E.A. Eady

Inducible erythromycin resistance in staphlyococci is encoded by a member of the ATP‐binding transport super‐gene family

A Staphylococcus epidermidis plasmid conferring inducible resistance to 14‐membered ring macrolides and type B streptogramins has been analysed and the DNA sequence of the gene responsible for resistance determined. A single open reading frame of 1.464kbp, preceded by a complex control region containing a promoter and two ribosomal binding sites, was identified. The deduced sequence of the 488‐amino‐acid protein (MsrA) revealed the presence of two ATP‐binding motifs homologous to those of a family of transport‐related proteins from Gram‐negative bacteria and eukaryotic cells, including the P‐glycoprotein responsible for multidrug resistance. In MsrA, but not these other proteins, the two potential ATP‐binding domains are separated by a Q‐linker of exceptional length. Q‐linkers comprise a class of flexible inter‐domain fusion junctions that are typically rich in glutamine and other hydrophilic amino acids and have a characteristic spacing of hydrophobic amino acids, as found in the MsrA sequence. Unlike the other transport‐related proteins, which act in concert with one or more hydrophobic membrane proteins, MsrA appears to function independently when cloned in a heterologous host (Staphylococcus aureus RN4220). MsrA might, therefore, interact with and confer antibiotic specificity upon other transmembrane efflux complexes of staphylococcal cells. The active efflux of [14C]‐erythromycin from cells of S. aureus RN4220 containing msrA has been demonstrated.

Antibiotic-resistant acne: lessons from Europe.

Summary Background Propionibacterium acnes and P. granulosum are widely regarded as the aetiological agents of inflammatory acne. Their proliferation and metabolism are controlled using lengthy courses of oral and/or topical antibiotics. Despite numerous reports of skin colonization by antibiotic‐resistant propionibacteria among acne patients, accurate prevalence data are available only for the U.K.

Prevalence of antibiotic‐resistant propionibacteria on the skin of acne patients: 10‐year surveillance data and snapshot distribution study

Summary Background Cutaneous propionibacteria are implicated in acne pathogenesis, although their exact role in the genesis of inflammation is still poorly understood. Agents, including antibiotics, that reduce the numbers of propionibacteria on skin are therapeutic. Resistance in the target organism is a well‐recognized consequence of antibiotic therapy for acne but formal prevalence and distribution data are lacking.

Propionibacterium acnes Resistance: A Worldwide Problem

Antibiotic therapy directed against Propionibacterium acnes has been a mainstay of treatment for more than 40 years. Despite years of widespread use of systemic tetracyclines and erythromycin, change in P. acnes sensitivity to antibiotics was not seen until the early 1980s. The first clinically relevant changes in P. acnes antibiotic sensitivity were found in the USA shortly after the introduction of topical formulations of erythromycin and clindamycin. By the late 1980s, P. acnes strains with very high MIC levels for erythromycin and elevated MICs for tetracycline were increasingly found in the UK and the USA. Mutations in the genes encoding the 23S and 16S subunits of ribosomal RNA were first identified in the UK and also seen in a recent survey from clinics in Europe, Japan, Australia and the USA. In addition, strains were found in which these known mutations could not be identified, indicating that as yet unidentified resistance mechanisms have evolved. These findings indicate the need to develop strategies to minimize the use of antibiotics in acne therapy.

Bacterial resistance in acne.

Antibiotics play a major role in acne therapy. Physicians base treatment choices on personal perceptions of efficacy, cost-effectiveness or risk-benefit ratios and rarely take bacterial resistance into account. It is well documented that resistant strains of coagulase-negative staphylococci within the resident skin flora increase in both prevalence and population density as duration of therapy increases. Acne patients represent a considerable reservoir of resistant strains of these important nosocomial pathogens which can be transferred to close contacts. Resistance in cutaneous propionibacteria has received scant attention in view of the central role of Propionibacterium acnes in inflammatory acne. Isolates resistant to one or more anti-acne antibiotics (most commonly erythromycin) have been reported in Europe, the USA, Japan and New Zealand. Carriage of resistant strains results in therapeutic failure of some but not all antibiotic regimens. In our region, skin carriage of resistant strains by 60% of acne patients and 1 in 2 of their close contacts suggests that resistant strains are widely disseminated. We are beginning to gain an understanding of those factors which encourage resistance development and can identify those patients most likely to possess resistant propionibacterial floras. Recommendations for the use of antibiotics in acne therapy to help prevent the emergence of resistance in P. acnes include the implementation of antibiotic usage policies and the encouragement of improved prescribing habits.

Phenotypic and genotypic characterization of antibiotic-resistant Propionibacterium acnes isolated from acne patients attending dermatology clinics in Europe, the U.S.A., Japan and Australia

Background Propionibacterium acnes is the target of antimicrobial treatments for acne vulgaris. Acquired resistance to erythromycin, clindamycin and tetracyclines has been reported in strains from diverse geographical loci, but the molecular basis of resistance, via mutations in genes encoding 23S and 16S rRNA, respectively, has so far only been elucidated for isolates from the U.K.

EFFECTS OF BENZOYL PEROXIDE AND ERYTHROMYCIN ALONE AND IN COMBINATION AGAINST ANTIBIOTIC-SENSITIVE AND -RESISTANT SKIN BACTERIA FROM ACNE PATIENTS

Topical formulations of erythromycin and benzoyl peroxide are popular and effective treatments for mild to moderate acne vulgaris. Use of the former is associated with resistance gain in both skin propionibacteria and coagulase‐negative staphylococci, whereas use of the latter is not. We evaluated the efficacy of a combination of erythromycin and benzoyl peroxide against a total of 40 erythromycin‐sensitive and ‐resistant strains of Staphylococcus epidermidis and skin propioni‐ bacteria in vitro. Using the checkerboard technique, five erythromycin resistant strains of Propionibacterium acnes were inhibited synergistically or additively by the combination. Complete mutual indifference was exhibited between the drugs against the remaining 35 strains. However, erythromycin resistant staphylococci and propionibacteria were inhibited by the same concentration of benzoyl peroxide as erythromycin‐sensitive strains. These results suggest that, although the combination of erythromycin and benzoyl peroxide is not synergistic against the majority of erythromycin‐resistant staphylococci and propionibacteria, the concomitant therapeutic use of both drugs should counteract the selection of erythromycin‐resistant variants and reduce the number of pre‐existing resistant organisms on the skin of acne patients.

The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin resistant propionibacteria

Summary Concomitant application of 5% w/w benzoyl peroxide and 3% w/w erythromycin has previously been shown to prevent the overgrowth, on the skin of acne patients, of crythromycin‐resistant coagulase‐negative staphylococci, which occurs when the antibiotic is used alone. Two in vivo studies were carried out to assess the ability of the same therapeutic combination to inhibit the growth of pre‐existing erythromycin‐resistant propionibacteria and to prevent the selection of resistant strains during treatment. A double‐blind clinical trial in 37 patients with mild to moderate acne vulgaris showed that the combination brought about a > 3 log10 c.f.u. reduction in total propionibacterial numbers/cm2 after 6 weeks therapy (P < 0.001, Wilcoxons matched pairs) and also significantly reduced the number of erythromycin‐resistant propionibacteria (P < 0.05). In contrast, erythromycin alone reduced the total propionibacterial count by < 1.5 log10 c.f.u./cm2 after 6 weeks (P < 0.05) and did not affect the number of erythromycin‐resistant strains. The combined formulation was significantly more effective at reducing total propionibacterial numbers at 6 (P < 0.01, Mann‐Whitney) and 12 weeks (P < 0.05) than erythromycin alone, although, after 12 weeks, the anti‐propionibacterial efficacy of both preparations was less marked. Five patients on combination therapy, and five treated with erythromycin alone, acquired erythromycin‐resistant strains de novo at week 6 or week 12. In an open study in 21 acne patients, who each carried > 103 c.f.u. erythromycin‐resistant propionibacteria/cm2 skin pretreatment, the combination of erythromycin and benzoyl peroxide reduced the total propionibacterial count by > 2.5 log10 and the number of erythromycin‐resistant strains by a similar amount (P < 0.001, Wilcoxon). This was accompanied by highly significant reductions in acne grade and lesion counts (P < 0.001). These data suggest that the combination of 5% w/w benzoyl peroxide and 3% w/w erythromycin has greater in vivo antipropionibacterial activity than 3% w/w erythromycin alone, and brings about significant clinical improvement in acne patients with high numbers of erythromycin‐resistant propionibacterial strains pretreatment.

Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne

Background  It is generally accepted that the onset of sebum secretion occurs before puberty in boys and girls as a result of increasing androgen output during the adrenarche. Propionibacteria are part of the commensal skin flora and, in adults, are found in highest numbers in sebum‐rich areas of skin such as the face and upper trunk. Previous studies investigating the association between sebum output and propionibacterial population densities have been cross‐sectional and have been carried out mainly in adults.

Short-term effects of topical fusidic acid or mupirocin on the prevalence of fusidic acid resistant (FusR) Staphylococcus aureus in atopic eczema.

Background  Staphylococcus aureus has a role in the pathophysiology of atopic eczema. Topical fusidic acid is widely used in its treatment. There is concern that topical use of fusidic acid may be driving the selection and dissemination of fusidic acid‐resistant (FusR) S. aureus.