Background
Acne is the most common dermatologic disorder in humans. It affects mostly adolescents (80%) at the age of puberty when hormonal changes begin and impacts both genders similarly. Resolution of acne begins as patients reach their twenties, nevertheless; acne persists in 54% of adult women and 40% of adult men [
1,
2]. It follows the distribution of the sebaceous glands in the body hence it forms on the face, along the jaw line (which is a common location in adults), neck, chest, and back [
3,
4]. The disease manifests as white comedons, black heads, moderate acne, or inflamed acne. The pathogenesis of acne is complicated; it develops as a result of hormonal imbalance leading to overproduction of sebum accompanied by follicular duct hyper-keratinisation. The accumulation of dead skin and fatty acids pave the way for
Cutibacterium acnes (
C. acnes) follicular enhanced colonization and the subsequent release of inflammatory mediators [
5,
6].
C. acnes, commonly known as the cause of acne vulgaris, is typically an aerotolerant anaerobic, Gram-positive bacillus that colonizes the pilosebaceous follicle, derives energy from hydrolyzing triglycerides of the sebum, and secretes fatty acid byproducts, mainly propionic acid. These byproducts can irritate the follicular wall and induce inflammation through neutrophilic chemotaxis [
7].
C. acnes promotes the abnormal proliferation and differentiation of keratinocytes as well as further sebum production. In addition,
C. acnes activate the innate immune system through the overexpression of toll-like receptors, protease-activated receptors and matrix metalloproteinase by keratinocytes [
8].
As a result of the complex pathogenicity of this condition, management is likewise diverse, including medications that control hormones, bacterial growth and the inflammatory response resulting from chemotactic factors produced by these bacteria. Control of bacterial growth is achieved by the use of antibiotics. Oral antibiotics are the standard treatment for moderate acne or for cases in which topical combinations were not tolerated or were ineffective [
9]. Systemic erythromycin and different generations of tetracyclines are known to be effective in the management of inflammatory acne [
10]. Vitamin A derivatives in the form of topical retinoids normalize the life cycle of follicles by preventing or reducing hyperkeritinization. Oral retinoid- (Isotretinoin) on the other hand, shrink the sebaceous glands, reduce sebum, cellular debris and metabolic byproducts from the surrounding skin tissue, which in turn reduces the amount of comedones produced [
5,
11].
Given that both topical and oral antibiotics against
C. acnes have been used for decades,
C. acnes resistance to used antibiotics, such as erythromycin and clindamycin has been detected with high prevalence in Mediterranean countries mainly due to antibiotic abuse. For instance, researchers from Spain reported 91 and 92.4% resistance respectively for both antibiotics. The rates of resistance in Greece were and 75.3% for both antibiotics and they were 59.5% in Italy [
12]. The increasing number of
C. acnes drug-resistant strains has provoked global concerns over the decreasing number of antibiotics that can be used to treat this common condition [
13].
Antibiotic resistance in
C. acnes can spread to other commensal bacteria colonizing the skin and the follicles such as
S. epidermidis through horizontal transfer of resistance genes [
14,
15]. Therefore, careless administration of antibiotics would not only result in emerging antibiotic resistant
C. acnes but also the spread of resistance to other bacterial species [
14].
So far, there is no available data regarding antibiotic resistance of C. acnes among Jordanians. This study aims to determine the prevalence of antibiotic resistance in C. acnes isolates from acne patients attending private and public dermatology clinics in Amman -Jordan.
Discussion
This study aimed to assess the prevalence of antibiotic resistant
C. acnes among a sample of Jordanian patients. While other studies showed that severe acne is more common in the second and third decade and may persist into their sixth decade [
4,
5,
19], 62.5% of severe pustular acne was seen between the age of 15–20 in our cohort. This might be related to hormonal changes as well as stresses that this age group undergoes due to high school/college entry exams [
20,
21], a well-known stressful period for this age group in Jordan. Moreover, the decreasing severity of acne with age is attributed to the reduction in sebaceous gland activity compared to puberty [
22]. Incidence of acne in middle-aged and older adults (above 35 yrs.) was minimal with the highest incidence being at age range between 15 and 35 yrs. (Fig.
2). This pattern of acne distribution was also demonstrated by others [
12,
16].
C. acnes was isolated from 100 samples with a recovery rate of 86.9%. Staphylococcus species, including
S. epidermidis and
S. aureus were isolated from the skin of patients harboring
C. acnes (Table
1). The presence of
Staphylococcus aureus as a transient normal flora of the skin is well documented with high carrier rates in the population [
15,
23].
S. epidermidis has been reported to aggravate inflammatory acne and an imbalance of skin commensals in favor of
S. epidermidis could aggravate inflammation of the sebaceous unit as a consequence [
16]. Claudel et al have recently reported a potential beneficial role of
S. epidermidis arguing that acne results from a disturbed equilibrium between
C. acnes and
S. epidermidis in pilosebaceous units of acne [
24].
S. epidermidis controls the proliferation of
C. acnes via the release of succinic acid, a fatty acid fermentation product, which inhibits surface Toll-like receptors of keratinocytes and tumor necrosis factor and suppresses
C. acnes-induced IL-6 [
24,
25].
Although
C. acnes are known to be very sensitive to a wide range of antibiotic classes, including clindamycin, erythromycin, and cyclines, the percentage of acne patients carrying
C. acnes strains resistant to these antibiotics is increasing worldwide and differ from one region to another [
26‐
28]. In this study all 100 patients harbored
C. acnes with varying degrees of resistance to variable antibiotics. Resistance to erythromycin and clindamycin was the highest while isolates were relatively susceptible to tetracycline (Table
2). These results are consistent with the overall resistance pattern throughout the world [
12,
28,
29].
Antibiotic resistance patterns varied between isolates. Some
C. acnes isolates demonstrated resistance to one antibiotic, others to two different antibiotics and yet a third group demonstrated multi-drug resistance towards three different antibiotics (Fig.
3). Multi-drug resistant
C. acnes was also reported recently by Zhang et al who isolated strains that were simultaneously resistant to clindamycin, erythromycin and moxifloxacin [
6].
Similarly, this pattern was also found in the staphylococcal strains isolated from the skin of patients and not from the acne lesions themselves (Fig.
3). Antibiotic resistance patterns between isolates from the same patient have shown similarity (Table
3). Multiple resistances often included resistance towards erythromycin and clindamycin. Cross-resistance between erythromycin and clindamycin is thought to be due to the presence of the erm(X) resistance gene that confers resistance to Macrolide, Lincosamide and Streptogramin B (MLS) group of antibiotics [
30]. This explains the similarity in antibiotic resistance patterns between isolates from the same patient suggesting gene- transfer between species
. S. epidermidis ability to transfer genes via plasmids to other more pathogenic staphylococcal species has been documented [
3].
Most
C. acnes isolates were resistant to the major five antibiotics (erythromycin, clindamycin, doxycycline, trimethoprim / sulfamethoxazole, and tetracycline). However, 97 and 85% of isolates were susceptible to minocycline and levofloxacin respectively (Table
2). Minocycline and levofloxacin are not used frequently in Jordan due to cost. Minocycline’s side effect profile also includes irreversible slate-grey hyper pigmentation of the skin and the development of lupus-like syndrome which both make it a less commonly used agent for the treatment of acne [
31]. The high susceptibility rates towards minocycline and levofloxacin accompanied with high resistance rates towards other antibiotics highlights the excessive use/abuse of the latter antibiotics. The high resistance rates towards erythromycin, clindamycin and doxycycline are similar to previously published reports and mirror the antibiotic-use history for the studied patients (Fig.
5). The presence of such resistant strains could explain the clinical unresponsiveness of these patients as well as the high relapse frequency.
It has been previously demonstrated that the use of topical antibiotics in acne results in antibiotic resistance if used for long periods (more than 8 weeks) [
5,
32,
33]. Similarly, 21% of
C. acnes resistance to clindamycin and erythromycin in our study was detected in isolates from patients who used topical antibiotics (results not shown).
In contrast to the majority of patients visiting the public dermatology clinics, patients attending private clinic were previously treated with antibiotics for acne management. This is reflected in the distribution of resistant
C. acnes isolate. Private clinic patients showed a higher percentage of resistant
C. acnes than public clinic patients (Fig.
4). This pattern of distribution of resistant strains was not restricted to
C. acnes but extended to
S. epidermidis and
S. aureus (Fig.
6). Thereby, we could correlate prior consumption of antibiotics with higher resistance patterns observed amongst private sector patients. Significant correlation was found between previous antibiotic administration with the prevalence of C
. acnes resistant strains [
34].
Thirty-nine percent of the patients in this study did not receive prior antibiotic treatment, while (61%) of patients received prior antibiotic therapy with mean treatment duration of 6 ± 2 weeks (Fig.
5). All non-previously treated patients carried antibiotic resistant strains, similarly to previously treated ones, indicating that antibiotic resistant strains are circulating and are emerging not only from acne treatment but also as a result of antibiotic use in treatment of other diseases.
The presence of antibiotic resistance in the normal flora of outpatients highlights the possibility of community spread of antibiotic resistant strains through horizontal transfer. In accordance with previous studies, the relationship between resistance and history of antibiotic use remains debated and resistance to antibiotics could be mainly acquired due to contact-mediated spread of resistant
C. acnes [
6,
35].
Comparing the resistance status of
C. acnes in Jordan to that in other countries; resistance in Jordan was above average for erythromycin, clindamycin, and doxycycline, and almost similar in the case of minocycline. Such results indicate that the frequent use of certain antibiotics has led to the emergence of resistant strains in comparison to minocycline that is not used as much. Outside of acne, erythromycin and clindamycin are commonly used antibiotics. Erythromycin is used in the treatment of upper respiratory tract infections caused by
M. pneumoniae, Legionella species, beta-hemolytic streptococcus, and
Streptococcus pneumoniae. Clindamycin is bactericidal to most non enterococcal gram-positive aerobic bacteria and many anaerobic microorganisms and is considered an excellent alternative to beta-lactam antibiotics for treatment of many staphylococcal infection [
36]. The co-existence of
C .acnes resistant strains with a similar resistance pattern indicates the likelihood of horizontal transfer of antibiotic resistance genes across different bacterial species as noted earlier.
In conclusion, our study demonstrates that the prevalence of C. acnes antibiotic-resistance in Jordan is above average compared to other countries. We showed higher resistance of C. acnes isolates to erythromycin and clindamycin and intermediate resistance to tetracycline, doxycycline, and trimethoprim/sulfamethoxazole. Furthermore, we demonstrated the presence of multi-drug resistant C.acnes strains in outpatients in Jordan. Levofloxacin and minocycline demonstrated the best in-vitro activity against the C. acnes isolates. Finally, S. aureus and S. epidermidis was also isolated from acne patients and demonstrated a similar antibiotic resistance pattern to C. acnes.
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