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The aim of this study is to evaluate the chlorhexidine gluconate (CHG) susceptibility in both planktonic cells and biofilm of 32 Gram-negative (Gn) and 6 Gram-positive (Gp) isolates by minimal inhibitory concentration (2–256 μg/mL for Gn and 2–32 μg/mL for Gp), minimal bactericidal concentration (4–256 μg/mL for Gn and 2–32 μg/mL for Gp) in planktonic cells, and minimal biofilm elimination concentration (128 ≥ 16,384 μg/mL in Gn and 32 ≥ 16,384 μg/mL in Gp) in biofilm environment. Our study showed that Gn isolates have higher minimal concentrations than Gp and bacteria in biofilms are more tolerant than planktonic ones. No correlation between MBC or MBEC and biofilm formation was statistically confirmed. The Eagle effect, previously described for antimicrobials and antifungals, was evidenced in this work for CHG, an antiseptic. Besides that, the phenomenon was described in 23/38 isolates (60.5%), raising minimal concentration up to ≥ 16,384 μg/mL. Our study showed that clinical isolates have a high ability to form biofilm allowing them to tolerate CHG concentrations as high as the ones used in clinical practice. Therefore, attention should be given to the occurrence of this phenomenon to avoid false susceptibility results. [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are two human neglected tropical diseases that cause major disabilities. Mass administration of drugs targeting the microfilarial stage has reduced transmission and eliminated these diseases in several countries but a macrofilaricidal drug that kills or sterilizes the adult worms is critically needed to eradicate the diseases. The causative agents of onchocerciasis and lymphatic filariasis are filarial worms that harbor the endosymbiotic bacterium Wolbachia. Because filarial worms depend on Wolbachia for reproduction and survival, drugs targeting Wolbachia hold great promise as a means to eliminate these diseases. Methods: To better understand the relationship between Wolbachia and its worm host, adult Brugia pahangi were exposed to varying concentrations of doxycycline, minocycline, tetracycline and rifampicin in vitro and assessed for Wolbachia numbers and worm motility. Worm motility was monitored using the Worminator system, and Wolbachia titers were assessed by qPCR of the single copy gene wsp from Wolbachia and gst from Brugia to calculate IC50s and in time course experiments. Confocal microscopy was also used to quantify Wolbachia located at the distal tip region of worm ovaries to assess the effects of antibiotic treatment in this region of the worm where Wolbachia are transmitted vertically to the microfilarial stage. Results: Worms treated with higher concentrations of antibiotics had higher Wolbachia titers, i.e. as antibiotic concentrations increased there was a corresponding increase in Wolbachia titers. As the concentration of antibiotic increased, worms stopped moving and never recovered despite maintaining Wolbachia titers comparable to controls. Thus, worms were rendered moribund by the higher concentrations of antibiotics but Wolbachia persisted suggesting that these antibiotics may act directly on the worms at high concentration. Surprisingly, in contrast to these results, antibiotics given at low concentrations reduced Wolbachia titers. Conclusion: Wolbachia in B. pahangi display a counterintuitive dose response known as the “Eagle effect.” This effect in Wolbachia suggests a common underlying mechanism that allows diverse bacterial and fungal species to persist despite exposure to high concentrations of antimicrobial compounds. To our knowledge this is the first report of this phenomenon occurring in an intracellular endosymbiont, Wolbachia, in its filarial host. [ABSTRACT FROM AUTHOR]

The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports. Highlights It is the 70th anniversary of the first report of the Eagle effect, yet our understanding of the mechanisms driving the effect remains poor. The Eagle effect, a paradoxical reduced killing activity at antibiotic concentrations above its MIC or MBC, has been extensively reported in Gram-positive and Gram-negative bacteria, mycobacteria, and fungi, with a diverse range of antibiotics from different classes. The Eagle effect resembles some elements of bacterial persistence and tolerance, yet has a number of distinguishing attributes, most notably an increased number of surviving bacteria at supra-MIC antibiotic concentrations. This phenomenon demonstrates that microorganisms have multiple means to evade antimicrobials. Further investigation could lead to clinical benefits, where high antibiotic exposures may compromise expedited clearance of infection. [ABSTRACT FROM AUTHOR]

Background. Acute bacterial skin and skin-structure infections (ABSSSIs) are common causes of hospital admissions. These infections are often caused by methicillin-resistant Staphylococcus aureus; therefore, vancomycin remains a commonly used therapy. The purpose of this study was to compare hospital length of stay (LOS) in patients treated with vancomycin monotherapy vs combination therapy with clindamycin for ABSSSIs. Methods. This was a retrospective analysis of 269 patients admitted with ABSSSIs to a 941-bed hospital in northern Alabama. Patients who received either vancomycin monotherapy or vancomycin in combination with clindamycin were included. The primary outcome was hospital LOS; secondary outcomes included 90-day readmission rate and the impact of the following on the primary outcome: organisms cultured, presence of abscess, incision and debridement (I&D), failure of a trial of outpatient antibiotics, and presence of diabetes. Results. Hospital LOS was similar between groups when evaluating all ABSSSIs (3.7 ± 1.5 days vs 4.0 ± 2.0 days, P = .192, combination andmonotherapy, respectively). In patients with abscesses, combination therapy was significantly associated with decreased LOS by 18.2% compared with monotherapy (95% confidence interval [CI], 0.818 [.679 to .985]; P = .034). Among the entire population, significantly fewer patients in the combination group were readmitted within 90 days (5.3% vs 15.3%; P = .006; odds ratio [OR], 3.2; 95% CI [1.35 to 7.66]). The 90-day readmission rates were significantly lower among patients with abscesses as well (2.0% vs 24.3%; P = .0001; OR, 14.6; 95% CI [2.98 to 71.37]). Conclusions. Combination therapy with vancomycin and clindamycin was associated with decreased hospital LOS for patients with an abscess. The 90-day hospital readmission rates for those with ABSSSIs may be reduced when combination therapy is utilized. A larger, prospective, multicentered study is needed to validate these findings. [ABSTRACT FROM AUTHOR]

Programmed death is often associated with a bacterial stress response. This behavior appears paradoxical, as it offers no benefit to the individual. This paradox can be explained if the death is ‘altruistic’: the killing of some cells can benefit the survivors through release of ‘public goods’. However, the conditions where bacterial programmed death becomes advantageous have not been unambiguously demonstrated experimentally. Here, we determined such conditions by engineering tunable, stress-induced altruistic death in the bacterium Escherichia coli. Using a mathematical model, we predicted the existence of an optimal programmed death rate that maximizes population growth under stress. We further predicted that altruistic death could generate the ‘Eagle effect’, a counter-intuitive phenomenon where bacteria appear to grow better when treated with higher antibiotic concentrations. In support of these modeling insights, we experimentally demonstrated both the optimality in programmed death rate and the Eagle effect using our engineered system. Our findings fill a critical conceptual gap in the analysis of the evolution of bacterial programmed death, and have implications for a design of antibiotic treatment. [ABSTRACT FROM AUTHOR]