Clindamycin: A Comprehensive Status Report with Emphasis on Use in Dermatology

Abstract

Clindamycin is a lincosamide antibiotic that has been used as a topical, oral, or injectable formulation for over five decades. It exhibits a narrow spectrum of microbiologic activity, primarily against gram-positive and anaerobic bacteria. In dermatology, clindamycin has been used primarily as a topical agent, usually for the treatment of acne vulgaris. Despite questions surrounding antibiotic resistance and/or its relative contribution to antibiotic treatment efficacy, a large body of data support the therapeutic value of topical clindamycin for acne vulgaris. As a systemic agent, clindamycin is used orally to treat a variety of cutaneous bacterial infections, and sometimes for acne vulgaris, with oral treatment for the latter less common in more recent years. The modes of action of clindamycin are supported by data showing both its anti-inflammatory and antibiotic mechanisms, which are discussed here along with pharmacokinetic profiles and structure-activity relationships. The diverse applications of clindamycin for multiple disease states, its efficacy, and safety considerations are also reviewed here, including for both topical and systemic formulations. Emphasis is placed on uses in dermatology, but other information on clindamycin relevant to clinicians is also discussed.

Clindamycin, a semisynthetic lincosamide antibiotic derived from Streptomyces lincolnensis, is a derivative of the naturally occurring antibiotic lincomycin, essentially replacing the latter due to augmented antibacterial activity and increased gastrointestinal tract absorption after oral administration.1 First synthesized in 1966, clindamycin has remained on the list of commonly prescribed antibiotics for almost six decades, due to its diversity of clinical applications and the progressive availability of oral, injectable, and topical formulations for multiple indications.2–4 Clindamycin is highly relevant to many medical disciplines, including dermatology. Its journey over time expanded from (i) a systemic agent “indicated in the treatment of serious infections caused by susceptible strains of designated organisms” infecting a variety of organ systems, to later encompass dermatologic uses either as a topical and/or systemic formulation for (ii) acne vulgaris (AV), (iii) uncomplicated skin and soft tissue infections (USSTIs), (iv) multiple “off label” uses (especially by topical application), and (v) gynecologic use for bacterial vaginosis.2–7 Although utilization for AV has often focused on clindamycin topically, oral clindamycin is still commonly used in the outpatient setting for treatment of AV and a variety of infectious diseases, including skin infections; the latter loosely captures disease states where a role for bacteria is suspected clinically, such as folliculitis, furunculosis, and hidradenitis suppurativa (HS).1,4 Due to the overall perception of its diverse therapeutic value and based on some publications, clindamycin is also sometimes used “off-label,” usually via topical application, for a variety of dermatologic disorders based primarily on case reports and/or limited study data, such as rosacea, perioral dermatitis, erythrasma, pitted keratolysis, progressive macular hypomelanosis, hidradenitis suppurativa, and others.8–15 Strong support for efficacy in these “off-label” conditions is usually limited and often based on older reports without more recent publications evaluating each use.8–15 Ultimately, use of clindamycin for “off-label” skin conditions is guided by individual anecdotal experience, which can have merit, despite lack of high level study-based evidence.

Clindamycin was initially approved by the United States (US) Food and Drug Administration (FDA) in 1970 as an oral formulation for systemic treatment of a variety of infections.6,7 Subsequently, after years of extemporaneous compounding of clindamycin to topically treat AV, clindamycin was approved by the FDA as a brand topical solution for AV prior to January 1, 1982, with subsequent brand approval of a topical gel (1987), and a topical lotion (1989), approved for twice-daily application for AV.5,16–18 Additional FDA approvals for AV followed with brand topical formulations approved for once-daily application, including a topical gel (2000) and a topical foam (2004); subsequent approval of generic topical formulations for AV emerged over time and are available today.16,19,20 Variations designed for delivery of the topical solution for AV have also been marketed in the US, including single-application pledgets and swabs. In addition to the oral and topical (for cutaneous use) formulations of clindamycin, a sterile solution for intravenous and intramuscular administration, and a suppository (ovule) and cream for vaginal application are available for their respective indications.16 Last but not least, clindamycin is also available in fixed-combination topical formulations, FDA-approved for AV, including benzoyl peroxide (BPO)-clindamycin, clindamycin-tretinoin, and BPO-clindamycin-adapalene.3,16

II. WHY CLINDAMYCIN AND WHY NOW?

Why are we taking a closer look at clindamycin, with emphasis on clinical use in dermatology? A few important reasons exist. Firstly, since its discovery in 1966, clindamycin still remains on the World Health Organization List of Essential Medicines, and in 2020 clindamycin ranked as the 125th most commonly prescribed medicine in the US.21,22 Data collected over the years 2013 through 2020 reported that between 4 million and 6 million total prescriptions for clindamycin were recorded each year, with between 2 million and 4 million patients treated per year with clindamycin. From this same database, the distribution of dosage forms prescribed in 2020 were 59.7% for oral capsules (300mg [39.0%], 150mg [20.7%]) and 36.6% for topical formulations (for cutaneous use).22 A second important reason is that dermatologists as a group are high prescribers of both oral and topical antibiotic therapy.23,24 Among individual types of physicians, dermatologists are the most common prescribers of antibiotics per clinician, with utilization of both oral and topical formulations.23–25 Although tetracyclines comprise the majority of oral antibiotic prescriptions written by dermatologists (~73%), primarily for AV, other antibiotics such as oral and topical clindamycin are also commonly prescribed for AV.23,24 The frequent prescribing of antibiotic therapy in dermatology, especially for prolonged durations for chronic disorders such as AV, warrants the need to address antibiotic resistance concerns and responsible antibiotic use (known as antibiotic stewardship).23–26 Additionally, there is desire among the public for more education to be provided and discussed regarding therapeutic options that can avoid or mitigate antibiotic resistance.27 Third, there has been limited attention given to exploring in more detail the molecular mode(s) of action of clindamycin, the functional impact of structure-activity relationships, potential biologic properties beyond antibiotic activity, and the continued clinical relevance of clindamycin in dermatology which this article intends to comprehensively address based on currently available information.4,28

The goal of this article is to provide a very thorough, updated review of clindamycin based on the fundamentals of its pharmacology, molecular mode(s) of action, molecular structure, microbiologic activity, anti-inflammatory properties, antibiotic resistance considerations, clinical efficacy and safety considerations with emphasis on topical use for AV, new information of interest especially to clinicians, and areas where further research studies are needed. We searched the PubMed database for peer-reviewed articles and clinical studies using the following terms: clindamycin, resistance, acne, minocycline, triple combination therapy, mechanism of action, and ribosome. Two of the authors (JDR, CGB) also contributed additional reference sources from their own database and knowledge of the subject area. It is our hope that this article will serve as a strong resource to anyone interested in understanding clindamycin use in dermatology, especially as a topical agent used for AV.

III. PHARMACOLOGY OF CLINDAMYCIN INCLUDING VEHICLE FORMULATION CONSIDERATIONS

Clindamycin is well-absorbed after oral administration with or without food, exhibits wide tissue distribution, and undergoes primarily hepatic metabolism, with a plasma half-life of 2.4 to 3.0 hours in adults and 2.5 to 3.4 hours in children with normal renal function.1,4 There is a modest increase in plasma half-life in adults with severe renal or hepatic failure, with dosage adjustment recommended in patients with severe impairment of liver function.4

All topical formulations of clindamycin are generally considered to exhibit equivalent efficacy for AV, although there may be differences in skin tolerability primarily related to individual vehicle characteristics.3 Two studies have demonstrated the presence of clindamycin within comedones at similar concentration levels after application of either clindamycin hydrochloride or clindamycin phosphate, providing some indirect support, albeit limited, for similar efficacy independent of the salt form used.29,30 An average of 4% to 5% of topically applied clindamycin hydrochloride 1% is reported to be systemically absorbed over 27 days of application, with some individuals exhibiting markedly greater systemic levels based on urinary clindamycin concentrations, and with no correlation with acne severity or skin color.31 Importantly, an evaluation of the effect of 14 different vehicles on the percutaneous absorption and bioavailability of topically applied clindamycin hydrochloride showed some differences in the ability to effectively solubilize clindamycin, with a water concentration of at least 20% or the presence of a “suitable cosolvent” required for adequate clindamycin solubilization; percutaneous absorption among the tested vehicles varied over a range of 0.7%to 12.9% of the applied dose in 24 hours.32 Specific penetration enhancers were noted to increase percutaneous penetration, permeation, and absorption of clindamycin, with some of the penetration enhancers potentially altering the skin tolerability profile of the final product. Among the 14 vehicles studied, there was a hundred-fold variability in clindamycin bioavailability; this information coupled with data suggesting a relationship between clindamycin bioavailability and clinical efficacy for AV argues against extemporaneous compounding of clindamycin in the absence of bioavailability data.32 Over time, multiple advances in vehicle formulation technology have improved delivery of active ingredients, skin tolerability, and efficacy for AV, allowing for development of fixed-dose combination products that contain one or more active ingredients that could not previously be combined.33 Clindamycin is one of the active ingredients that is often combined with other active ingredients, such as benzoyl peroxide (presumably for both bactericidal activity and ability to reduce antibiotic resistance) and/or a topical retinoid (e.g., tretinoin, adapalene), in some of the FDA-approved fixed-dose topical combination formulations for AV.3,16

Structural characteristics that may contribute to specific pharmacologic and antibiotic activity patterns of lincosamides including clindamycin, and factors influencing antibiotic resistance, have been described in the literature.34,35 Evaluations which have included the crystal structures of the large ribosomal subunit of S. aureus in complex with individual lincosamides appear to provide a more complete understanding of targeted drug selectivity and the potential impact of different drug-specific chemical moieties that affect drug binding and inhibitory effects on bacterial proliferation.34 It has also been reported that resistance to clindamycin can impart resistance to macrolides if the erm-coded enzymes are constitutively expressed.4 Many of these important aspects related to clindamycin are covered below in other sections of this article.

IV. ANTIBIOTIC MECHANISMS OF ACTION OF CLINDAMYCIN

The primary mechanism of action of clindamycin is to inhibit protein synthesis by the bacterial ribosome. In the treatment of AV, this means targeting and inhibiting the the Cutibacterium acnes (C. acnes) ribosome. Despite decades of antibiotic therapy for AV, only in 2023 was the molecular structure of the C. acnes ribosome determined.36 The cryo-electron microscopy structure of the 70S C. acnes ribosome was determined in the presence of sarecycline, a narrow-spectrum tetracycline-derived antibiotic used to treat AV. To date, there is not an experimentally determined structure of the C. acnes ribosome bound to clindamycin published—a knowledge gap for understanding species-specific antibiotic function. However, due to the high sequence and structural conservation among bacterial ribosomes, other ribosome structures bound to clindamycin suffice to guide our molecular understanding.

The 70S bacterial ribosome comprises two major subunits: the 30S small and 50S large ribosomal subunits. The 30S subunit houses the decoding center, where messenger RNA (mRNA) codons are “read” by transfer RNAs (tRNAs) through codon: anti-codon pairing in the “A-site.” The information at the decoding center is translated into a growing amino acid chain (protein) via P-site tRNAs at the peptidyl transferase center (PTC), which is housed in the 50S subunit. Additionally, extending from the PTC to the exterior of the 50S subunit is a tunnel, termed the nascent peptide exit tunnel (NPET). The growing polypeptide chain extends into, through, and out of the NPET; however, clindamycin and another class of antibiotic used in AV, the macrolides (e.g., erythromycin), both inhibit the 50S subunit by binding to adjacent and partially overlapping cavities at the PTC and proximal NPET, respectively, where new amino acids are added to the growing protein. When clindamycin or another antibiotic occupies this PTC or proximal NPET region, through molecular contacts with 23S rRNA, it inhibits bacterial ribosome function. Unexpectedly, the cryo-electron microscopy structure of sarecycline identified a second binding site for this drug in the proximal NPET adjacent to, but not overlapping with, the clindamycin and erythromycin binding sites (Figure 1). The canonical binding site for tetracycline antibiotics (e.g., tetracycline, doxycycline, minocycline, sarecycline) is in the 30S decoding center “A-site” through molecular contacts with 16S rRNA. Therefore, the structural mechanism of action of clindamycin is distinct from tetracyclines, but has similarities to macrolides. For more details regarding the clindamycin-RNA interactions within the bacterial ribosome, please see our scientific-focused review on the subject.37 The secondary mechanism of action of clindamycin, after inhibiting protein synthesis, is the reduction of bacterial proteins and enzymes involved in AV pathogenesis and/or inflammation of the pilosebaceous unit (see Section VI).

FIGURE 1.

Clindamycin interactions with the 70S ribosome differ from other antibiotics. Clindamycin (CLI, green) sarecycline (SAR, gold) and erythromycin (ERI, blue) are shown as balls (top) or sticks (bottom). The molecular surface of the 70S ribosome subunits are shown in red (30S) and blue (50S) (top), with the decoding center (DC) and the peptidyl transferase center (PTC) shown in each subunit, respectively. P-site (P)-bound tRNA is colored gray; A is the location of A-site and E the exit site of the ribosome. The binding sites of sarecycline (SAR1 in 30S and SAR2 in 50S) and clindamycin (50S) are depicted, with the nascent polypeptide exit tunnel (NPET) masked in blue. Messenger RNA (mRNA) is in purple at the DC. The bottom panel shows the NPET depicted as a gray molecular surface, with the different binding locations of three antibiotics shown: CLI, ERI, and SAR2. Superposition of models with Protein Data Bank IDs 8CRX, 4V7V and 7NSO and PyMOL Version 2.0 were used to make this figure.38

V. ANTIBIOTIC PROPERTIES AND CLINICAL USES OF CLINDAMYCIN

Overview of properties. At the inception of its use, systemic clindamycin was commonly used to treat bacterial infections caused by staphylococci and streptococci, including pneumococci.7,39 Clindamycin, reported to be bacteriostatic, also exhibits activity against a wide spectrum of anaerobic bacteria, including Clostridium perfringens and Bacteroides spp, although clindamycin resistance in the latter has experienced a notable increase over time.4 As resistance patterns to individual antibiotics change over time, and vary depending on relative usage patterns of antibiotics in specific communities, it is important for clinicians to be aware of current and changing patterns in their regional areas of practice, information that can be obtained from the reference microbiology laboratories they utilize for culture and sensitivity testing. Through to today, systemic clindamycin remains a viable option for many ambulatory and hospital-based infections.4,35,39–41 The majority of aerobic gram-negative bacteria, including Pseudomonas spp and Hemophilus influenzae, are innately resistant to clindamycin, apparently due to poor organism penetration by the drug.4 Clindamycin’s poor activity against gram-negative bacilli like E. coli, in particular, is one reason it is incorrect to classify it as a “broad-spectrum” antibiotic. Some protozoa, such as Toxoplasma gondii, may be inhibited by clindamycin.

Use for acne vulgaris. The use of clindamycin in dermatology is ubiquitous, with topical therapy being the predominant focus for treatment of AV over the past several years, supported by FDA approval.4,22,23,40,42–48 With regard to AV treatment, C. acnes (formerly Propionibacterium acnes) may be susceptible to clindamycin, with susceptibility exhibiting some decrease over time, likely related to widespread use both topically and systemically in the US and in some other countries, with some regional differences noted globally.23,42,43,45,46,48

An in vivo study assessed the antibiotic activity of clindamycin 1% gel applied once daily for six weeks in subjects with facial AV.45 Greater C. acnes reductions were documented in subjects with clindamycin minimum inhibitory concentrations (MICs) of ≤256 μg/mL than in those with clindamycin MICs ≥512 μg/mL (P=0.0001). These outcomes support that topical clindamycin produces variable in vivo antibiotic activity against C. acnes, with an observed MIC breakpoint of 256 μg/mL that separates the relative magnitudes of C. acnes reduction. It was also noted that topical clindamycin appeared to be more clinically effective in vivo in patients with MIC levels of ≤256 μg/mL as compared to higher MIC levels.45

Analyses of clinical studies evaluating the efficacy of topical antibiotics used to treat AV from 1977 through 2002 showed a marked reduction in the efficacy of erythromycin with both inflammatory and comedonal lesion counts (P=0.001 and P=0.001, respectively), likely due to the widespread prevalence of high level C. acnes resistance to erythromycin.23,49 AV lesion count reductions with topical clindamycin had remained more stable since the mid-1970s over that same 25-year duration of time.49 This may be due at least partially to the greater in vitro variability in susceptibility of C. acnes based on MICs (as described above), although approximately two-thirds of individuals are likely to have facial skin colonized by clindamycin-resistant C. acnes.23 The possibility of anti-inflammatory properties of clindamycin exerting effects that improve AV has been discussed in the literature and will be addressed in more detail below.28 Additional and subsequent randomized and controlled clinical trials published between 2000 and 2008, inclusive of approximately 2000 subjects actively treated with topical clindamycin in monotherapy study arms, consistently demonstrated reductions in inflammatory and non-inflammatory (comedonal) lesions ranging from 45% to 49%, and from 30% to 41%, respectively.44 On the basis of these controlled clinical trials, and a more recent Phase II clinical study published in 2021, topical clindamycin appears overall to sustain clinical efficacy for AV over time.44,50

From a skin tolerability perspective, clindamycin monotherapy is generally well-tolerated, especially with vehicles that limit excipients that are drying or inherently irritating.44,51 When combined with other topical agents such as tretinoin or benzoyl peroxide, clindamycin is not typically a major contributor to reported application site reactions.50–53 Systemic safety of both systemic and topical clindamycin are discussed later in this article.

Importantly, there are factors other than the magnitude of antibiotic exposure and results from in vitro antibiotic testing methods that may influence the therapeutic effects of a drug such as clindamycin for both AV and other indications. These include biologic properties other than in vitro antibiotic activity, various antibiotic resistance mechanisms (i.e., encoded genes, cell envelope alterations, efflux pumps, biofilms), binding site characteristics, and other structure-activity relationships.23,35 For example, resistance to clindamycin may be imparted by methylation of 23S ribosomal RNA, modification of clindamycin by specific enzymes, and active transfer of clindamycin out of the bacterial cell by efflux pumps.35

With regard to the treatment of AV, use of antibiotic therapy as monotherapy, including topical clindamycin, is not recommended when treating AV due to antibiotic resistance concerns. Optimally, topical clindamycin is best combined within a formulation that also contains BPO, as the latter reduces the emergence and progression of both new and pre-existing C. acnes strains.1,25,26,45-51

Use for rosacea. Data are limited on the utilization of topical clindamycin for rosacea, with very little current support for its use for this indication in consensus recommendations and other publications.11,54–57 The cogent arguments against using topical clindamycin for rosacea are as follows: limited published evidence supporting favorable efficacy, especially as monotherapy, the inevitable “ecologic mischief” that occurs with both short-term and prolonged durations of repeated application (increased exposure leading to emergence of antibiotic-resistant bacteria), the availability of multiple other effective topical therapies for rosacea that are well-supported by an extensive body of scientific evidence, and the lack of an identified causative bacterium shown to contribute to rosacea pathophysiology that may be targeted by clindamycin.11,23,54–63 Topical clindamycin is best avoided as a therapeutic option for rosacea for the above reasons; oral clindamycin is not suggested as either a primary or alternative option for treatment of rosacea when one weighs the potential risks versus benefits, primarily due to concerns regarding antibiotic resistance and antibiotic-associated colitis.4,11,54–57,60

Other non-antibiotic dermatologic uses. As stated above, clindamycin is sometimes used “off-label,” primarily by topical application, for dermatologic disorders such as rosacea, perioral dermatitis, erythrasma, pitted keratolysis, progressive macular hypomelanosis, hidradenitis suppurativa (HS), and others.8–15 Strong support for efficacy in these skin disorders is usually limited and based primarily on older reports with a conspicuous absence of additional cogent data in more recent publications.64 In treatment of HS, oral clindamycin 300mg twice daily is often combined with rifampin 300mg twice daily (or 600mg once daily) for moderate to severe HS; this regimen achieved a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) rate of 48.2% at Week 12 compared to 40.1% for oral tetracyclines65 (doxycycline and minocycline dosed 100mg once daily). Due primarily to concerns regarding emergence of antibiotic resistant bacteria, prolonged administration of antibiotic therapy is not generally recommended, especially for a chronic skin disorder such as HS.

Dermatologic infections. Oral clindamycin is commonly used for the treatment of multiple clinical presentations of USSTIs, primarily caused by staphylococci, and in some cases streptococci; these include folliculitis, cellulitis, furunculosis, abscesses, impetigo, and ecthyma.4,64 Where indicated, systemic clindamycin remains a viable option for patients who are allergic to penicillin (as often arises in surgical considerations), and for treatment of some cutaneous, subcutaneous, and systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA), although not often as a primary choice for MRSA, including for community-acquired infections, due to pre-existing clindamycin-resistant MRSA organisms or the development of MRSA strains that rapidly acquire resistance to clindamycin shortly after starting therapy.1,4,35,40,64 Systemic clindamycin may also be used to treat deep soft tissue infections, such as necrotizing fasciitis, streptococcal myositis, and infections caused by C. perfringens, and as part of a combination regimen used to treat infected diabetic foot ulcers.4

The most common cutaneous presentations of USSTIs caused by MRSA are abscesses, cellulitis, and sometimes folliculitis.64,66,67 Importantly, with abscesses caused by S. aureus including MRSA strains, oral antibiotic therapy such as with clindamycin is adjunctive to incision and drainage which is the primary therapy needed to resolve the abscess.64,68 Systemic clindamycin can also be used to treat some S. epidermidis infections, but the presence of clinically relevant resistant strains to clindamycin should generally be excluded via culture and sensitivity testing before administration of clindamycin.41

Gynecologic and obstetrical infections. A sometimes forgotten area where clindamycin is used is in the fields of gynecology and obstetrics. Clindamycin may be used either topically via vaginal mucosal application, or orally, for bacterial vaginosis, and is also used to treat perinatal infections caused by group B streptococci (GBS).69 Perinatal streptococcal infections may be associated with serious morbidity, developing when GBS, which asymptomatically colonize the lower genital tract of almost 20 percent of females, ascends the genital tract in some cases to become an invasive pathogen associated with preterm birth, stillbirth, and fetal injury.70,71 Invasive GBS infections in pregnancy can result in vertical transmission to the neonate during or after birth resulting in life-threatening neonatal infections, such as pneumonia, sepsis, and meningitis.70 Hence, measures to preserve the antibiotic susceptibility of GBS to clindamycin is an important goal.

VI. ANTI-INFLAMMATORY PROPERTIES OF CLINDAMYCIN

Historically, most of the attention related to use of clindamycin for AV has focused on antibiotic activity against C. acnes.1,3,72 However, similar to what has been noted with tetracyclines, clindamycin has been reported to exhibit several anti-inflammatory properties unrelated to its antibiotic effects.28 The correlation between the individual anti-inflammatory effects of clindamycin and their potential contributions to therapeutic activity for AV are not fully understood. Nevertheless, this is no different than with many other agents used for AV treatment, where anti-inflammatory effects are proposed to contribute, at least partially, to their therapeutic effects, including tetracyclines, topical retinoids, and macrolides. Some anti-inflammatory effects of clindamycin occur secondary to its antibiotic activity with reduction in C. acnes, as this organism has been correlated with several mechanisms involved in AV pathophysiology and lesion development.72–74 Over time, reductions in colony counts of C. acnes have been directly correlated with clinical improvement in AV with use of several antibiotics and/or benzoyl peroxide.1,3,45,46,72,75

Table 1 collectively summarizes the reported anti-inflammatory effects of clindamycin.28 Clindamycin possesses several commonalities with tetracyclines with regard to anti-inflammatory effects.76–79 First, both clindamycin and tetracyclines decrease pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Clindamycin also reduces IFN-γ, while tetracyclines reduce IL-8. Second, both clindamycin and tetracyclines reduce reactive oxygen species thereby limiting oxidative stress and damage. Furthermore, they both inhibit nitric oxide synthase, providing another mechanism for reducing oxidative damage. Third, clindamycin and tetracyclines share the capacity to inhibit C. acnes lipase production. Tetracyclines further possess abilities to inhibit matrix metalloproteinases, mast cell activation, and T-cell activation and proliferation; further research is needed to clarify if clindamycin also can inhibit these pro-inflammatory mechanisms.

TABLE 1.

Anti-inflammatory properties of clindamycin

PROINFLAMMATORY FACTORS AND COMPONENTS	STUDY TYPE		INHIBITS		ENHANCESa
	ACNEb	OTHER	YES	NO	YES	NO
Cutibacterium acnes growth	X126		X126
C. acnes protein synthesis (50S ribosomal subunit binding)		X121,125	X121,125
C. acnes lipase production	X127		X127
C. acnes and the release of follicular free fatty acids	X119,128		X119,128
Proinflammatory Chemokines (Attractants)
C. acnes release of leukocyte chemotactic components	X120,123,129,130		X120,123,129,130
IL-8	X122,c			X122,c
Phagocytosis
Opsonization of bacteria for enhanced phagocytosis		X131–134			X131–134
Enhances and potentiates phagocytosis		X131,135,136			X131,135,136
Respiratory burst (ROS as 02-, H202)		X137,138	X137,138
iNOS enzymes		X139	X139
Protein kinase C enzyme/granuloma formation	X140			X140
Proinflammatory cytokines (primarily monocytes)
IL-1a	X122,c			X122,c
IL-1 B	X122,d	X141–143	X122,141–143,d
IL-6	X122,c,e		X122,c,e
IL-12070	X122,d			X122,d
IFN-y	X122,d		X122,d
TNF-a	X122,d	X139,141–144	X139,141–144	X122,d
Keratinocyte Cytokines (Stimulants)
GM-CSF	X122,c,e		X122,c,e

Abbreviations: ROS, reactive oxygen species; O₂-, superoxide; H²⁰², hydrogen peroxide; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-y; TN-α, tumor necrosis factor α; GM-CSF, granulocyte-macrophage colony-stimulating factor.

a: In several instances, clindamycin can actually enhance rather than inhibit a process associated with inflammation. These enhancements can actually be beneficial therapeutically and therefore can be ranked as anti-inflammatory in nature.

b: Acne related based on available understanding of inflammatory mechanisms involved in pathogenesis.

c: From human keratinocytes activated by heat-killed C. acnes.

d: From human monocytes activated by heat-killed C. acnes.

e: Inhibits at high concentration; however, the investigators suggest that the high concentration of clindamycin used "may be achievable in acne lesions after single topical application..."122

Table adapted with permission from Cutis. 2010;85;15-24.28

Many articles have been published that discuss several anti-inflammatory effects of clindamycin, and have been reviewed and referenced collectively in detail elsewhere.28 The anti-inflammatory properties noted with clindamycin that potentially relate to therapeutic activity for AV are primarily immunomodulatory cascades that involve the inhibition of cytokines that promote innate inflammatory responses. Although it is not fully understood which of these anti-inflammatory properties are operative in AV pathophysiology, or the relative magnitudes of their positive contributions to AV therapy, “...the net effect of these anti-inflammatory properties suggest that the efficacy of clindamycin in acne treatment is not likely related to antibacterial activity alone”.28 When one considers that the efficacy of clindamycin for AV has been sustained for approximately five decades, despite decreased sensitivity of some C. acnes strains over time, one cannot discard the concept that anti-inflammatory effects of clindamycin contribute, at least partially, to its therapeutic effectiveness for AV.28,44,49,80–82

VII. CLINDAMYCIN ANTIBIOTIC RESISTANCE MECHANISMS, PATTERNS, AND IMPLICATIONS

Antimicrobial resistance (AMR) is a global concern. A recent systematic analysis83 published in Lancet examined the worldwide problem of AMR in 2019. The study found that 4.95 million deaths were associated with bacterial AMR, while 1.27 million deaths could be directly attributable to bacterial AMR. While the highest burdens were found in “lower resource” areas of the globe, the data signals a larger problem of increasing AMR and its impact on human health. Given that S. aureus was one of the top six organisms leading to AMR-related deaths, it is prudent to examine clindamycin, which can treat S. aureus infections, further as it relates to clindamycin-specific AMR.

In relation to AV, 79% of C. acnes strains were resistant to clindamycin in 1983 in the United States; for comparison, at the same time 81% of C. acnes strains were resistant to erythromycin and 57% to doxycycline.84 While more recent data from the United States is lacking, and this represents a major unmet need to understand the evolution of AMR among AV-treated patients in the US, there is 2020 data on AMR in C. acnes from Jordan and Israel. In Jordan, 59% of C. acnes isolates were resistant to clindamycin, compared to 3% to minocycline, 37% to doxycycline, and 73% to erythromycin.85 In Israel, 16.7% of C. acnes isolates were resistant to clindamycin, whereas 11.1%, 19.4%, and 25% were resistant to minocycline, doxycycline, and erythromycin, respectively.86 A study examining C. acnes AMR in AV patients in Japan from 2013 to 2018 identified ~40% of strains were resistant to clindamycin.87 Importantly, the Japan study demonstrated that C. acnes resistance patterns can change depending on the prescribing habits and usage of antibiotics by doctors and AV patients. This potential for AMR reduction through changes in medical practice underlies the concept of antibiotic stewardship.

C. acnes, and other bacteria, acquire resistance to clindamycin through several direct and indirect mechanisms (Table 2). First, certain strains of bacteria (phylotypes) can possess unique genetic elements that can confer clindamycin resistance. Second, rRNA alterations at the clindamycin binding site can neutralize the effectiveness of clindamycin. This can be accomplished by the bacteria through either mutation of the rRNA sequence, or by methylation at the clindamycin binding site, both of which make it more difficult for clindamycin to bind and exert its effect. Third, proteins exist that can modify free clindamycin (lin genes) to reduce its ability to bind the bacterial ribosomes. Fourth, other ribosomal protection proteins (ATP-binding cassette) exist that can remove clindamycin already bound to the ribosome. Fifth, drug efflux pumps can translocate clindamycin from inside to outside of the bacterium, thereby preventing effective concentrations of clindamycin inside the organism. Lastly, bacteria can organize into biofilms, in essence forming a difficult-to-penetrate or eradicate “bacterial castle.”

TABLE 2.

Mechanisms of bacterial resistance to the lincosamide antibiotic clindamycin

RESISTANCE MECHANISM	SCIENTIFIC BASIS	REFERENCES
Genetics of virulent bacterial strains	Specific bacterial phylotypes correlate with virulent strains that possess clindamycin resistance. For example, C. acnes phylotype IA-2 may resist clindamycin through certain genetic elements.88	Dréno B et al88
rRNA mutation at clindamycin binding site disrupts clindamycin binding	Mutations in nucleotides 752, 2057-2059, 2452, and 2611 in 23S rRNA89	Canu A et al89
rRNA methylation at clindamycin binding site alters clindamycin binding	(i) N6-dimethylation of nucleotide A2058 by erythromycin-resistant rRNA methyltransferase; (ii) C8 methylation of A2503 by Cfr methyltransferase (iii) acquisition of erm(X) and erm(50) genes which encode for rRNA methyltransferase genes90–93	Giessing AM et al90 Koyanagi S et al91 Leclercq R et al92 Long KS et al93
Protein inactivation of clindamycin	(i) free clindamycin can be inactivated by drug modification, such as by adenylation by lin genes; ii) bound clindamycin can be evicted from the ribosome by ribosomal protection proteins such as ATP-binding cassette (ABC) proteins94–96	Crowe-McAuliffe C et al94 Morar M et al95 Murina V et al96
Drug efflux pumps	Pumps clindamycin out of the bacterial cell. Examples include mefA and msrA, which also can pump out macrolides.97,98	Chouchani C et al97 Johnson AF et al98
Bacterial biofilm formation	Indirect mechanism whereby bacteria, such as C. acnes, form biofilms which render the bacteria more difficult to penetrate by clindamycin, thereby reducing its effectiveness88,99	Dréno B et al88 Walsh TR et al99

VIII. SAFETY OF SYSTEMIC AND TOPICAL CLINDAMYCIN

The safety issues related to use of clindamycin are highly dependent on the route of administration.

Systemic (oral) administration. Gastrointestinal adverse reactions are the most commonly recognized and reported side effects associated with systemic use of clindamycin, including oral administration, and can include diarrhea, nausea, and vomiting.1 Diarrhea has been noted in up to 20% of treated patients100 and typically resolves with discontinuation of therapy.4 Antibiotic-associated colitis (originally referred to as pseudomembranous enterocolitis), caused by toxin-producing strains of Clostridium difficile, has been reported to occur in 0.1%–10% of patients treated with clindamycin.1 As colitis secondary to C. difficile can be associated with significant morbidity and potential mortality, recognition of clindamycin use as a causative factor is very important clinically. A high index of suspicion and very early discontinuation of clindamycin may lessen the severity of colitis. Clindamycin-associated colitis is believed to the major factor that has led to a marked reduction over time in the prescribing of oral clindamycin for AV.4

Hepatotoxicity including acute cholestatic hepatitis, bone marrow suppression, and renal impairment are rare associations with clindamycin use.1,101–103 Transient elevations in hepatic aminotransferase enzymes may occur during clindamycin therapy; if persistent and caused by clindamycin, discontinuation of clindamycin should result in resolution of the increased transaminase enzymes.1,102,103

Cutaneous adverse reactions to clindamycin are usually maculopapular exanthematous eruptions; hypersensitivity reactions, acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (Sweet’s syndrome), and Stevens-Johnson syndrome are uncommon and have been reported sporadically.1,104–109

Topical clindamycin. The majority of skin tolerability and safety considerations with topical clindamycin relate primarily to formulations used to treat AV, where clindamycin has been incorporated as a single active ingredient or in combination with other agents (benzoyl peroxide, tretinoin, adapalene) for almost five decades.1,3,44,51 As noted earlier, clindamycin monotherapy is very well tolerated overall, especially when formulated with vehicles that do not induce xerosis or irritation; contact allergy is reported to be rare to clindamycin itself.3,44,51 Local skin tolerability reactions, which are usually mild, include visible signs such as erythema, peeling, and dryness, and symptoms such as stinging, burning, and itching, and are usually attributed to the vehicle rather than the clindamycin, including in formulations that also contain other active ingredients for AV.3,110–113

Systemic adverse reactions related to topical clindamycin use have focused on concerns related to the potential for antibiotic-associated colitis, which although rare, has been reported sporadically in a few cases with topical administration.1,4,114 Interestingly, the FDA-approved labeling/prescribing information of products containing topical clindamycin has consistently stated over several years, and to date, that topical clindamycin is contraindicated in patients with “history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis”.115–117 An extensive pharmacovigilance safety review and retrospective analysis of gastrointestinal events has recently been completed. In this review, global pharmacovigilance data showed that despite hundreds of millions of patients exposed to topical clindamycin therapy, less than 0.001% of treated patients reported gastrointestinal adverse drug reactions including colitis, and no cases of C. difficile infection/colitis were noted.114 A thoroughly designed retrospective data analysis demonstrated that rates of colitis occurring in patients with AV who were prescribed topical clindamycin are low; it was also shown that clinicians prescribed clindamycin equally to patients with AV, with or without a history of inflammatory bowel diseases, despite the warnings and contraindications noted in the prescribing information.114 As warnings, precautions, and contraindications may be recycled forward in FDA-approved prescribing information with any given medication over many years, and are not automatically updated, there is a high possibility that clinicians can overlook or be unaware of this information. This is especially true when the contraindication, warning and/or precaution is no longer consistent with current beliefs, or is no longer supported by enough cogent evidence to justify their continued presence or degree of emphasis in the approved product labeling. The authors did openly recognize the potential limitations of spontaneous reporting and retrospective data analysis.114

It was noted above that systemic clindamycin has been associated with acute febrile neutrophilic dermatosis (drug-induced Sweet’s syndrome). Two reported cases of this entity were possibly related to use of topical clindamycin; however, other inciting factors may have contributed in these cases according to the authors.118

IX. CLINDAMYCIN USE DURING PREGNANCY AND LACTATION

Clindamycin, both oral and topical, has generally been considered to be safe during pregnancy and lactation, though some conflicting statements do appear in the literature, especially as clindamycin is excreted into breast milk.1,3,4,114 In the case of systemic clindamycin being used for a significant systemic infection, especially in the absence of other viable options known to be safe, strong consideration and discussion of the benefits versus risks are warranted, factoring in the health of both the mother and fetus. Overall, for the management of AV, there is a conspicuous absence of data supporting the prolonged use of either oral or topical clindamycin in pregnant patients; most stated information relates to use of systemic clindamycin for the treatment of infections which is typically a much shorter course than what is used for AV.

It is also important to remember that oral clindamycin is not FDA-approved for the treatment of AV. Overall, it is prudent to generally avoid the use of clindamycin in pregnant women and in those who are breastfeeding; individual patient-related circumstances may warrant more involved discussion with the patient and her obstetrician or the baby's pediatrician.

X. SUMMARY POINTS AND CLOSING COMMENTARY

Over approximately five decades, clindamycin continues to serve as an important antibiotic agent, both systemically and topically, in many disciplines of medicine. In dermatology, it is commonly used as a topical agent primarily for treatment of AV. It is well recognized that topical clindamycin is best coupled with BPO for AV to circumvent antibiotic resistance. Local tolerability reactions are not common with topical clindamycin, but are more likely if the vehicle itself is irritating to the skin. Clindamycin exhibits an antimicrobial spectrum that supports its use for treatment of infections caused by several gram-positive and anaerobic bacteria, usually as a systemic agent. It continues to be used topically, primarily for AV, with a large body of clinical trial data collected over many years demonstrating its efficacy and safety, including in topical combination formulations. Rates of colitis occurring in patients with AV that were prescribed topical clindamycin are low, with clinicians prescribing clindamycin equally to patients with AV, with or without a history of inflammatory bowel diseases. Finally, the pharmacokinetic profiles of topical and oral clindamycin formulations; its modes of action including antimicrobial (antibacterial) activity, anti-inflammatory properties and structure-activity relationships; multiple clinical trials demonstrating efficacy, especially with topical therapy for AV completed over several years; and safety, present clindamycin as a favorable option especially for topical use.