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. Author manuscript; available in PMC: 2022 May 5.
Published in final edited form as: Antimicrob Comb Devices (2019). 2020 Nov 23;STP1630:53–64. doi: 10.1520/stp163020200019

The In Vitro Efficacy of Doxycycline over Vancomycin and Penicillin in the Elimination of Cutibacterium Acnes Biofilm

Matthew D Budge 1, John A Koch 1,2, Jonathan B Mandell 2, Alex J Cappellini 2, Sara Orr 2, Samik Patel 2, Dongzhu Ma 2, Olivia Nourie 1, Kimberly M Brothers 2, Kenneth L Urish 3
PMCID: PMC9070841  NIHMSID: NIHMS1647851  PMID: 35529525

Abstract

Cutibacterium acnes (formerly Propionibacterium acnes) is a significant pathogen in periprosthetic joint infections (PJIs) in total shoulder arthroplasty. Poor outcomes seen in PJIs are due to the established C. acnes bacterial biofilms. The prolonged nature of C. acnes infections makes them difficult to treat with antibiotics. The goal of this study was to determine the relative efficacy of vancomycin compared with penicillin and doxycycline against planktonic and mature biofilms. Clinical isolates from PJI patients as well as a laboratory strain of C. acnes were tested. Planktonic minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were obtained using modified clinical laboratory standard index assays. Biofilm MICs and MBCs were also obtained. The MIC was determined for both using the PrestoBlue viability stain. The MBC was determined using differential reinforced clostridial medium agar plates for colony-forming unit analysis. Using the PrestoBlue viability reagent, the planktonic MIC values for vancomycin were significantly higher than doxycycline. Across 10 strains of C. acnes, all three antibiotics had decreased efficacy when comparing planktonic and biofilm cultures. Although effective antibiotic doses ranged from 1 to 1,000 μg/mL, only doxycycline achieved inhibitory and bactericidal concentrations in all tested strains. Penicillin failed to achieve the minimum biofilm inhibitory concentration (MBIC) in 60% of tested strains, whereas vancomycin failed in 80% of tested strains. Penicillin, doxycycline, and vancomycin have similar abilities in inhibiting C. acnes growth planktonically. The MBIC for doxycycline was within the clinical dosing range, suggesting C. acnes biofilm offers minimal tolerance to these antibiotics. The MBIC for penicillin was within clinical dosing ranges in only 60% of trials, suggesting the relative tolerance of C. acnes to penicillin. The minimum biofilm bactericidal concentration (MBBC) of doxycycline showed efficacy in 90% of trials, whereas penicillin and vancomycin achieved MBBC in 15% of samples.

Keywords: periprosthetic joint infection, arthroplasty, Cutibacterium acnes, antibiotic tolerance, biofilm, planktonic

Introduction

Cutibacterium acnes (formerly Propionibacterium acnes) is an aerotolerant gram-positive bacillus that has been recognized as a significant pathogen in the genesis of acute and delayed periprosthetic joint infections (PJIs) in total shoulder, knee, and hip arthroplasty.1–7 Rates of PJIs range from 0.7% to 4% for primary total shoulder arthroplasty (TSA) and up to 15% for revision arthroplasty,7–12 with C. acnes being responsible for up to 70% of these infections.13–15 Treating PJIs is challenging, often involving revision surgery, prolonged antibiotic use, and hospitalization, which can lead to increased costs and significant morbidity for the patient.12,16–18 Given the rapid increase in the number of arthroplasties being performed, an effective antibiotic treatment strategy for C. acnes PJIs is needed.12,19,20

C. acnes infections are difficult to treat in part due to their ability to form biofilm. C. acnes exists clinically in two distinct states: a single-cell planktonic form and as a multicellular biofilm. In implant-related infections, C. acnes exists primarily as an established biofilm, a characteristic of invasive isolates.21 This has significant consequences for the treatment and prevention of PJIs, as organisms in a biofilm state have increased antibiotic tolerance,22,23 resistance to host immune response,24 and are difficult to isolate via conventional synovial fluid sampling.25,26 Testing of bacteria cultured as biofilms could potentially provide a more accurate determination of antibiotic susceptibility.

Recent clinical studies have shown rates of contamination with C. acnes in primary TSA to be up to 33%, with contamination likely spreading from the subdermal layer.6,27 Given the difficulty of excluding this region from the surgical field, recent efforts have focused on decontamination of the field after implant placement to decrease infection rates.28–32 Topical use of vancomycin has been proposed as an adjuvant to decrease bacterial counts during procedures in which implants may predispose patients to infection with biofilm-forming bacterium. Topically applied vancomycin powder has been reported to decrease infection rates in spine, arthroplasty, and neurosurgery, without significant complications or systemic toxic effects.33–39 It has also been reported to be cost-effective as a prophylactic medication for infection prevention in TSA.40

Additional antimicrobials are known to be effective against C. acnes, including penicillin and doxycycline. Penicillin is a well-described treatment for C. acnes PJIs either alone or in combination with additional agents.41 The efficacy of penicillin against C. acnes biofilm formation has been demonstrated in vitro in laboratory samples.42 Similarly, doxycycline has been described as the standard treatment for C. acnes skin infections. Doxycycline has been shown to be active against C. acnes planktonic cells in vitro43; however, its efficacy against clinical strains in PJI biofilm have not been determined.

The purpose of our study was to determine the efficacy of penicillin, doxycycline, and vancomycin against a mature C. acnes biofilm in an in vitro model. Our hypothesis was that these antibiotics would require higher doses to be effective in eradicating C. acnes biofilm compared with its planktonic form and that there would be variability in the effectiveness between individual antibiotics.

Methods

C. ACNES BACTERIAL STRAINS AND CULTURE CONDITIONS

All strains were inoculated in differential reinforced clostridium medium (DRCM; Becton, Dickinson and Company) anaerobically for 96 h at 37 °C. Strains were diluted in DRCM to a final concentration of 0.5 × 106 CFU/mL using the 0.5 Mac-Farland Standard (GFS Chemicals) and an Infinite M200 spectrophotometer (Tecan). Assays were performed using high-throughput methods. All experiments were performed in 96-well plates. All experiments were performed in triplicate at least three independent times with freshly inoculated cultures. One lab strain (ATTC 11828) and three clinical isolates were tested. Institutional review board guidelines and regulations were followed for completing this study.

PLANKTONIC CULTURE MIC AND MBC

Both the lab strain and clinical isolates of C. acnes were grown planktonically. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed using high-throughput standardized clinical laboratory standard index (CLSI) assays. Two-fold serial dilutions of three antibiotics (vancomycin, penicillin, doxycycline) were tested in each isolate. After 72 h of treatment, MIC was assessed by using the PrestoBlue viability assay (Thermo Fisher Scientific) on the treated cultures according to the manufacturer’s instructions and read on a SynTek microplate reader measuring fluorescence at 590 nm. Prior to the addition of PrestoBlue, the contents of plate wells were plated on DRCM agar plates and incubated anaerobically for 72 h at 37°C. Colony-forming unit (CFU) analysis on plates was performed, and a 99.9% reduction in the CFUs of the original plating density represented the MBC.

MATURE BIOFILMS MIC AND MBC

For bacterial biofilm treatment, C. acnes strains were planktonically grown for 72 h, at which point fresh DRCM was exchanged. Mature biofilms were treated with the same panel of antibiotics used in planktonic assays 72 h after media exchange. Mature biofilms were washed with Dulbecco’s phosphate buffered saline (dPBS) to remove background planktonic bacteria and then subsequently treated with antibiotics diluted in DRCM. In addition to controls, antibiotic concentrations were raised to 250, 125, 62, 31, 16, 8, 4, 2, 1, 0.5, and 0.25, μg/mL, respectively. After 72 h of treatment, antibiotic-supplemented broth was removed, biofilms were washed with dPBS, and 100 μL dPBS was added. To test the minimum biofilm inhibitory concentration (MBIC), wells were manually scraped for 1 min with autoclaved 0.1–10-uL micropipette tips to homogenize biofilms. The MBIC was assessed using the PrestoBlue viability assay, increasing the incubation time to 1 h. For the minimum biofilm bactericidal concentration (MBBC), prior to the addition of PrestoBlue, biofilm well contents were scraped and plated onto DRCM agar plates, and CFU analysis was performed.

STATISTICAL ANALYSIS

Antibiotic susceptibility and tolerance between planktonic and established biofilms of PJI clinical isolates were collected and compared. All graphical and statistical analyses were performed using GraphPad Prism. When comparing two groups, a Mann-Whitney test was performed.

Results

VARIABILITY IN C. ACNES SENSITIVITY TO CLINICALLY USED ANTIBIOTICS

We hypothesized there would be significant differences between C. acnes planktonic and biofilm MICs. CLSI protocol and an in vitro mature biofilm model were used to quantify variations in the planktonic MIC, planktonic MBC, biofilm MIC, and biofilm MBC of different antibiotics across several C. acnes isolates. Penicillin, doxycycline, and vancomycin demonstrated a similar inhibition and bactericidal efficacy within the clinical dosing range against C. acnes planktonic strains based on a relative comparison of MICs and MBCs (figs. 1A and B). Planktonic MBC was above clinical dosing levels in 50% of the strains, indicating increased tolerance of C. acnes to penicillin compared with doxycycline and vancomycin. Of the 10 tested strains, four showed resistance to penicillin in the planktonic state and were removed from the study. There were no statistical differences when comparing antibiotic planktonic MICs and MBCs (figs. 1A and B). Doxycycline MBIC was significantly lower than penicillin MBIC, and doxycycline MBBC was significantly lower than vancomycin MBBC (figs. 1C and D).

FIG. 1.

FIG. 1

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Variability in antibiotic effectiveness between planktonic and biofilm states of the four C. acnes samples. Across sampled isolates, C. acnes demonstrated varying resistances in both planktonic (blue) and increased resistance to antibiotics in biofilm (red) cultures. MICs were determined using a PrestoBlue fluorescence assay. To determine the MBC, a CFU analysis was performed using DRCM plates. The differences between the MBIC of doxycycline and penicillin, as well as the MBBC of doxycycline and vancomycin were statistically significant. The dashed line represents the maximum tested dose (1,000 μg/mL).

C. ACNES BIOFILMS SHOW INCREASED TOLERANCE TO KILLING BY DOXYCYCLINE, VANCOMYCIN, AND PENICILLIN

Sensitivity to antibiotics was compared between C. acnes strains grown planktonically and grown as mature biofilms. In all but two tested isolates, biofilm MIC was greater than planktonic MIC (fig. 2A). In addition, C. acnes biofilms also demonstrated a greater MBC compared with their planktonic counterparts (fig. 2B). The biofilm MBC for doxycycline and vancomycin was measurable in 75% of the strains, indicating minimal tolerance of C. acnes biofilm to these antibiotics. Vancomycin, doxycycline, and penicillin had significantly decreased efficacy against MBIC compared with planktonic MIC (fig. 3A). Doxycycline, vancomycin, and penicillin biofilm MBC values were significantly higher than planktonic MBC values (fig. 3B). The MBBC for penicillin was measurable in only 25% of strains, indicating relative tolerance of C. acnes to this antibiotic (fig. 3B).

FIG. 2.

FIG. 2

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C. acnes biofilm demonstrates increased antibiotic tolerance. Individual isolates were compared against themselves between planktonic and biofilm sensitivities. Across all but two tested isolates, biofilm MIC was greater than planktonic MIC (A). All tested isolates demonstrated greater biofilm MBC than planktonic MBC (B).

FIG. 3.

FIG. 3

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C. acnes biofilms show increased tolerance to killing by doxycycline, vancomycin, and penicillin. Sensitivity to antibiotics was compared between C. acnes strains grown planktonically compared to mature biofilms. Doxycycline, vancomycin, and penicillin had similar planktonic MIC and planktonic MBCs. A Mann-Whitney test showed statistically significant differences between MIC and MBIC for all antibiotics, as well as between MBC and MBBC for all tested antibiotics, as denoted by the asterisk (*p > 0.05). In all cases, biofilms demonstrated significantly increased tolerance to the antibiotics tested compared with their planktonic counterpart.

Discussion

Treatment of C. acnes PJIs is a complex and often difficult task, frequently involving multiple surgical procedures, diagnostic tests, and prolonged antibiotic treatment.3,7–12,16–18 Resolution of the infection is further complicated by the propensity of C. acnes to form biofilm in the setting of foreign material, specifically in and around total joint arthroplasties.21,23 The difficulties in treatment associated with biofilm-producing bacteria are myriad and include increased virulence, antimicrobial tolerance, resistance to the host immune system, and difficulty in isolation by conventional methods.22–26 The biofilm may also serve as a refuge for other pathogenic bacteria, allowing for polymicrobial bacterial infection.44

Determining the proper antibiotic regimen for a given C. acnes infection is complicated by the fact that routine susceptibility testing done on cultured planktonic bacteria may not represent the true antibiotic resistance of the organism in a biofilm. Given these challenges, we sought to determine the variations in antibiotic sensitivity between clinical C. acnes isolates when cultured as established biofilms compared with their typical planktonic culture. It is important to note that of the 10 tested strains, four demonstrated resistance to penicillin in their planktonic state and were removed from the study. This is not an unusual finding, as Ridberg et al. demonstrated C. acnes can develop resistance to antibiotics.45 As with prior studies, we found a large decrease in antibiotic sensitivity in C. acnes biofilms compared with planktonic cells across all three antibiotics. This is similar to the findings with other bacteria such as Staphylococcus aureus as well as other studies with C. acnes42,46 and is in close agreement with other groups showing a clear tolerance of biofilms to traditional antibiotics.47,48

Penicillin, doxycycline, and vancomycin demonstrated a similar ability to inhibit C. acnes bacterial growth in the planktonic state based on a relative comparison of MICs and MBCs. This result is consistent with other studies showing the efficacy of these antibiotic treatment regimens in both in vitro and clinical scenarios.41–43 However, once C. acnes was allowed to form a biofilm, differences in antibiotic efficacy became apparent. The MBIC for doxycycline within clinical dosing ranges in 100% of the strains indicated minimal tolerance of C. acnes biofilm to doxycycline and likely clinical efficacy with routine dosing. The MBIC for penicillin was significantly higher than doxycycline, indicating relative tolerance of C. acnes to this antibiotic and likely clinical failure with this antibiotic treatment choice. This is an important finding in that penicillin is a well-described treatment for C. acnes infections but likely has limited effectiveness when treating C. acnes biofilm. The MBBC for doxycycline showed efficacy at treatment doses in 90% of tested samples, while penicillin MBBC was above treatment doses in 60% of samples; vancomycin MBBC exceeded treatment doses in 80% of tested strains, again indicating relative tolerance of C. acnes biofilm for penicillin and vancomycin.

In this study doxycycline was shown to be effective in eliminating both planktonic C. acnes (MIC/MBC) and mature biofilm (MBIC/MBBC). We did note that 10% of the clinical isolates in the mature biofilm category had a dose higher than measurable to achieve MBBC (>1,000 μg/mL). With intravenous dosing, a plasma concentration at this level would be toxic to the patient and could lead to significant morbidity and mortality.

This study is limited in its comparison of antibiotic activity in mature biofilms and planktonic cultures, as this comparison can be complicated and differences can exist in strain growth and biofilm characteristics. We found significantly increased antibiotic tolerance in biofilms against all tested antibiotics. These observations may be limited due to differences in biofilm biophysical properties, secreted extracellular matrix, metabolic output, and the population density within biofilms grown from each isolate.

Established bacterial biofilms have a significant and varied tolerance to antibiotics compared with their planktonic counterparts. Our data suggest that clinically effective antibiotic treatment of C. acnes PJIs may depend on the antibiotic resistance in the biofilm state of a specific bacteria as opposed to their antibiotic resistance in their planktonic state. Our results should not be interpreted in the context that standard planktonic antibiotic sensitivity testing is ineffective. Standard CLSI testing for MIC provides invaluable clinical data on genetic antibiotic resistance. This work does suggest that there is a large and varied phenotypic tolerance to antibiotics that occurs between planktonic and biofilm phenotypes of C. acnes. Further, it suggests from a clinical perspective that doxycycline may have a stronger ability to control implant-associated infections compared with penicillin and vancomycin. Further clinical studies are warranted to confirm these results.

C. acnes has an increased tolerance to antibiotics in a mature biofilm compared with its planktonic state. Doxycycline demonstrates efficacy in elimination of C. acnes in the biofilm state, while penicillin and vancomycin demonstrate a decreased ability to eliminate C. acnes biofilm.

ACKNOWLEDGMENTS

Kenneth Urish is supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS K08AR071494), the National Center for Advancing Translational Science (NCATS KL2TR0001856), the Orthopaedic Research and Education Foundation, and the Musculoskeletal Tissue Foundation.

Footnotes

4

ASTM Symposium on Antimicrobial Combination Devices on November 5, 2019 in Houston, TX, USA.

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