Antihypertensives suppress the emergence of fluoroquinolone-resistant mutants in pneumococci: An in vitro study

Pletz, Mathias W.; Michaylov, Nikolay; Schumacher, Ulrike; Linden, Mark van der; Duesberg, Christoph; Fuehner, Thomas; Klugman, Keith P.; Welte, Tobias; Makarewicz, Oliwia

doi:10.1016/j.ijmm.2013.02.014

Cited by 13 publications

(10 citation statements)

References 32 publications

(36 reference statements)

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“…Other frequently described substitutions are K137N in parC and I460V in parE, which are commonly found in susceptible strains and appear not to contribute to fluoroquinolone resistance (197). Our recent data for ABCs isolates from 2015 are in agreement with previous surveillance data that demonstrate the association of specific causative QRDR substitutions with a wide range of increased fluoroquinolone MICs (194), quite likely due to the added effects of separate mechanisms such as increased active efflux (198)(199)(200)(201)(202).…”

Section: Target Alterationsupporting

confidence: 87%

“…Little is known about the expression regulation mechanism, but the efflux pump can be blocked by the plant alkaloid reserpine and, to a lesser degree, by verapamil (200). Efflux may not confer complete resistance but may be able to decrease the levels of intracellular fluoroquinolone to sublethal concentrations, fostering the occurrence of QRDR mutations (201).…”

Section: Efflux Pumpsmentioning

confidence: 99%

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Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

et al. 2016

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SUMMARYStreptococcus pneumoniaeinflicts a huge disease burden as the leading cause of community-acquired pneumonia and meningitis. Soon after mainstream antibiotic usage, multiresistant pneumococcal clones emerged and disseminated worldwide. Resistant clones are generated through adaptation to antibiotic pressures imposed while naturally residing within the human upper respiratory tract. Here, a huge array of related commensal streptococcal strains transfers core genomic and accessory resistance determinants to the highly transformable pneumococcus. β-Lactam resistance is the hallmark of pneumococcal adaptability, requiring multiple independent recombination events that are traceable to nonpneumococcal origins and stably perpetuated in multiresistant clonal complexes. Pneumococcal strains with elevated MICs of β-lactams are most often resistant to additional antibiotics. Basic underlying mechanisms of most pneumococcal resistances have been identified, although new insights that increase our understanding are continually provided. Although all pneumococcal infections can be successfully treated with antibiotics, the available choices are limited for some strains. Invasive pneumococcal disease data compiled during 1998 to 2013 through the population-based Active Bacterial Core surveillance program (U.S. population base of 30,600,000) demonstrate that targeting prevalent capsular serotypes with conjugate vaccines (7-valent and 13-valent vaccines implemented in 2000 and 2010, respectively) is extremely effective in reducing resistant infections. Nonetheless, resistant non-vaccine-serotype clones continue to emerge and expand.

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Section: Target Alterationsupporting

confidence: 87%

Section: Efflux Pumpsmentioning

confidence: 99%

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

et al. 2016

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“…Although there has been considerable interest in blocking of calcium channels for the control of various multidrug resistant infectious diseases including malaria, schistosomiasis, tuberculosis, and inflammatory responses, [5][6][7][8][9][10][11][12][13][14][15][16][17] our retrospective analysis of this large renal transplant trial database does not provide any support for the hypothesis that calcium channel blocking agent use provides protection from infectious, all-cause, or cardiovascular mortality. A recent study also demonstrated that calcium sensitizing agents would not improve organ dysfunction in sepsis.…”

Section: Discussionmentioning

confidence: 74%

“…In vitro and prior observational studies have suggested that the use of calcium channel blocking agents may decrease the expression of sepsis in resistant infections or enhance antibiotic effectiveness in differing nontransplant populations. [5][6][7][8][9][10][11][12][13][14][15][16][17] Our retrospective study suggested a beneficial impact of calcium channel blocking agents on prevalence of sepsis in immunosuppressed transplant recipients, 1 a population that has not been prospectively studied. We, therefore, performed a post hoc analysis of a large 2 Weinrauch et al prospective trial of renal transplant recipients 18 to determine the difference in prevalence of cardiovascular, noncardiovascular (including infection related), and all-cause deaths between the two groups of patients, ie, those receiving CCB and those not.…”

Section: Introductionmentioning

confidence: 85%

Calcium channel blockade and survival in recipients of successful renal transplant: an analysis of the FAVORIT trial results

Weinrauch¹,

Liu²,

Claggett³

et al. 2017

IJNRD

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Introduction: Single-center and observational studies have suggested that calcium channel blocking agents may decrease the expression of sepsis in individual populations. In the renal transplant population, a role for calcium channel blockers in allograft protection and in prevention of sepsis has been postulated. We hypothesized that any important survival benefit or risk related to chronic use of calcium channel blocking agents should be discernable through an analysis of a large database of stable recipients of renal allografts who had enrolled in a large international trial. Methods: A retrospective analysis of 4,110 renal transplant recipients who enrolled in the international Folic Acid for Vascular Outcome Reduction in Transplantation trial between 2002 and 2007 and were followed until 2010 was undertaken comparing cohorts (FAVORIT) of patients either taking (n=1,436) or not taking (n=2,674) calcium channel blocking medications. The endpoint was all-cause mortality (cardiovascular, noncardiovascular mortality, or unknown). Results were adjusted for country, age, race, sex, smoker, systolic blood pressure, diabetes mellitus, low-density lipoprotein, and chronic kidney disease status. Results: There were no statistically significant differences in incidence rates of cardiovascular, noncardiovascular, and all-cause mortality between patients taking or not taking calcium channel blocking medications. Conclusion: Although physiologic reasoning and small series results suggest a benefit for calcium channel blocking agents for allograft protection and sepsis prevention in immunosuppressed patients, we find no clear survival benefit in a large international renal transplant trial.

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“…22 Specific calcium-related hypothetical mechanisms for protection from sepsis by calcium channel blockers include: (a) A decrease in cytosolic calcium of inflammation mediating cells, thereby limiting excessive cytokine responses, such as occurs in the adult respiratory distress syndrome; 23 (b) an improved capacity to combat pathogens (chemotaxis, movement, adhesion, phagocytosis) through an increase in cytosolic calcium of polymorphonuclear cells and macrophages by release from intracellular stores (endoplasmic reticulum, sarcoplasmic reticulum, mitochondria) by homeostatic calcium movement by non-slow L channels; 23 (c) an effect on invading pathogens to limit their capacity to select strains capable of rapid development of resistance to antibiotics. Calcium channel blockers have been studied in quinoloneresistant pneumococcal pneumonia, 24 rifampicin-resistant pulmonary tuberculosis, 25 quinine-resistant Plasmodium falciparum malaria infestation, 26,27 and praziquantel-resistant Schistosoma mansoni infestation. 28,29 The mechanism does involve slow L channels blocking calcium entry from the exterior.…”

mentioning

confidence: 99%

Does calcium channel blockade have a role in prevention of expression of sepsis in renal transplant recipients?

D’Elia¹,

Gleason²,

Monaco³

et al. 2016

IJNRD

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Abstract:Many antihypertensive agents have been demonstrated to assist in preservation of kidney function, among them those that modulate calcium channels. Calcium channel blockers may also be of value in protecting hemodialysis patients from complications of sepsis. In diabetic recipients of kidney transplant allografts treated with cyclosporine, calcium channel blockade has been retrospectively linked to improved graft preservation and to fewer episodes of sepsis. This brief review outlines clinical and experimental publications on potential protection from sepsis by addition of calcium channel blockers to standard antibiotic therapy in individuals who may or may not have normal kidney function, or in the presence or absence of immunosuppression. Such mechanisms include blockade of antibiotic cytosolic extrusion in the cases of Pneumococci, Mycobacterium tuberculosis, Plasmodium falciparum malaria, or Schistosoma mansoni; blockade of the calcineurin/calmodulin pathway (in immunosuppressed patients allowing for lower dosage of cyclosporine); stabilization of calcium movement at the level of sarcoplasmic reticulum by which shock (vasopressor instability) is prevented; or of cytosolic calcium influx and cell death (in the case of allograft acute tubular necrosis). Given the high cost of development of new antibiotics, a role for generic calcium channel blockade in sepsis prevention should be pursued by additional studies to investigate potential links between blockade of calcium channels and expression of sepsis in at-risk populations.

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Antihypertensives suppress the emergence of fluoroquinolone-resistant mutants in pneumococci: An in vitro study

Cited by 13 publications

References 32 publications

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

Calcium channel blockade and survival in recipients of successful renal transplant: an analysis of the FAVORIT trial results

Does calcium channel blockade have a role in prevention of expression of sepsis in renal transplant recipients?

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