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Biomedical subjects

E A Eady

Publications and source records attributed to E A Eady.

At least 37 records · Page 2Linked to original sources
PubMed1997

Does oral isotretinoin prevent Propionibacterium acnes resistance?

Oral and topical 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. Propionibacterium acnes isolates resistant to one or more anti-acne antibiotics have been reported in Europe, the USA, Japan and New Zealand. Therapeutic failure on some but not all antibiotic regimens is an increasing management problem. In Leeds, UK, resistant strains are found in 60% of acne patients and 50% of close contacts. 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. Strategies to reduce the resistant P. acnes population are necessary. This paper reports preliminary data demonstrating that oral isotretinoin (Roaccutane/Accutane) significantly reduces total numbers of resistant P. acnes on the skin of all patients.

Acne Vulgaris↗
PubMed1997

Comparison of serum antibiotic levels in acne patients receiving the standard or a modified release formulation of minocycline hydrochloride.

Serum levels of minocycline hydrochloride were determined by bioassay in a total of 223 acne patients (123 male, 100 female) receiving either the recommended dose (100mg/day) or a high dose (200mg/day) of the standard preparation (101 patients) of a modified release formulation (132 patients). Sera were collected within 6 h of the morning dose 7-10 days after the start of treatment. Mean minocycline serum levels were consistently higher in females than in males, irrespective of dose or formulation. The differences only reached statistical significance (P < 0.05, Student's t-test) in the case of the standard preparation at a dose of 50 mg, b.d. Serum levels were increased significantly in both sexes at the higher dosage of each formulation (P < 0.01) but there was no significant difference between formulations at either dosage. Variation in serum concentrations was not accounted for by variation in body mass. Serum levels above the modal minimum inhibitory concentration (MIC) of minocycline for fully sensitive strains of Propionibacterium acnes I (0.125 micrograms/mL) were recorded in all patients. In contrast, serum levels equal to or greater than the modal MIC of minocycline for resistant propionibacteria (2 micrograms/mL) were recorded in only 17.9% of patients on the low dose standard preparation compared with 55.6% on the high dose standard preparation (P < 0.001, chi 2). Even in females on the high-dose modified release formulation, 32.2% had serum levels below the modal MIC of minocycline for resistant strains. We conclude that, in terms of achievable serum levels over a short time period, there is no advantage of the modified release formulation over the standard preparation of minocycline. Whichever formulation is used, dose manipulation may be necessary to achieve maximum therapeutic benefit, especially in those individuals who are colonized by propionibacteria with reduced sensitivity to minocycline.

Acne Vulgaris↗
PubMed1996

Minimal functional system required for expression of erythromycin resistance by msrA in Staphylococcus aureus RN4220.

Previous studies have suggested that inducible erythromycin (Er) resistance in staphylococci mediated by the plasmid-borne ABC-transporter msrA is dependent on additional unidentified chromosomally encoded transmembrane (TM) domains. The requirement for two S. aureus candidate sequences, stpC and smpC, highly similar to sequences adjacent to msrA on the original S. epidermidis plasmid was investigated. Deletion of the sequences by allelic replacement was accomplished by electroporation of S. aureus RN4220 with a nonreplicating suicide vector. S. aureus strains carrying a delta(stpC-smpC) mutation showed an identical ErR phenotype to those arising from single crossover events and unmutated RN4220 containing msrA. This proves that neither stpC nor smpC is required for ErR. To further define the minimal functional unit required for MSR, the control region within the leader sequence of msrA was deleted. This resulted in constitutive resistance to Er and type B streptogramins (Sg), proving that SgR does not require the presence of Er. Deletion constructs containing the N- or C-terminal ABC regions of MsrA did not confer ErR in RN4220 singly or in combination.

Anti-Bacterial Agents↗
PubMed1996

Sequential antibiotic therapy for acne promotes the carriage of resistant staphylococci on the skin of contacts.

The selection of a predominantly resistant staphylococcal skin flora in acne patients during antibiotic treatment has been extensively documented. This study sought to determine whether antibiotic therapy for acne had any effect on skin carriage of resistant coagulase-negative staphylococci (CNS) by close contacts of treated patients. Bacterial samples were obtained using a scrub wash technique from facial skin of 41 contacts (parents, siblings or partners) of patients who had been treated with at least three different antibiotics over a minimum period of 2 years. Samples were also obtained from 41 control subjects who had no known contact with any antibiotic treated acne patient. None of the contacts or controls had received any antibiotic therapy in the preceding two years. The number, percentage and prevalence of CNS resistant to each of seven antibiotics was estimated by plating serial ten-fold dilutions of wash fluid directly onto antibiotic-containing and antibiotic-free medium. Significantly more contacts than controls carried strains resistant to erythromycin, clindamycin, fusidic acid, trimethoprim and chloramphenicol as well as more multiply resistant strains (P < 0.05, chi 2). The number and percentage of staphylococci resistant to tetracycline, erythromycin, clindamycin, fusidic acid and chloramphenicol were also significantly raised (P < 0.05, Mann-Whitney U-test) in contacts. Only aminoglycoside resistance was not increased by any of the above criteria. These observations provide evidence that sequential antibiotic therapy for acne exerts selective pressure for increased skin carriage of resistant CNS not only in patients but also in their close contacts.

Acne Vulgaris↗
PubMed1996

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

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 erythromycin-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, Wilcoxon's 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 > 10(3) 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 anti-propionibacterial 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.

Acne Vulgaris↗
PubMed1995

The use of PCR to isolate a putative ABC transporter from Saccharopolyspora erythraea.

A gene (ertX) encoding a putative ABC transporter was cloned from the erythromycin producer Saccharopolyspora erythraea, using PCR. The primers were based on regions of homology from ABC transporters which confer resistance to macrolide antibiotics. While ertX encodes a protein with a strong degree of similarity to other macrolide ABC transporters from streptomycetes and staphylococci, it did not confer resistance to erythromycin, tylosin, spiramycin, oleandomycin, josamcin, chalcomycin or midecamycin when subcloned into sensitive streptomycete hosts. Southern blot analysis suggested that ertX did not constitute part of the erythromycin gene cluster as identified to date.

ATP-Binding Cassette Transporters↗
PubMed1995

Identification of a chromosomally encoded ABC-transport system with which the staphylococcal erythromycin exporter MsrA may interact.

The energy-dependent efflux of erythromycin (Er) in staphylococci is due to the presence of msr A, which encodes an ATP-binding protein. MsrA is related to the multi-component ATP-binding cassette (ABC) transporters which characteristically also contain membrane-spanning domains. Since MsrA functions in a heterologous host in the absence of other plasmid-encoded products, the requirement for a transmembrane (TM) complex might be fulfilled by hijacking a chromosomally encoded protein. Two genes, stpA and smpA, were identified upstream from msrA on the original Staphylococcus epidermidis plasmid, encoding an ATP-binding protein and a hydrophobic TM protein, respectively. Sequences highly similar to stpA and smpA (stpB and smpB) were also found adjacent to a chromosomal copy of msrA in S. hominis. In Southern blots, internal fragments of stpA or smpA hybridized to the chromosome of the Ers S. aureus RN4220. Cloning and sequence analysis of the region identified revealed the presence of two genes, stpC and smpC, related to stpA and smpA. The deduced amino-acid sequences of the gene products showed that StpA and StpC were 85% identical, whereas SmpA and SmpC were 65% identical. A gene similar to msrA was not present in the S. aureus chromosome. There was no further sequence similarity outside these conserved regions. These results indicate that the chromosomes of S. hominis and S. aureus contain sequences encoding a potential TM protein with which MsrA might interact.

Amino Acid Sequence↗
PubMed1995

In vitro modulation of keratinocyte-derived interleukin-1 alpha (IL-1 alpha) and peripheral blood mononuclear cell-derived IL-1 beta release in response to cutaneous commensal microorganisms.

The ability of a range of skin commensal microorganisms to modulate interleukin-1 (IL-1) release by cultured human keratinocytes and peripheral blood mononuclear cells (PBMCs) was investigated by a combination of enzyme-linked immunosorbent assays and bioassays. Three fractions (formaldehyde-treated whole cells, culture supernatants, and cellular fractions) were prepared from Propionibacterium acnes, Propionibacterium granulosum, Staphylococcus epidermidis, Staphylococcus capitis, Staphylococcus hominis, and Malassezia furfur serovar B. The levels of immunochemical IL-1 alpha released by cultured keratinocytes during coincubations with these microbial fractions ranged from 0 to 136 pg/ml and were maximal after 72 h. No microbial fraction consistently upregulated immunochemical IL-1 alpha release by freshly isolated keratinocytes from two donors and a transformed cell line, all of which produced the cytokine constitutively to various extents. Bioassays revealed that most of the IL-1 released was biologically inactive. In contrast, whole cells of formaldehyde-treated P. granulosum and S. epidermidis significantly stimulated release of IL-1 beta by PBMCs from three donors compared with the negative control (culture medium). Release was maximal at 24 h. Coincubation with intact cells of the yeast M. furfur significantly decreased levels of IL-1 beta below the values for the negative control by PBMCs from all three donors. There was good correlation between bioassay data and immunoassay data for IL-1 beta, and the depressive effect of M. furfur cells on cytokine production by all three cultures of PBMCs was mirrored in the levels of bioactive cytokine. This reduction in IL-1 beta release by PBMCs by M. furfur may provide an explanation why dermatoses thought to be caused by this yeast are essentially noninflammatory or only mildly inflammatory.

Humans↗
PubMed1994

Inhibition of erythromycin-resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc.

Propionibacteria resistant to high concentrations of erythromycin [minimal inhibitory concentration (MIC) > or = 0.5 mg/ml] are now commonly isolated from the skin of antibiotic-treated acne patients. This double-blind study was carried out to assess the ability of 4% w/v erythromycin with and without 1.2% w/v zinc acetate to reduce the numbers of erythromycin-resistant propionibacteria in vivo, and also to monitor the acquisition of resistant strains de novo during therapy. Under laboratory conditions, erythromycin-resistant propionibacteria were shown to be as sensitive to zinc acetate as fully sensitive strains. In vivo, the erythromycin/zinc complex and erythromycin alone produced highly significant reductions in total propionibacteria (P < 0.001) and in the number of erythromycin-resistant strains (P < 0.001 at 8 weeks). After 12 weeks, resistant propionibacteria were reacquired, or acquired de novo, by three patients treated with erythromycin alone and four patients treated with the erythromycin/zinc complex. In contrast, changes in numbers of Micrococcaceae were slight and, after 12 weeks, erythromycin-resistant strains were predominant in both treatment groups. In vitro MIC determinations suggested that this finding might be explained by the exceptionally high degree of erythromycin resistance displayed by some staphylococcal strains (MIC > 4 mg/ml) and by the relative insensitivity of all staphylococcal strains to zinc acetate. Erythromycin with and without zinc was clinically effective, and both preparations produced significant reductions in acne grade, and inflamed and non-inflamed lesion counts (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1994

Variation in comedonal antibiotic concentrations following application of topical tetracycline for acne vulgaris.

A miniaturized sensitive bioassay was used to detect tetracycline in open comedones following topical twice daily application of 0.22% tetracycline hydrochloride for a minimum of 4 weeks to the facial skin of patients with mild to moderate acne. The lower limit of detection was 4.8 +/- 0.8 ng per comedone or per 10 microliters. Using this method, 111 of 155 open comedones from 15 patients were found to contain a detectable amount of tetracycline, ranging from 1.8 to 156.9 ng per comedone, and between 4.5 and 1140.1 ng per mg comedonal material. There was a significant effect of comedone weight on tetracycline content, with smaller comedones containing proportionately more tetracycline. The Spearman rank correlation coefficient was -0.5619 (P < 0.001). All 111 comedones in which tetracycline was detected contained sufficient drug to inhibit fully antibiotic-sensitive propionibacteria. However, conditions favourable to the selection and overgrowth of highly tetracycline-resistant strains (MIC > or = 32 micrograms/ml) prevailed in at least 18.7% (29 of 155) of the comedones tested.

Acne Vulgaris↗
PubMed1994

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 propionibacteria 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.

Acne Vulgaris↗
PubMed1993

Distribution of genes encoding erythromycin ribosomal methylases and an erythromycin efflux pump in epidemiologically distinct groups of staphylococci.

Erythromycin-resistant staphylococci can be divided into two phenotypic classes based on their pattern of cross-resistance to other macrolides, lincosamides and type B streptogramins. Strains inducibly or constitutively resistant to all MLS antibiotics possess erythromycin ribosomal methylase (erm) genes, whereas strains inducibly resistant to only 14 and 15-membered ring macrolides and type B streptogramins harbour msrA, which encodes an ATP-dependent efflux pump. Dot-blot hybridization was used to study the distribution of ermA, ermB, ermC and msrA in five epidemiologically distinct groups of staphylococci. The most widely-distributed resistance determinant was ermC, which was detected in 112 (50.6%) of 221 isolates, alone in 106 isolates and in combination with a second erythromycin resistance determinant in six strains. MsrA was detected in 73 (33%) of isolates, alone in 65 and in combination with a methylase gene in eight strains. This determinant was responsible for erythromycin resistance in over one-third (36.4%) of clinical isolates of coagulase-negative staphylococci. ErmA and ermB were present in only a minority of isolates (5.9 and 7.2% of strains, respectively). The resistance determinants present in ten strains did not hybridize to any of the four probes although, in all cases, their resistance phenotype was consistent with the possession of a methylase gene. Interestingly, ermB was found exclusively in animal isolates of Staphylococcus intermedius, Staphylococcus xylosus and Staphylococcus hyicus, but not in coagulase-negative staphylococci of human origin. This determinant has previously only been found in a small number of epidemiologically related strains of Staphylococcus aureus.

Animals↗
PubMed1993

Modulation of comedonal levels of interleukin-1 in acne patients treated with tetracyclines.

To understand the basis for the anti-inflammatory activity of tetracyclines in acne, we compared the cytokine profiles [interleukin 1 (IL-1) alpha and beta, tumor necrosis factor (TNF) alpha, and IL-6] and bacterial flora of 66 open comedones removed from eleven patients before and after at least 8 weeks treatment with either tetracycline or minocycline. Pre-treatment, the only cytokine regularly recovered from comedones was bioactive IL-1 alpha-like material. The mean concentration of IL-1 alpha-like bioactivity/mg comedonal material rose from 272.0 +/- 88.6 pg to 844.3 +/- 196.7 pg following treatment (p < 0.05, Wilcoxon matched pairs). All six minocycline-treated patients showed an increase in bioactive IL-1 alpha-like material compared with three of five tetracycline-treated patients. The incidence (p < 0.001, chi 2) and concentration (p < 0.05, Wilcoxon) of immunochemical IL-beta were also raised post-treatment, although significantly more patients assigned to minocycline therapy had detectable levels of this cytokine before therapy was initiated. However, the mean concentration of IL-1 beta/mg comedonal material post-treatment was similar in both groups (72.5 +/- 23.3 pg for tetracycline-treated compared with 78.6 +/- 41.9 pg for minocycline-treated patients). The other cytokines were either absent (IL-6) or present in < 10% of comedones (TNF alpha) before and after therapy. Following treatment, only three of 11 patients showed a decrease of > or = 1 log10 in propionibacterial numbers/mg comedonal material, whereas six patients showed an increase of > 0.5 log10 in numbers of staphylococci. In eight patients, the increase or decrease in staphylococcal numbers correlated with the change in concentration of IL-1 alpha-like bioactivity. This is the first study to show an effect of antibiotic therapy on cytokine levels in vivo. Increased levels of IL-1 in comedones destined to become inflamed may enhance resolution and promote repair of the damaged follicular epithelium. Hence, these results provide further evidence of the augmentation of immune responses by tetracyclines and support the hypothesis that epidermal IL-1 plays a physiologic role in wound healing.

Acne Vulgaris↗
PubMed1993

Tetracycline-resistant propionibacteria from acne patients are cross-resistant to doxycycline, but sensitive to minocycline.

Antibiotic-resistant propionibacteria are being isolated with increasing frequency from antibiotic-treated acne patients. Minimum inhibitory concentrations (MICs) of three tetracyclines, extensively used in acne therapy, were determined for 46 resistant and 19 sensitive propionibacteria isolates. Sensitive strains were inhibited by < or = 1 microgram/ml of all three tetracyclines. For every resistant strain tested, the MIC of tetracycline exceeded that of doxycycline which, in turn, exceeded that of minocycline. The mean MIC for resistant strains was 20.61 +/- 4.56 micrograms/ml of tetracycline, 9.70 +/- 2.03 micrograms/ml of doxycycline and 1.95 +/- 0.35 micrograms/ml of minocycline. In order to determine whether these strains could be inhibited by concentrations of minocycline achievable in vivo, serum levels of minocycline were determined in acne patients receiving either the recommended dose of 50 mg b.d. (20 males, 14 females), or twice this dose (21 males, 12 females). Serum levels were significantly higher (P < 0.001, Student's t-test) in patients receiving 100 mg b.d. Males on 50 mg b.d. had significantly lower serum levels than females on the same dose (P < 0.05. Student's t-test). For all patients, the mean serum level on high-dose minocycline was 2.46 +/- 0.45 micrograms/ml, compared with 1.38 +/- 0.30 micrograms/ml on the smaller dose. These results indicate that tetracycline-resistant propionibacteria should be considered clinically minocycline sensitive, if patients who harbour such strains are prescribed 100 mg b.d. The recommended dose of minocycline for treating acne, especially in male patients, should be re-assessed.

Acne Vulgaris↗
PubMed1992

Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris.

The factors that initiate the inflammatory response in acne are not known. The presence of pro-inflammatory cytokines in acne comedones was therefore investigated. One hundred eight open comedones were collected from 18 untreated acne patients (10 male, 8 female). Each comedone was homogenized and centrifuged, and the supernatant was analyzed for bioactive and immunochemically detectable IL-1 alpha, IL-1 beta, and TNF alpha. Viable counts of propionibacteria, staphylococci, and Malassezia spp. were determined in the comedone pellet. Bioactive IL-1 alpha-like material was demonstrated in 76% of open comedones (range of 23-4765 pg IL-1 alpha-like bioactivity/mg of comedone material). In 58% of comedones, levels exceeded 100 pg/mg. There was no correlation between IL-1 alpha-like bioactivity and IL-1 alpha determined immunochemically. Bioactive IL-1 beta was not detected in any comedones. Twenty-four percent contained low levels of immunochemical IL-1 beta (range 12-103 pg IL-1 beta/mg comedone material). Bioactive TNF alpha was detected in three comedones with a further five comedones containing immunochemical TNF alpha (range of 61-820 pg TNF alpha/mg comedone material). The majority of open comedones (97%) contained microorganisms. There was, however, no significant correlation (Spearman's rank) between levels of any cytokine, in particular IL-1 alpha-like bioactivity, and numbers of microorganisms. Thus, bioactive IL-1 alpha-like material in the majority of open comedones may be concerned in the initiation of inflammation in acne following spongiosis or rupture of the pilosebaceous follicle wall.

Acne Vulgaris↗
PubMed1992

The effect of zinc and erythromycin on the growth of erythromycin-resistant and erythromycin-sensitive isolates of Propionibacterium acnes: an in-vitro study.

The effect of zinc and erythromycin on cultures inoculated with mixtures of different ratios of erythromycin sensitive (ES) and resistant (ER) Propionibacterium acnes cells was studied in vitro. Propionibacterium acnes ES outgrew P. acnes ER in the absence of erythromycin and zinc. At low levels of erythromycin ES outgrew ER, whilst the addition of 600 pg/ml zinc further reduced the growth of ER compared to ES. Growth of ER and ES were similar at levels of erythromycin near the minimum inhibitory concentration (MIC) of ES cells. Concentrations above the MIC for ES cells inhibited ES but not ER cells. At the higher concentrations of erythromycin, the addition of 96 ng/ml zinc delayed the growth of ER cells, whilst the addition of 300 micrograms/ml zinc prevented the growth of ER cells. The combination of erythromycin and zinc, at appropriate concentrations, inhibits both ES and ER.

Bacteriological Techniques↗
PubMed1992

Seborrhoea--an indicator for poor clinical response in acne patients treated with antibiotics.

The relationship between sebum excretion rate (SER) and clinical improvement was investigated in 255 acne patients treated for 6 months with either oral erythromycin (1 g/day), minocycline (100 mg/day), oxytetracycline (1 g/day) or cotrimoxazole (400 mg/day); topical therapy was 5% benzoyl peroxide. In all but the cotrimoxazole treated group, there was a significant correlation between a high SER and reduced clinical response. This was particularly evident in those patients with an SER of greater than 2.5 micrograms/cm2/min. These patients showed only 17% improvement compared with 100% improvement in those subjects with an SER of 1.0 micrograms/cm2/min or less. The presence of obvious seborrhoea in a patient who has failed to respond to an adequate 6-month course of antimicrobial therapy, should indicate the earlier rather than later use of isotretinoin for their acne.

Acne Vulgaris↗