A Novel, Broad-Spectrum Antimicrobial Combination for the Treatment of Pseudomonas aeruginosa Corneal Infections

Chojnacki, Michaelle; Philbrick, Alesa; Scherzi, Tyler; Pecora, Nicole; Dunman, Paul M.; Wozniak, Rachel A. F.

doi:10.1128/aac.00777-19

Cited by 11 publications

(16 citation statements)

References 18 publications

(10 reference statements)

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“…While this study did not investigate the efficacy in polymicrobial keratitis [39,40], in which P. aeruginosa is one of several agents present. Future investigations can be done to determine its efficacy when given in combination with various broad-spectrum antibiotics which has been [41]. For example, tobramycin is often the standard for P. aeruginosa infections tobramycin's efficacy in the treatment of keratitis is limited [42], a previous study investigated the efficacy of tobramycin and MEDI3902 in combination [3].…”

Section: Discussionmentioning

confidence: 99%

Multifunctional Monoclonal Antibody Targeting Pseudomonas aeruginosa Keratitis in Mice

2020

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A worrisome trend in the study and treatment of infectious disease noted in recent years is the increase in multidrug resistant strains of bacteria concurrent with a scarcity of new antimicrobial agents to counteract this rise. This is particularly true amongst bacteria within the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) designation. P. aeruginosa is one of the most common causes of bacterial keratitis. Therefore, it is of vital importance to characterize new antimicrobial agents with anti-Pseudomonal activity for use with the ocular surface. MEDI3902 is a multifunctional antibody that targets the P. aeruginosa persistence factor Psl exopolysaccharide, and the type 3 secretion protein PcrV. We initially assessed this antibody for ocular surface toxicity. The antimicrobial activity of the antibody was then tested by treating mice with established P. aeruginosa keratitis with both topical and intravenous treatment modalities. MEDI3902, was shown to be non-toxic to the ocular surface of mice when given topically. It was also effective compared to the control antibody at preventing P. aeruginosa keratitis with a one-time treatment at the time of infection. Both topical and intravenous administration of MEDI3902 has been proved significant in treating established keratitis infections as well, speeding the resolution of infection significantly more than that of the control IgG. We report the first use of a topical immunotherapeutic multifunctional agent targeting Psl and type 3 secretion on the ocular surface as an antimicrobial agent. While MEDI3902 has been shown to prevent Pseudomonas biofilm formation in keratitis models when given prophylactically intravitally, we show that MEDI3902 has the capability to also treat an active infection when given intravenously to mice with Pseudomonas keratitis. Our data indicate antibodies are well tolerated and nontoxic on the ocular surface. They reduce infection in mice treated concurrently at inoculation and reduced the signs of cornea pathology in mice with established infection. Taken together, these data indicate treatment with monoclonal antibodies directed against Psl and PcrV may be clinically effective in the treatment of P. aeruginosa keratitis and suggest that the design of further antibodies to be an additional tool in the treatment of bacterial keratitis.

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Section: Discussionmentioning

confidence: 99%

Multifunctional Monoclonal Antibody Targeting Pseudomonas aeruginosa Keratitis in Mice

2020

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“…In order to further highlight the potential of PT + rifampin as an effective drug combination, a formulation containing commercially available ophthalmic PT (1000 u polymyxin B/1mg ml −1 trimethoprim) combined with 0.5 mg ml −1 of rifampin was evaluated toward the 11 isolates shown in Table 5. Previously, this 2:1 combination has demonstrated in vivo synergistic antimicrobial activity and effectively treated both S. aureus and P. aeruginosa corneal infections in a murine model 7,8 . All 11 strains tested were susceptible to this 2:1 combination of PT + rifampin at MICs well below the concentrations used in our in vivo models.…”

Section: Synergistic Activity Of Polymyxin B/trimethoprim + Rifampinmentioning

confidence: 98%

“…In response to the critical need for novel therapeutics to treat keratitis, we recently described the synergistic antimicrobial activity of a novel drug combination, polymyxin B/ trimethoprim (PT) + rifampin toward S. aureus and Pseudomonas aeruginosa, another leading cause of keratitis, in both in vitro and in vivo studies 7,8 . While PT alone is commonly used for the treatment of mild bacterial conjunctivitis, its use in more serious corneal infections is limited due to poor antimicrobial potency and inadequate tissue penetration compared to fluoroquinolones [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

“…However, we have demonstrated that the combination of PT + rifampin overcomes these liabilities and displays antimicrobial efficacy in a murine model of bacterial keratitis that equals or exceeds that of moxifloxacin 8 . Furthermore, PT + rifampin exhibits in vivo efficacy toward fluoroquinolone-resistant strains, suggesting that it may be an effective treatment option for strains that otherwise might fail currently available options 7,8 .…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of a Novel Ophthalmic Antimicrobial Drug Combination Toward a Large Panel of Staphylococcus aureus Clinical Ocular Isolates From Around the World

Laskey

Chen

Sohn

et al. 2020

Cornea

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Purpose: Staphylococcus aureus is a leading cause of keratitis requiring urgent antimicrobial treatment. However, rising antibiotic resistance has rendered current ophthalmic antibiotics increasingly ineffective. First, a diverse, ocular S. aureus strain set was evaluated for resistance to six commonly used ophthalmic antibiotics. Next, a recently discovered antimicrobial drug combination containing polymyxin B/trimethoprim + rifampin that displayed impressive efficacy towards S. aureus in both in vitro and in vivo studies was evaluated as a potential novel keratitis therapeutic through testing this combination's efficacy against the clinical strain set.Methods: 163 S. aureus isolates were collected commercially or from the University of Rochester, Flaum Eye Institute. The minimum inhibitory concentrations (MICs) of moxifloxacin, levofloxacin, vancomycin, erythromycin, tobramycin, rifampin and polymyxin B/trimethoprim (PT) were determined for the entire strain set to establish the incidence of resistance to current treatment options among a contemporary clinical isolate set and compared to the performance of PT + rifampin.Results: Among all 163 isolates tested, high rates of antibiotic resistance were found toward erythromycin (69% resistance), moxifloxacin (33%), levofloxacin (40%) and tobramycin (17%). Conversely, the entire strain set, including multi-drug resistant (MDR) isolates, was sensitive to PT + rifampin, demonstrating the potency of this combination. Conclusions:We establish that antibiotic resistance is pervasive among clinical S. aureus isolates, underscoring the concern for the effectiveness of current ophthalmic antibiotics. The drug combination of PT + rifampin, however, eradicated 100% of isolates tested, demonstrating the

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“…Effective combinations for S. aureus include meropenem/ciprofloxacin [57], cefazolin/tobramycin [56], and polymyxin B-trimethoprim/rifampin [58]. There are other antibiotics not normally considered for ophthalmology that have been researched in the context of bacterial keratitis; examples include balofloxacin [59] and tigecycline [60,61]. Both were shown to be potential alternatives to vancomycin.…”

Section: Novel Therapeuticsmentioning

confidence: 99%

Staphylococcus aureus Keratitis: Incidence, Pathophysiology, Risk Factors and Novel Strategies for Treatment

Lee

Somerville

Kaye

et al. 2021

JCM

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Bacterial keratitis is a devastating condition that can rapidly progress to serious complications if not treated promptly. Certain causative microorganisms such as Staphylococcus aureus and Pseudomonas aeruginosa are notorious for their resistance to antibiotics. Resistant bacterial keratitis results in poorer outcomes such as scarring and the need for surgical intervention. Thorough understanding of the causative pathogen and its virulence factors is vital for the discovery of novel treatments to avoid further antibiotic resistance. While much has been previously reported on P. aeruginosa, S. aureus has been less extensively studied. This review aims to give a brief overview of S. aureus epidemiology, pathophysiology and clinical characteristics as well as summarise the current evidence for potential novel therapies.

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A Novel, Broad-Spectrum Antimicrobial Combination for the Treatment of Pseudomonas aeruginosa Corneal Infections

Cited by 11 publications

References 18 publications

Multifunctional Monoclonal Antibody Targeting Pseudomonas aeruginosa Keratitis in Mice

Multifunctional Monoclonal Antibody Targeting Pseudomonas aeruginosa Keratitis in Mice

Efficacy of a Novel Ophthalmic Antimicrobial Drug Combination Toward a Large Panel of Staphylococcus aureus Clinical Ocular Isolates From Around the World

Staphylococcus aureus Keratitis: Incidence, Pathophysiology, Risk Factors and Novel Strategies for Treatment

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