Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR<i>Stenotrophomonas maltophilia</i>

Kumaraswamy, Monika; Lin, Leo; Olson, Joshua; Sun, Ching-Fang; Nonejuie, Poochit; Corriden, Ross; Döhrmann, Simon; Ali, Shariq; Amaro, Deirdre; Rohde, Manfred; Pogliano, Joe; Sakoulas, George; Nizet, Victor

doi:10.1093/jac/dkv487

Cited by 53 publications

(53 citation statements)

References 15 publications

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“…Intriguingly, our in vitro MIC data obtained in CA-MHB containing 44 mM NaHCO 3 was a better predictor of in vivo outcomes than the tissue culture medium, RMPI 1640. Although use of this latter medium for AST is gaining some traction as a “host mimicking milieu” [especially for Gram-negative pathogens (20, 25, 39)], we found that it falsely predicted efficacy of oxacillin and cefazolin for the in vivo treatment of some study MRSA strains, (e.g., BMC1001). Further head-to-head screening in both media, using larger MRSA strain collections, will be required to fully identify which medium is the best predictor of β-lactam efficacy in vivo against MRSA.…”

Section: Discussionmentioning

confidence: 83%

“…In addition, several recent investigations have promoted the use of the tissue culture medium, RPMI 1640, as a more physiologic, host-mimicking media and a better predictor of in vivo susceptibility to various antimicrobials than standard growth media, especially for Gram-negative bacteria (20, 25). As opposed to our NaHCO 3 assays, we found that MICs to both β-lactams were decreased in RPMI for all five of our study strains, although the effect was somewhat less substantive for strain COL ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

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Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Preprint

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23Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) 24 are a major healthcare concern, especially infective endocarditis (IE). Standard 25 antimicrobial susceptibility testing (AST) defines most MRSA strains as 'resistant' to β-26 lactams, often leading to use of costly and/or toxic treatment regimens. In this 27 investigation, five prototype MRSA strains, representing the range of genotypes in 28 current clinical circulation, were studied. We identified two distinct MRSA phenotypes 29 upon AST using standard media, with or without sodium bicarbonate (NaHCO 3 ) 30 supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin 31 and cefazolin ('NaHCO 3 -responsive') and one resistant to such agents ('NaHCO 3 -32 nonresponsive'). These phenotypes accurately predicted clearance profiles of MRSA 33 from target tissues in experimental MRSA IE treated with each β-lactam. 34Mechanistically, NaHCO 3 reduced expression of two key genes involved in the MRSA 35 phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 36 (PBP) 2a (that mediates methicillin resistance), in NaHCO 3 -responsive (but not in 37 NaHCO 3 -nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically 38 killed NaHCO 3 -responsive strains in the presence of the host defense antimicrobial 39 peptide (LL-37) in NaHCO 3 -supplemented media. These findings suggest that AST of 40 MRSA strains in NaHCO 3 -containing media may potentially identify infections caused by 41 NaHCO 3 -responsive strains that are appropriate for β-lactam therapy. 42 Word count: 199 43 44 3 Keywords: 45 Methicillin-resistant Staphylococcus aureus (MRSA); Infective Endocarditis (IE) 46 Antimicrobial Susceptibility Testing (AST); Beta-lactams (β-lactams); 47 50 Staphylococcus aureus is a major bloodstream pathogen in both community-51 acquired and nosocomially-acquired scenarios, and is the leading cause of infective 52 endocarditis (IE) in the industrialized world (1). Compounding the danger of S. aureus 53 bloodstream infections (BSIs) is the steady rise of methicillin-resistant Staphylococcus 54 aureus (MRSA) strains in many geographic regions in the US (2). MRSA is a serious 55 infectious threat, causing more than 15,000 deaths in the U.S. each year (3). 56 MRSA have high minimal inhibitory concentrations (MICs) that are above Clinical 57 Laboratory Standards Institute [CLSI] resistance breakpoints for most conventional β-58 lactam antibiotics, such as oxacillin, on standard antimicrobial susceptibility testing 59 (AST) media. This finding implies a lack of efficacy of these agents in treating MRSA 60 infections, as confirmed in selected experimental IE studies (4-6). Treatment options for 61 MRSA are generally limited to costlier and/or more toxic drugs such as vancomycin, 62 daptomycin, lipoglycopeptides, and fifth generation cephalosporins, such as ceftaroline 63 (7-9). Additionally, great expense and effort have gone into development of such newer 64 anti-MRSA drug...

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Preprint

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“…Recent research has also shown that certain antibiotics that have no demonstrable activity against a particular pathogen in standard laboratory minimum inhibitory concentration (MIC) testing do nevertheless sensitize the pathogen to killing by endogenous host defense peptides, such as human cathelicidin LL-37. Examples include (a) the use of the β-lactam antibiotic nafcillin against MRSA, which promotes LL-37 killing and bacterial clearance in human whole blood, in a murine necrotizing skin infection model and in human patients with recalcitrant bacteremia [47]; and (b) the use of azithromycin to sensitize highly multidrug-resistant Gram-negative bacterial pathogens such as P. aeruginosa , A. baumannii , Klebsiella pneumoniae and Stenotrophomonas maltophilia to LL-37 killing, human serum and clearance in murine models of pneumonia with each pathogen [48, 49]. …”

Section: Neutralization Of Virulence Factors: Disarming the Pathogenmentioning

confidence: 99%

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

Munguia

Nizet

2017

Trends in Pharmacological Sciences

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111

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The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies “outside-the-box” of current antibiotic paradigms.

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“…Clinical studies have shown that azithromycin therapy can facilitate significant improvements in the lung function attributable to its anti-inflammatory action (20, 21). Combinations of azithromycin and colistin have also been shown to exhibit synergistic antibacterial action against some multidrug resistant (MDR) Gram-negative bacterial strains (22, 23). Thus, azithromycin could be a suitable candidate for combination with colistin for improved inhalation antibiotic therapy.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation

Mangal

Park

et al. 2018

Pharm Res

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Purpose: Dissolution behavior of dry powder inhaler (DPI) antibiotic formulations in the airways may affect their efficacy especially for poorly-soluble antibiotics such as azithromycin. The main objective of this study was to understand the effects of surface composition on the dissolution of spray dried azithromycin powders by itself and in combination with colistin. Methods: Composite formulations of azithromycin (a poorly water-soluble molecule) and colistin (a water-soluble molecule) were produced by spray drying. The resultant formulations were characterized for particle size, morphology, surface composition, solid-state properties, solubility and dissolution. Results: The results demonstrate that surfaces composition has critical impacts on the dissolution of composite formulations. Colistin was shown to increase the solubility of azithromycin. For composite formulations with no surface colistin, azithromycin released at a similar dissolution rate as the spray-dried azithromycin alone. An increase in surface colistin concentration was shown to accelerate the dissolution of azithromycin. The dissolution of colistin from the composite formulations was significantly slower than the spray-dried pure colistin. In addition, FTIR spectrum showed intermolecular interactions between azithromycin and colistin in the composite formulations, which could contribute to the enhanced solubility and dissolution of azithromycin. Conclusions: Our study provides fundamental understanding of the effects of surface concentration of colistin on azithromycin dissolution of co-spray-dried composite powder formulations.

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Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDRStenotrophomonas maltophilia

Abstract: Despite lack of activity in standard MIC testing, azithromycin synergizes with cationic peptide antibiotics to kill SM in medium mimicking tissue fluid conditions. Azithromycin, alone or in combination with colistin, merits further exploration in therapy of drug-resistant SM infections.

Cited by 53 publications

References 15 publications

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation

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