Use of the Surgical Wound Infection Model To Determine the Efficacious Dosing Regimen of Retapamulin, a Novel Topical Antibiotic

Rittenhouse, Stephen; Singley, Christine M.; Hoover, Jennifer L.; Page, Roni; Payne, D. J.

doi:10.1128/aac.00183-06

Cited by 39 publications

(32 citation statements)

References 12 publications

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“…In this experiment, no antibiotic control was included, which is considered a limitation of this work. However, it has previously been shown that retapamulin and mupirocin ointments reduced the numbers of S. aureus bacteria in this model by 3 to 4 log 10 CFU/ wound following application two or three times per day for 5 to 7 days when the initial infection was comparable to that in this study (approximately 6 log 10 CFU/wound) (21).…”

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confidence: 63%

“…In this model, a silk suture contaminated with the most common pathogen in SSIs, S. aureus, was implanted into an incision wound on the back of mice and assessment of the infection was performed by counting viable bacteria in the tissue homogenate. The same model has been used previously to assess the effect of systemic and topical antimicrobial agents, and the results observed have been shown to correlate closely with efficacy in clinical trials with human subjects (19)(20)(21). For further details of the experimental model used, see the supplemental material.…”

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confidence: 95%

“…This time point was selected on the basis of previous studies using a mouse surgical wound infection model (19)(20)(21), combined with our experiments on infection kinetics in the wound, suggesting that at 2 h postinfection, the exponential phase of bacterial growth with a high viable count of approximately 10 5.5 CFU/ wound was reached (Fig. 1B).…”

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confidence: 99%

“…In a mouse model of the management of experimental surgical wound infections, which is viewed as a valuable tool for predicting the effect of topical antibiotics in humans (19)(20)(21), PXL150 was shown to be efficient in reducing bacterial counts of the most common pathogen in SSIs, S. aureus. These results, in combination with our previous studies showing that PXL150 has a broad antimicrobial spectrum, an advantageous safety profile, and a low potential for resistance development (18), support the progression of PXL150 as a novel topical treatment of microbial infections.…”

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confidence: 99%

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Efficacy of the Novel Topical Antimicrobial Agent PXL150 in a Mouse Model of Surgical Site Infections

Håkansson

Björn

Lindgren

et al. 2014

Antimicrob Agents Chemother

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bAntimicrobial peptides have recently emerged as a promising new group to be evaluated in the therapeutic intervention of infectious diseases. This study evaluated the anti-infectious effect of the short, synthetic, broad-spectrum antimicrobial peptide PXL150 in a mouse model of staphylococcal surgical site infections. We found that administration of PXL150, formulated in an aqueous solution or in a hydroxypropyl cellulose gel, significantly reduced the bacterial counts in the wound compared with placebo treatment, warranting further investigations of the potential of this peptide as a novel local treatment of microbial infections.

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confidence: 63%

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confidence: 95%

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confidence: 99%

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confidence: 99%

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Efficacy of the Novel Topical Antimicrobial Agent PXL150 in a Mouse Model of Surgical Site Infections

Håkansson

Björn

Lindgren

et al. 2014

Antimicrob Agents Chemother

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“…1A) is a selective, prokaryotic protein synthesis inhibitor being developed as a topical antibiotic for treating bacterial infections of the skin. This semisynthetic pleuromutilin has potent in vitro activity against susceptible and multidrug-resistant organisms commonly associated with bacterial skin infections (15,16). Furthermore, in laboratory experiments, retapamulin shows a low propensity for development of resistance, indicating a low likelihood that resistance would develop via target mutation during therapy (9).…”

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confidence: 99%

Biochemical Characterization of the Interactions of the Novel Pleuromutilin Derivative Retapamulin with Bacterial Ribosomes

Yan

Madden

Choudhry

et al. 2006

Antimicrob Agents Chemother

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Retapamulin is a semisynthetic pleuromutilin derivative being developed as a topical antibiotic for treating bacterial infections of the skin. It is potent in vitro against susceptible and multidrug-resistant organisms commonly associated with bacterial skin infections. We report detailed mode of action studies demonstrating that retapamulin binds to the bacterial ribosome with high affinity, inhibits ribosomal peptidyl transferase activity, and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site. Taken together, these data distinguish the mode of action of retapamulin from that of other classes of antibiotics. This unique mode of action may explain the lack of clinically relevant, target-specific cross-resistance of retapamulin with antibacterials in current use.Pleuromutilin is a tricyclic, diterpene natural product first identified from the basidiomycete bacterial species Pleurotus mutilus (now referred to as Clitopilus scyphoides) that possesses modest antibacterial activity against primarily gram-positive bacterial organisms (8). Early studies on the mode of action of tiamulin and other semisynthetic pleuromutilin derivatives showed that it interfered with cell-free protein synthesis and formylmethionine-puromycin synthesis (5). Further work has shown that the binding of these compounds to the bacterial 50S ribosomal subunit is displaced by puromycin and chloramphenicol (6). Competitive rRNA footprinting experiments also indicated that tiamulin and another analogue, valnemulin, can bind concurrently with the macrolide antibiotic erythromycin. In contrast, these compounds compete with the peptidyl transferase inhibitor carbomycin (13). Additional evidence for the binding of pleuromutilins to the peptidyl transferase center has come from recent x-ray crystallographic data (17) which show tiamulin having interactions with both the ribosomal A-and P-sites. The interaction of pleuromutilins also appears to involve ribosomal protein L3 near the peptidyl transferase center, since Brachyspira sp. isolates with reduced tiamulin susceptibility have recently been identified with mutations in L3 (14). Thus, it is becoming clear that pleuromutilins have a mechanism of action which involves nucleotides within the peptidyl transferase center.Despite the discovery and development of tiamulin and valnemulin, which have become important veterinary agents to treat swine disease, there has been little progress in the identification of pleuromutilin derivatives to treat bacterial infections in humans. Hence, there has been a renewed interest in the exploitation of novel pleuromutilin derivatives for deployment in human clinical practice (2,7,20). Retapamulin (Fig. 1A) is a selective, prokaryotic protein synthesis inhibitor being developed as a topical antibiotic for treating bacterial infections of the skin. This semisynthetic pleuromutilin has potent in vitro activity against susceptible and multidrug-resistant organisms commonly associated with bacterial skin infections (15, 16). Furthermor...

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Gold Standard Animal Models

Castaneda

LaPointe

2011

Pharmaceutical Sciences Encyclopedia

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This chapter highlights how to make smart use of several good animal models. However, these animal experiments must be augmented with human‐based in vitro experiments, good toxicity databases, and computer modeling technology. Differences in animal and human cells do result in differences in the efficacy and toxicology of certain drugs. The old industrial adage does hold true for the development of drugs and other therapeutics–“cheaper, faster, better.” As will be shown here, it is accomplished by the use of computer models, in vitro testing using human cells or cell lines, and gold standard animal models, before human trials begin.

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Use of the Surgical Wound Infection Model To Determine the Efficacious Dosing Regimen of Retapamulin, a Novel Topical Antibiotic

Cited by 39 publications

References 12 publications

Efficacy of the Novel Topical Antimicrobial Agent PXL150 in a Mouse Model of Surgical Site Infections

Efficacy of the Novel Topical Antimicrobial Agent PXL150 in a Mouse Model of Surgical Site Infections

Biochemical Characterization of the Interactions of the Novel Pleuromutilin Derivative Retapamulin with Bacterial Ribosomes

Gold Standard Animal Models

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