Antimicrobial stewardship: concepts and strategies in the 21st century

Owens, Robert C.

doi:10.1016/j.diagmicrobio.2008.02.012

Cited by 170 publications

(131 citation statements)

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“…There has been a relentless rise in antibiotic resistance over many years in most regions of the world and in many different classes of microbial cells (41). In recent times the phenomenon has become even more worrying, with concerns that hitherto fairly trivial infections could again become untreatable as in the days before antibiotics were discovered (3).…”

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confidence: 99%

Stable Synthetic Cationic Bacteriochlorins as Selective Antimicrobial Photosensitizers

Huang

Mróz

et al. 2010

Antimicrob Agents Chemother

120

112

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Photodynamic inactivation is a rapidly developing antimicrobial treatment that employs a nontoxic photoactivatable dye or photosensitizer in combination with harmless visible light to generate reactive oxygen species that are toxic to cells. Tetrapyrroles (e.g., porphyrins, chlorins, bacteriochlorins) are a class of photosensitizers that exhibit promising characteristics to serve as broad-spectrum antimicrobials. In order to bind to and efficiently penetrate into all classes of microbial cells, tetrapyrroles should have structures that contain (i) one or more cationic charge(s) or (ii) a basic group. In this report, we investigate the use of new stable synthetic bacteriochlorins that have a strong absorption band in the range 720 to 740 nm, which is in the near-infrared spectral region. Four bacteriochlorins with 2, 4, or 6 quaternized ammonium groups or 2 basic amine groups were compared for light-mediated killing against a Gram-positive bacterium (Staphylococcus aureus), a Gramnegative bacterium (Escherichia coli), and a dimorphic fungal yeast (Candida albicans). Selectivity was assessed by determining phototoxicity against human HeLa cancer cells under the same conditions. All four compounds were highly active (6 logs of killing at 1 M or less) against S. aureus and showed selectivity for bacteria over human cells. Increasing the cationic charge increased activity against E. coli. Only the compound with basic groups was highly active against C. albicans. Supporting photochemical and theoretical characterization studies indicate that (i) the four bacteriochlorins have comparable photophysical features in homogeneous solution and (ii) the anticipated redox characteristics do not correlate with cell-killing ability. These results support the interpretation that the disparate biological activities observed stem from cellular binding and localization effects rather than intrinsic electronic properties. These findings further establish cationic bacteriochlorins as extremely active and selective near-infrared activated antimicrobial photosensitizers, and the results provide fundamental information on structure-activity relationships for antimicrobial photosensitizers.

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confidence: 99%

Stable Synthetic Cationic Bacteriochlorins as Selective Antimicrobial Photosensitizers

Huang

Mróz

et al. 2010

Antimicrob Agents Chemother

120

112

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“…Consequently, existing and new antimicrobials should be viewed as precious resources in need of careful stewardship (1,2). An important aspiration is to maximize the therapeutically useful life span of a compound, the time a given antimicrobial yields clinical benefits before drug efficacy is undermined by resistance evolution.…”

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confidence: 99%

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Read

Day

Huijben

2011

Proc. Natl. Acad. Sci. U.S.A.

249

295

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The evolution of drug-resistant pathogens is a major challenge for 21st century medicine. Drug use practices vigorously advocated as resistance management tools by professional bodies, public health agencies, and medical schools represent some of humankind's largest attempts to manage evolution. It is our contention that these practices have poor theoretical and empirical justification for a broad spectrum of diseases. For instance, rapid elimination of pathogens can reduce the probability that de novo resistance mutations occur. This idea often motivates the medical orthodoxy that patients should complete drug courses even when they no longer feel sick. Yet “radical pathogen cure” maximizes the evolutionary advantage of any resistant pathogens that are present. It could promote the very evolution it is intended to retard. The guiding principle should be to impose no more selection than is absolutely necessary. We illustrate these arguments in the context of malaria; they likely apply to a wide range of infections as well as cancer and public health insecticides. Intuition is unreliable even in simple evolutionary contexts; in a social milieu where in-host competition can radically alter the fitness costs and benefits of resistance, expert opinion will be insufficient. An evidence-based approach to resistance management is required.

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“…The results of this study suggest a possible role for dihydrophthalazine antifolates in the treatment of staphylococcal infections, including those caused by methicillin-and vancomycin-resistant strains and Lzd NS strains. The dihydrophthalazines were bactericidal at low concentrations, and the application of good antibiotic stewardship (29) ought to preserve their antistaphylococcal activities and retard the emergence and dissemination of resistance toward these compounds. The MICs of BAL0030543, BAL0030544, and BAL0030545 were Յ0.5 g/ml for 98.7% of the S. aureus strains surveyed, whereas the MICs of the three compounds were Յ1 g/ml for 98.1% of the CoNS strains surveyed.…”

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confidence: 99%

Antistaphylococcal Activity of Dihydrophthalazine Antifolates, a Family of Novel Antibacterial Drugs

Clark

Ednie

Lin

et al. 2009

Antimicrob Agents Chemother

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For a panel of 153 Staphylococcus aureus clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC 50 s and MIC 90 s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 g/ml, respectively, for methicillin-susceptible strains and 0.03 and <0.25 g/ml, respectively, for methicillin-resistant strains. For a panel of 160 coagulase-negative staphylococci (including 5 vancomycin-intermediate and heterogeneous vancomycin-intermediate strains and 7 linezolid-nonsusceptible strains), MIC 50 s and MIC 90 s were <0.03 and <0.06 g/ml, respectively, for methicillin-susceptible strains and 0.06 and 0.5 g/ml, respectively, for methicillin-resistant strains. Vancomycin was active against 93.0% of 313 staphylococci examined; linezolid was active against all S. aureus strains and 95.6% of coagulase-negative staphylococcus strains, whereas elevated MICs of clindamycin, minocycline, trimethoprim, and rifampin for some strains were observed. At 4؋ MIC, the dihydrophthalazines were bactericidal against 11 of 12 staphylococcal strains surveyed. The prolonged serial passage of some staphylococcal strains in the presence of subinhibitory concentrations of BAL0030543, BAL0030544, and BAL0030545 produced clones for which dihydrophthalazines showed high MICs (>128 g/ml), although rates of endogenous resistance development were much lower for the dihydrophthalazines than for trimethoprim. Single-step platings of naïve staphylococci onto media containing dihydrophthalazine antifolates indicated considerable variability among strains with respect to preexistent subpopulations nonsusceptible to dihydrophthalazine antifolates.The prevalence of multidrug-resistant staphylococci (2,18) and the emergence of methicillin-resistant Staphylococcus aureus (MRSA) as a prominent cause of community-acquired skin and skin structure infections (28) are of concern to the medical community. Infections caused by coagulase-negative staphylococci (CoNS), once considered rare, are becoming increasingly frequent, particularly in patients with indwelling medical devices and those who are immunocompromised, and such infections are associated with significant morbidity and mortality (40). The adhesion of Staphylococcus epidermidis to endothelial cells is enhanced at temperatures encountered during a moderate fever (27), and the internalization of CoNS by host cells (1,7,27) probably contributes to antibiotic failure and infection persistence in some patients. Glycopeptides, especially vancomycin, are the current standard of care for the empirical treatment of suspected methicillin-resistant staphylococcal infections, but staphylococci with reduced susceptibility, tolerance, or resistance to vancomycin have appeared in clinical settings (2,15,19,33), and their frequency is almost certainly underreported due to problems with identification and confusion over breakpoints (2,39).The spread of multidrug-resistant staphylococci mandates the ...

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Antimicrobial stewardship: concepts and strategies in the 21st century

Cited by 170 publications

References 100 publications

Stable Synthetic Cationic Bacteriochlorins as Selective Antimicrobial Photosensitizers

Stable Synthetic Cationic Bacteriochlorins as Selective Antimicrobial Photosensitizers

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Antistaphylococcal Activity of Dihydrophthalazine Antifolates, a Family of Novel Antibacterial Drugs

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