Activity of Dapsone versus Community and Hospital Pathogens from the Canward Study

| March 1, 2016
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aGeorge G. Zhanel, PhD; bJames Q. Del Rosso, DO aProfessor, Department of Medical Microbiology and Infectious Diseases, College of Medicine, Faculty of Health Sciences, University of Manitoba; Director of Canadian Antimicrobial Resistance Alliance, Manitoba, Canada; bAdjunct Clinical Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, Nevada

Disclosure: Dr. Zhanel received research grant support from Galderma. Dr. Del Rosso received no direct or indirect form of compensation related to this article. He does serve as an advisor, speaker, and/or clinical researcher for Allergan, Aqua/Almirall, Bayer, BioPharmX, Dermira, Galderma, Promius, SunPharma, and Valeant. 


 

Abstract

Background: Topical dapsone gel is a sulfone antibiotic approved for acne treatment. No microbiology studies were conducted during dapsone gel clinical trials and it is unclear whether 1) dapsone has antimicrobial activity that may be of clinical relevance in dermatology and 2) dapsone could affect the normal microbiome of facial skin where it is most commonly applied. This study assessed the in vitro activity of dapsone versus Gram-positive and Gram-negative bacterial pathogens obtained from patients with infections. Methods: CANWARD is a national, annual, and ongoing surveillance system to assess the patterns of antibiotic-resistant pathogens in Canada. In 2014, 15 tertiary care medical centers collected 3,511 isolates from blood, respiratory tract, urine, and wounds. Antimicrobial susceptibility was assessed using CLSI broth microdilution method. Results: Dapsone demonstrated relatively poor activity versus Gram-negative bacilli with most MIC50, MIC90 in the range of 512?g/mL and >512?g/mL, respectively. In contrast, dapsone demonstrated activity versus Gram-positive cocci, such as Staphylococcus (including methicillin-resistant S. aureus [MRSA], methicillin-sensitive S. aureus [MSSA]), Streptococcus, and Enterococcus—several strains of S. epidermidis had MICs of 32 and 64?g/mL; there were strains of E. faecalis with MICs of 8, 16, 32, and 64?g/mL; and several strains of S. agalactiae and S. pyogenes demonstrated dapsone MICs of 4, 8, 16, 32, and 64?g/mL. Conclusion: Dapsone has demonstrated antimicrobial activity in vitro. Whether this activity is part of the mechanism of action of topical dapsone in acne remains unknown. There are limited cutaneous pharmacokinetic data with topical dapsone including skin concentrations achieved with topical dapsone therapy; however, topical dapsone as a 2% nanoemulsion has shown very high (1196–3837.34?g/cm2) local skin concentrations. At these high concentrations, topical dapsone would be expected to affect the skin flora of patients with acne (especially Gram-positive cocci, such as Staphylococcus and Streptococcus). These concentrations are multiple times higher (20x–1000x) than the dapsone MICs found for many MSSA, MRSA, S. epidermidis, S. agalactiae, and S. pyogenes, any of which may be present on the skin of acne patients. Whether this results in resistance to dapsone or more importantly results in resistance to chemically unrelated antimicrobials is currently unknown. (J Clin Aesthet Dermatol. 2016;9(3):42–47.)


 

Dapsone gel is a sulfone antibiotic approved for topical treatment of acne vulgaris, with primary activity against inflammatory lesions (Figure 1).[1],[2] Systemic dapsone is indicated for treatment of leprosy and dermatitis herpetiformis; it also has orphan drug approval for treatment of Pneumocystic carinii pneumonia and prevention of toxoplasmosis in immune-compromised individuals.[3–5] In the past, the systemic formulation of dapsone was sometimes used for treatment of severe inflammatory acne vulgaris; however, the risk for hematologic reactions and the development of oral isotretinoin markedly limited its use.[6] The gel formulation was developed for topical application with the expectation that it would be effective for acne and have considerably lower systemic absorption and fewer adverse hematologic effects.[6]

The mechanism of action of topically applied dapsone in acne is not known.[2] As an antibacterial agent, dapsone has actions similar to the sulfonamides, inhibiting bacterial synthesis of dihydrofolic acid via competition with para-aminobenzoate for the active site of dihydropteroate synthetase.[7],[8] There is no current evidence evaluating whether topically applied dapsone modulates any pathways that are involved in the pathophysiology of acne. The use of the topical dapsone in acne is based on efficacy and safety data from clinical studies.[1]

The efficacy and safety of dapsone gel 5% (dapsone gel) in acne were evaluated in two double-blind, randomized, parallel group Phase 3 studies (n=3,010).1 Dapsone gel was shown to be superior to vehicle gel in achieving treatment success on investigator global assessment (P<0.001) and reducing the mean percentage of all types of acne lesions (P<0.001 at Week 12), with greatest reductions observed with inflammatory lesions (47.5% dapsone vs. 42% vehicle gel at Week 12). Dapsone gel was well tolerated in clinical trials, with adverse events comparable to vehicle gel.[1] Though the likelihood of hematologic adverse events is low, it should be noted that a case of methemoglobinemia was recently reported after therapeutic use of dapsone gel for facial acne.[9]

The pharmacokinetics of dapsone gel have not been well investigated, but Thiboutot et al[6] reported a small (n=18) open-label Phase 1 pharmacokinetic crossover study. Plasma concentrations of dapsone gel twice daily for two weeks were compared with concentrations after a single 100mg dose of oral dapsone.[2],[6] On Day 14, the mean serum AUC for dapsone gel was 415±224ng*h/mL versus 52,641±36,223ng•h/mL for the oral formulation.6 In a second study, systemic exposure was also assessed after twice-daily application of dapsone gel to acne-affected areas for up to 12 months and mean plasma concentrations ranged from 7.5 to 11ng/mL.[2],[6] Further, concentrations of both dapsone and its metabolites achieved a steady state and did not continuously increase during treatment.[6]

To the authors’ knowledge, no pharmacokinetic data have been reported regarding concentrations of dapsone on the skin or face after topical administration (in healthy volunteers or acne patients). Further, no microbiology or immunology studies were reported during dapsone gel clinical trials.[2] Thus, it is unknown whether dapsone has antimicrobial activity and whether topical dapsone could affect the normal microbiome of the skin where the drug is applied. The purpose of the authors’ study was to assess the in vitro antibiotic activity of dapsone versus various clinical Gram-positive and Gram-negative bacterial pathogens obtained from patients with infections.

METHODS

CANWARD is a national, annual, and ongoing population-based surveillance system to assess the pathogens causing infections in hospitals as well as the changing pattern of antibiotic-resistant pathogens in Canada. In this study, 15 tertiary care medical centers participated from major population centers in 8 of 10 Canadian provinces. Each study site was asked to collect and submit pathogens (one per patient) as detailed here: Isolates from patients hospitalized with respiratory tract infections (community or nosocomial) [100 consecutive pathogens]; isolates from patients with skin/skin structure infections (25 consecutive isolates); isolates from patients with urinary tract infections (25 consecutive isolates), and 10 consecutive blood stream infection isolates/month (one per patient), collected for 10 months.

Isolate identification was performed by the submitting site and confirmed at the reference site as required, based on morphological characteristics and antimicrobial susceptibility patterns. Amies semi-solid transport media containing charcoal (Difco Laboratories, Detroit, Michigan) was inoculated with the isolate and sent to the coordinating laboratory (Health Sciences Centre, Winnipeg, Manitoba, Canada), where isolates were subcultured onto appropriate media and stocked in skim milk at -70ºC until tested for susceptibility in the antibiotic panels.

Antimicrobial susceptibility was assessed using the CLSI broth microdilution method as outlined in CLSI M100-S23 (2013). Custom-made minimum inhibitory concentration (MIC) panels were prepared by the department of clinical microbiology at the Health Sciences Centre in Winnipeg, Canada. The antimicrobial agents tested were obtained as laboratory-grade powders from their respective manufacturers or commercial sources. Stock solutions were prepared as described by the CLSI (M07-A9, 2012). Dapsone powder was dissolved in either a low concentration of ethanol or hydrogen chloride (HCl) to achieve dissolution without inhibiting bacterial growth. Separate drug dilutions were made in cation-adjusted Mueller-Hinton broth (MHB), MHB with lysed horse blood (LHB), as necessary. CLSI M100-S23 breakpoints were used to interpret MIC values for all drugs evaluated in the study; however, no current breakpoints are available for oral or topical dapsone.

RESULTS

A total of 3,511 isolates were received: these came from blood 1,448 (41.2%), respiratory 1,363 (38.8%), urine 370 (10.5%), and wounds 330 (9.4%). In vitro activity of dapsone against a representative sample of Gram-negative and Gram-positive pathogens is presented in Table 1A and Table 1B. The MIC distribution of dapsone against Gram-positive and Gram-negative pathogens is presented in Table 2.

It is clear from these MIC data that with the exception of Stenotrophomonas maltophilia, dapsone demonstrates relatively poor activity versus Gram-negative bacilli with most MIC50, MIC90 in the range of 512?g/mL and >512?g/mL, respectively (Table 1A). However, dapsone demonstrated activity versus Gram-positive cocci, such as Staphylococcus spp., Streptococcus spp., and Enterococcus spp. With Staphylococcus aureus (both methicillin-susceptible S. aureus-MSSA and methicillin-resistant S. aureus-MRSA), dapsone MIC50, MIC90 were 128?g/mL and 256?g/mL, respectively, and several strains of both MSSA and MRSA demonstrated dapsone MICs of 16, 32, and 64?g/mL. For Staphylococcus epidermidis overall, dapsone MIC50, MIC90 were 128?g/mL and 256?g/mL, respectively, but several strains of S. epidermidis demonstrated dapsone MICs of 32 and 64?g/mL. Overall results with Enterococcus faecalis, dapsone MIC50, MIC90 were 256?g/mL and 512?g/mL, respectively, but several strains of E. faecalis demonstrated dapsone MICs of 8, 16, 32, and 64?g/mL. With Streptococcus agalactiae, although dapsone MIC50, MIC90 were reported overall to be 32?g/mL and 256?g/mL, respectively, several strains of S. agalactiae demonstrated dapsone MICs of 16, 32, and 64?g/mL. Lastly, for Streptococcus pyogenes, dapsone MIC50, MIC90 were 32?g/mL and 512?g/mL, respectively; however, several strains of S. pyogenes demonstrated dapsone MICs of 4, 8, 16, 32, and 64?g/mL.

DISCUSSION

Like other sulfones and sulfonamides, dapsone is active against many bacteria and protozoans.10 However, problems with drug toxicity at dosage concentrations thought to be sufficient for inhibition of common bacteria limited its use to specific indications and the literature about dapsone’s in vitro activity is quite sparse.[10] Dapsone demonstrates in vitro activity against Mycobacterium leprae and several other species of Mycobacterium.[10] However, Shen et al[11] reported that dapsone has little to no activity against rapidly growing mycobacteria (M. abscessus, M. fortuitum, and M. chelonae).[11] Activity against Pneumocystis jirovecii (formerly P. carinii) and moderate activity against Plasmodium species have also been reported.[10] Resistance has been reported in M. leprae and Plasmodium spp. and by the 1980s, rising resistance led to change in therapy away from oral dapsone monotherapy to multidrug regimens including dapsone, rifampicin, and clofazimine.

In the authors’ study, dapsone demonstrated relatively poor activity against Gram-negative bacilli with most MIC50, MIC90 in the range of 512?g/mL and >512?g/mL, respectively. In contrast, dapsone demonstrated activity versus Gram-positive cocci, such as Staphylococcus spp., Streptococcus spp., and Enterococcus spp. Several strains of both MSSA and MRSA demonstrated dapsone MICs of 16, 32, and 64?g/mL, several strains of S. epidermidis demonstrated dapsone MICs of 32 and 64?g/mL, a number of strains of E. faecalis demonstrated dapsone MICs of 8, 16, 32, and 64?g/mL, and strains of S. agalactiae and S. pyogenes demonstrated dapsone MICs of 4, 8, 16, 32, and 64?g/mL.

With the antimicrobial activity of dapsone against Gram-positive cocci listed above, it is important to relate this in vitro activity to potential dapsone concentrations achieved on the skin/face after topical dapsone application. While the dapsone gel 5% formulation is approved by the United States Food and Drug Administration (FDA) for treatment of acne vulgaris, there is an absence of pharmacokinetic data regarding cutaneous dapsone levels that are achieved after application. However, a topical dapsone 2% nanoemulsion has been reported to result in dapsone drug release from 1196 +/- 44.44?g/cm2 to 3837.34 +/- 410.87?g/cm2 over 24 hours.[12] This concentration of local dapsone skin concentrations would be expected to affect the skin flora of patients with acne, especially Gram-positive cocci, such as Staphylococcus spp., Streptococcus spp., and Enterococcus spp. These local dapsone concentrations are multiple times higher (20x–1000x) than the dapsone MICs found for many MSSA, MRSA, S. epidermidis, S. agalactiae, and S. pyogenes, which may be found on the skin, including with patients treated for acne.

Altering the normal and/or transient skin flora may potentially result in clinically relevant microbiologic changes that can create “ecologic mischief” that extends beyond specific commensal bacteria. Currently, bacteria often display a multi-drug resistant (MDR) phenotype in part due to acquisition of plasmids that codes for genes conferring resistance to a variety of chemically unrelated drug classes—the multi-drug resistant phenotype is now the norm rather than the exception. Organisms may also express efflux pumps that are non-specific for particular antibiotic molecules.

CONCLUSION

Dapsone has demonstrated antimicrobial activity in vitro. Whether this activity is part of the mechanism of action of topical dapsone in acne remains unknown. There are very sparse data in the literature about cutaneous dapsone concentrations during topical application, especially with dapsone gel 5%, which is FDA-approved for treatment of acne. However, existing data suggest skin concentrations that may be achieved after topical administration of dapsone are well above concentrations needed to achieve microbial inhibition of several pathogenic or potentially pathogenic organisms.

Application of topical dapsone gel used for treatment of acne may achieve high enough local skin concentrations of dapsone, which can inhibit the growth of and modify the normal skin microbiome (especially Gram-positive cocci, such as Staphylococcus spp. and Streptococcus spp.). Whether this results in resistance to dapsone (i.e., in Gram-positive cocci, such as Staphylococcus spp. and Streptococcus spp.) or more importantly results in resistance to chemically unrelated antimicrobials is currently unknown.

References

1. Draelos ZD, Carter E, Maloney JM, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol. 2007;56:439 e1–e10.

2. Aczone [package insert]. Irvine, CA: Allergan; 2009. 3. Sung SM , Kobayashi TT. Diagnosis and treatment of leprosy type 1 (reversal) reaction. Cutis. 2015;95:222–226.

4. Antiga E , Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Invest Dermatol. 2015;8:257–265.

5. Leoung GS, Mills J, Hopewell PC, et al. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med. 1986;105: 45–48.

6. Thiboutot DM, Willmer J, Sharata H, et al. Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris. Clin Pharmacokinet. 2007;46:697–712.

7. Seydel JK, Richter M, Wempe E. Mechanism of action of the folate blocker diaminodiphenylsulfone (dapsone, DDS) studied in E. coli cell-free enzyme extracts in comparison to sulfonamides (SA). The International Journal of Leprosy and Other Mycobacterial Diseases. 1980;48:18–29.

8. Zhu YI , Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45: 420–434.

9. Swartzentruber GS, Yanta JH , Pizon AF. Methemoglobinemia as a complication of topical dapsone. N Engl J Med. 2015;372:491–492.

10. Grayson ML, Crowe SM, McCarthy JS, et al. Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. CRC Press; 2010.

11. Shen GH, Wu BD, Hu ST, et al. High efficacy of clofazimine and its synergistic effect with amikacin against rapidly growing mycobacteria. Int J Antimicrob Agents. 2010;35: 400–404.

12. Borges VR, Simon A, Sena AR, et al. Nanoemulsion containing dapsone for topical administration: a study of in vitro release and epidermal permeation. Int J Nanomedicine. 2013;8: 535–544.

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