cell membrane or inhibit protein synthesis. Increased streptomycin uptake was produced by penicillin only in actively growing bacteria. These observations are consistent with the hypothesis that enterococci exhibit a natural barrier to the entry of streptomycin which can be overcome by agents which inhibit cell wall synthesis, thus producing a synergistic effect.

/pdf/ii-effect-of-various-antibiotics-on-the-uptake-of-4c-labeled-10ginuil20.pdf

Ii. effect of various antibiotics on the uptake of 4c-labeled streptomycin by enterococci

This paper deals with the fluorescent antibody (FA) method for identifying six commonly occuring and two rare groups of streptococci by using commercially prepared (Difco) conjugates. We have shown that group-specific FA produced frequent cross-reactions with heterologous groups of organisms. These reactions varied with different strains of the same serogroup. Nonetheless, there was distinct overall patterns in the intensity and appearance of the homologous and heterologous reactions. When monitored by the precipitin test with Rantz and Randall extracts, these patterns led to the correct identification of 90 to 100% of specimens of serogroup A, B, C, and G streptococci. Many members of groups D and F also showed distinctive reaction patterns. However, there was a significant number of strains of both groups D and F that either failed to strain or stained poorly with the homologous conjugate. As a result, the identification of these serogroups by FA was less reliable.

Identification of streptococci: serogrouping by immunofluorescence.

Staphylococcus aureus is a pathogen that has caused human disease for centuries, and despite efforts to control it via modern antibiotics, this organism has persisted and continues to cause major clinical problems throughout the world. A remarkably versatile pathogen, it has virulence mechanisms that enable it to cause a broad variety of serious infections in man, and it has the ability to acquire new exogenous genes, which make it possible for it to adapt to a variety of changing environmental conditions and to modulate its pathogenicity. It can establish a symptomatic carriage that permits widespread dissemination. It has shown a remarkable ability to develop resistance to the major antibiotics directed against it including the penicillins. The development of methicillin resistance in staphylococci has resulted in organisms that continue to plague patients in institutionalized settings and elsewhere. More recently, there has been a worldwide outbreak (currently most prominent in the United States) of infections due to community-associated methicillin-resistant staphylococci. The factors that have made it possible for this to occur are defined in this article.

Why Has Methicillin-Resistant Staphylococcus aureus Become Such a Successful Pathogen in Adults?

The in vitro activities of cefpiramide and apalcillin were compared with those of other third-generation cephalosporins and extended-spectrum penicillins against over 1,000 clinical bacterial isolates. The activity of cefpiramide against Pseudomonas aeruginosa was comparable to those of piperacillin and cefoperazone, inhibiting 90% of strains at concentrations less than or equal to 16.0 micrograms/ml. This drug was also active against a broad range of gram-negative organisms but was generally less active than many of the other cephalosporins tested against members of the family Enterobacteriaceae. The activity of cefpiramide against gram-positive organisms was comparable to that of cefoperazone. Apalcillin, along with ceftazidime, was the most active agent tested against P. aeruginosa and Acinetobacter calcoaceticus subsp. anitratus, inhibiting 90% of these strains at concentrations less than or equal to 8 micrograms/ml. Against other gram-negative and gram-positive organisms, its activity was similar to that of piperacillin. The activities of both cefpiramide and apalcillin were significantly reduced by the presence of several plasmid-mediated beta-lactamases in a series of otherwise isogenic strains of P. aeruginosa in comparison with their activities against a parent strain which lacks these enzymes. Many strains of Enterobacter cloacae were synergistically inhibited by the combination of gentamicin with either cefpiramide (5 of 10 strains) or apalcillin (6 of 10 strains). Most strains of P. aeruginosa were synergistically inhibited by the combination of gentamicin with either cefpiramide (8 of 10 strains) or apalcillin (10 of 10 strains). However, cefoxitin antagonized the activity of both cefpiramide and apalcillin against most of these same strains.

Comparative in vitro activities of cefpiramide and apalcillin individually and in combination.

To assess the potential efficacy of fleroxacin in combination with clindamycin or metronidazole in mixed aerobic and anaerobic infections, we used a rat model of intra-abdominal abscesses in which the inoculum consisted of pooled rat feces mixed with BaSO4. Two hours after bacterial challenge, antimicrobial therapy was begun intravenously with regimens designed to stimulate human pharmacokinetics. A combination of clindamycin and gentamicin was included as an established treatment regimen. After 8.5 days of therapy, final bacterial counts in abscesses showed that fleroxacin alone or combined with metronidazole or clindamycin effectively eradicated Escherichia coli, with bacterial densities of < or = 2.84 +/- 0.1, < or = 2.9 +/- 0.1, and < or = 2.9 +/- 0.1 (mean +/- standard error of the mean) log10 CFU/g, respectively. The addition of either clindamycin or metronidazole to fleroxacin substantially enhanced the effectiveness of the regimens against Bacteroides fragilis, with bacterial counts of < or = 3.0 +/- 0.1 or < or = 2.9 +/- 0.1 log10 CFU/g, respectively, versus 9.2 +/- 0.2 log10 CFU/g for fleroxacin alone. The combination of metronidazole and fleroxacin also resulted in a significantly greater reduction of peptostreptococci and Bacteroides thetaiotaomicron than fleroxacin alone (< or = 2.9 +/- 0.1 versus 6.1 +/- 0.9 log10 CFU/g and 3.3 +/- 0.4 versus 8.3 +/- 0.1 log10 CFU/g, respectively). Except for those of B. fragilis, counts of other anaerobes were reduced to a greater extent by metronidazole plus fleroxacin than by clindamycin plus fleroxacin, although differences were not always significant. Metronidazole plus fleroxacin was at least as active a clindamycin plus gentamicin against all species and was significantly more active against Clostridium spp. No regimen effectively eradicated enterococci from the abscesses. These results suggest that the addition of either metronidazole or clindamycin would effectively enhance the spectrum of fleroxacin for treatment of mixed aerobic and anaerobic infections.

Robert C. Moellering

Papers

Ii. effect of various antibiotics on the uptake of 4c-labeled streptomycin by enterococci

Identification of streptococci: serogrouping by immunofluorescence.

Why Has Methicillin-Resistant Staphylococcus aureus Become Such a Successful Pathogen in Adults?

Comparative in vitro activities of cefpiramide and apalcillin individually and in combination.

Activity of fleroxacin alone and in combination with clindamycin or metronidazole in experimental intra-abdominal abscesses.