Revisiting “Older” Antimicrobials in the Era of Multidrug Resistance

Pogue, Jason M.; Marchaim, Dror; Kaye, Donald; Kaye, Keith S.

doi:10.1592/phco.31.9.912

Cited by 44 publications

(36 citation statements)

References 57 publications

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“…Due to increasing antibiotic resistance, colistin is playing a more important role in fighting antibiotic-resistant infections and is used as the last resort for the treatment of multidrug-resistant infections caused by Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii (23). It has been reported that polymyxin has a synergistic effect with carbapenems, rifampin, and azithromycin against antibiotic-resistant Acinetobacter baumannii in vitro (24).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics

Cui

Niu

Shi

et al. 2016

Antimicrob Agents Chemother

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cPersisters are small populations of quiescent bacterial cells that survive exposure to bactericidal antibiotics and are responsible for many persistent infections and posttreatment relapses. However, little is known about how to effectively kill persister bacteria. In the work presented here, we found that colistin, a membrane-active antibiotic, was highly active against Escherichia coli persisters at high concentrations (25 or 50 g/ml). At a clinically relevant lower concentration (10 g/ml), colistin alone had no apparent effect on E. coli persisters. In combination with other drugs, this concentration of colistin enhanced the antipersister activity of gentamicin and ofloxacin but not that of ampicillin, nitrofurans, and sulfa drugs in vitro. The colistin enhancement effect was most likely due to increased uptake of the other antibiotics, as demonstrated by increased accumulation of fluorescence-labeled gentamicin. Interestingly, colistin significantly enhanced the activity of ofloxacin and nitrofurantoin but not that of gentamicin or sulfa drugs in the murine model of urinary tract infection. Our findings suggest that targeting bacterial membranes is a valuable approach to eradicating persisters and should have implications for more effective treatment of persistent bacterial infections. P ersisters are a small fraction of nonreplicating, metabolically quiescent bacteria that survive the lethal action of bactericidal antibiotic treatment and can potentially regrow after antibiotic removal, while remaining susceptible to the same antibiotic (1, 2). Persister cells are thought to be responsible for many persistent bacterial infections, such as tuberculosis (3), urinary tract infections (UTIs) (4), and biofilm infections (5). These infections require prolonged treatment, have a high risk of relapse, and can lead to genetic antibiotic resistance during prolonged and repeated treatment.Although the persister phenomenon was first discovered in the 1940s (6, 7), only recently did we begin to understand the molecular mechanisms of persisters (1,8,9). Common antibiotics that inhibit macromolecule synthesis generally have poor activity against persister bacteria, and how the persister bacteria survive treatment with current antibiotics is still unclear. Theoretically, at least two possibilities exist: one is that the drugs cannot enter the persister cells, and the other is that the drugs enter the persister cells but cannot generate lethal effects as they do in growing cells. Work on Mycobacterium tuberculosis demonstrated that the intracellular concentrations of many antibiotics were considerably lower in nonreplicating bacteria than in replicating bacilli (10). Consistent with this observation, increasing the uptake of aminoglycosides by using mannitol (11) and silver (12) was shown to enhance the killing of bacterial persisters by gentamicin. Based on these observations, it is reasonable to postulate that lack of antibiotic entry may play an important role in the survival of persisters during antibiotic exposure and...

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Section: Discussionmentioning

confidence: 99%

Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics

Cui

Niu

Shi

et al. 2016

Antimicrob Agents Chemother

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“…In the present study, ceftaroline demonstrated good activity against S. aureus strains with reduced susceptibility to vancomycin, with a MIC 50/90 of 0.5/1 g/ml (91.9% susceptible and 0.0% resistant according to CLSI breakpoint criteria). Although some older compounds, such as tetracycline and sulfamethoxazole-trimethoprim, also exhibited good activity against MRSA, including multidrug-resistant strains, the lack of robust clinical efficacy data and concerns regarding toxicity prevent the use of these compounds for the treatment of severe invasive staphylococcal infections (19). (4) 2 (50.0) 2 (100.0)…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid, Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Sader

Flamm

Jones

2013

Antimicrob Agents Chemother

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Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, >8 g/ml), 18 (0.09%) to daptomycin (MIC, >2 g/ml), and 369 (1.9%) to vancomycin (MIC, >2 g/ml; 368 isolates at 2 g/ml and 1 at 4 g/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, >8 g/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, >2 g/ml). Ceftaroline was very active against S. aureus overall (MIC 50/90 , 0.5/1 g/ml; 98.5% susceptible), including MRSA (MIC 50/90 , 0.5/1 g/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of >2 g/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC 50/90 , 0.25/0.5 g/ml; 99.1% inhibited at <1 g/ml), including methicillin-resistant (MIC 50/90 , 0.25/0.5 g/ml), linezolid-resistant (MIC 50/90 , 0.5/0.5 g/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 g/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.

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“…This lack of new antimicrobials to replace those that become ineffective brings added urgency to the need to protect the efficacy of existing drugs. In the last few years there has been a resurgence of old antibiotics, and specially polymyxins discovered in the 1940s [6], as drugs of last resort for the treatment of infections caused by multi-drug resistant Gram-negative pathogens, despite their toxicity (nephro-and neurotoxicity) and the lack of clinical efficacy data [7,8]. Polymyxins belong to the class of antimicrobial peptides (AMPs), a class of antibiotics that have attracted great interest in the last few years because they rarely spur the development of resistant organisms.…”

Section: Introductionmentioning

confidence: 99%

Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity

Grau-Campistany

Pujol

Marqués

et al. 2015

Colloids and Surfaces A: Physicochemical and Engineering Aspect

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ARTICLE IN PRESS• Sp-85 is a new synthetic antibiotic lipopeptide with broad spectrum activity.• Pressure-area curves of mixed monolayers show non-ideal mixing.• Binding to anionic liposomes results in fusion and leakage of aqueous contents.• TEM images of antibiotic-exposed bacteria show damaged membranes.• A mechanism of action based on bacterial membrane destabilization is proposed.g r a p h i c a l a b s t r a c t a r t i c l e i n f o a b s t r a c tAntimicrobial peptides offer a new class of therapeutic agents to which bacteria may not be able to develop genetic resistance, since their main activity is in the lipid component of the bacterial cell membrane. We have developed a series of synthetic cationic cyclic lipopeptides based on natural polymyxin, and in this work we explore the interaction of sp-85, an analog that contains a C12 fatty acid at the N-terminus and two residues of arginine. This analog has been selected from its broad spectrum antibacterial activity in the micromolar range, and it has a disruptive action on the cytoplasmic membrane of bacteria, as demonstrated by TEM. In order to obtain information on the interaction of this analog with membrane lipids, we have obtained thermodynamic parameters from mixed monolayers prepared with POPG and POPE/POPG (molar ratio 6:4), as models of Gram positive and Gram negative bacteria, respectively. Langmuir-Blodgett films have been extracted on glass plates and observed by confocal microscopy, and images are consistent with a strong destabilizing effect on the membrane organization induced by sp-85. The effect of sp-85 on the membrane is confirmed with unilamelar lipid vesicles of the same composition, where biophysical experiments based on fluorescence are indicative of membrane fusion and permeabilization starting at very low concentrations of peptide and only if anionic lipids are present. Overall, results described here provide strong evidence that the mode of action of sp-85 is the alteration of the bacterial membrane permeability barrier.

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Revisiting “Older” Antimicrobials in the Era of Multidrug Resistance

Cited by 44 publications

References 57 publications

Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics

Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics

Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid, Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity

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