Antibiotic Duration, but Not Abscess Size, Impacts Clinical Cure of Limited Skin and Soft Tissue Infection After Incision and Drainage

Abstract

Antibiotics are frequently prescribed following incision and drainage of cutaneous abscesses. In subgroup analyses from a recent clinical trial, we observed higher likelihood of cure with antibiotic courses beyond 5 or 7 days (up to 10). Among this cohort, for abscesses ≤5 cm, size did not modify the antibiotic effect.

Abscesses account for >50% of physician visits related to skin and soft tissue infections (SSTIs) [1]. Staphylococcus aureus is the most frequently isolated pathogen from skin abscesses. Incision and drainage (I&D) is the mainstay of therapy, and adjunctive antibiotic prescribing practices vary by patient age, clinician specialty, methicillin-resistant S. aureus (MRSA) prevalence, and geographic region [2–5]. Recent clinical trials have demonstrated improved outcomes with adjunctive antibiotic therapy [6–8], though questions remain regarding optimal treatment length and the necessity of antibiotics for the smallest abscesses.

A recent multicenter randomized controlled trial of outpatients with limited (≤5 cm) skin abscesses demonstrated that a prescribed 10-day regimen of either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with I&D was superior to I&D alone, though number of days completed was not included in the primary analysis [6]. We performed a subgroup analysis of data from this trial to measure the effect of treatment duration on clinical cure following I&D, and whether abscess size modified treatment effect.

METHODS

Trial methods have been previously described [6]. In brief, outpatients were enrolled from 6 academic medical centers between May 2009 and January 2015. Eligible participants had a single abscess with a greatest diameter ≤5 cm (≤3 cm for participants 6 to 11 months of age and ≤4 cm for participants 1–8 years of age). All participants underwent I&D and abscess fluid was sent for microbiologic culture. Participants were assigned in a 1:1:1 ratio to placebo, clindamycin, or TMP-SMX, for 10 days of therapy. Adherence (ie, length of therapy) was assessed by pharmacist assessment of blister packs or suspension bottles as well as patient report. In-person longitudinal study visits were conducted at the end of treatment, 7–10 days after treatment completion (test of cure [TOC]), and approximately 30 days after treatment completion (1-month follow-up [OMFU]). The primary endpoint was clinical cure at the TOC visit, with clinical failure including lack of resolution, recurrence, infection at a new site, unplanned surgical intervention, or hospitalization. Participants with documented days of therapy and who were evaluated at the TOC or OMFU visits were included in the subgroup analysis.

Effects of antibiotic duration (ie, days of therapy) and abscess size (largest dimension [cm]) were assessed continuously and categorically. To evaluate antibiotic duration, pharmacy accounted data were employed. Categorical analysis of days of therapy was >5 days (>15 doses) vs ≤5 days (≤15 doses) and >7 days (>21 doses) vs ≤7 days (≤21 doses). For the size-by-treatment effect analysis, all participants with complete follow-up data were included, and median abscess size for each age group (defined above) was used to create a dichotomous variable (ie, greater than or equal to the median vs less than the median). Demographic, microbiologic, and baseline clinical features were compared using t test, Pearson χ ² or Fisher exact test, or a nonparametric equivalent where appropriate. Univariable and multivariable analyses were by logistic regression. P < .05 was considered significant. Factors significant in univariable analysis were considered for multivariable analysis. Only antibiotic duration was associated with clinical cure in the treatment duration analysis; thus, the only multivariable analysis performed was for the treatment-by-size analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for independent variables. The Breslow-Day test for homogeneity was used to assess interaction between treatment (ie, placebo vs antibiotic) and abscess size. Statistical analyses were performed using SAS version 9.4 software (SAS Institute, Cary, North Carolina).

RESULTS

Of 786 participants in the intention-to-treat analysis, for treatment duration analysis, pharmacy accounted antibiotic data were available for 380 participants at TOC and 362 at OMFU. Within the participants randomized to the clindamycin and TMP-SMX groups, 77% (TOC, n = 292; OMFU, n = 279) completed 10 days of therapy. Demographic and baseline clinical features were similar between groups (Table 1) . Assessed continuously, each additional day of therapy (ie, 3 additional doses) was associated with an increased odds of cure at TOC (OR, 1.9 [95% CI, 1.6–2.2]) and at OMFU (OR, 1.6 [95% CI, 1.4–1.9]). Completion of >5 days (>15 doses) of antibiotics (vs ≤5 days [≤15 doses]) achieved higher cure at TOC (OR, 41 [95% CI, 15–112]) and OMFU (OR, 19 [95% CI, 7.7–48]). Completion of >7 days (>21 doses) of antibiotics (vs ≤7 days [≤21 doses]) achieved higher cure at TOC (OR, 25 [95% CI, 9.6–64]) and OMFU (OR, 8.8 [95% CI, 4.1–19]) (Table 1).

Table 1.

Demographic and Clinical Characteristics of the Study Population and Factors Associated With Cure

Characteristic	TOC (n = 380), No. (%)		Univariable Analysisa, OR (95% CI)	OMFU (n = 362), No. (%)		Univariable Analysisa, OR (95% CI)
	Evaluated	Cure		Evaluated	Cure
Child (age <18 y)	132	125 (95)	1.2 (.49–3.1)	125	113 (90)	1.4 (.67–2.8)
Adult (age ≥18 y)	248	232 (94)	Ref	237	207 (87)	Ref
Male sex	210	195 (93)	0.64 (.27–1.6)	200	177 (89)	1.0 (.54–2.0)
Female sex	170	162 (96)	Ref	162	143 (88)	Ref
Race/ethnicity
Non-Hispanic/Latinob	303	283 (93)	0.58 (.17–2.0)	286	251 (88)	0.74 (.31–1.7)
Hispanic/Latino	76	73 (96)	Ref	75	68 (91)	Ref
Black	220	208 (95)	1.3 (.55–3.0)	210	187 (89)	1.2 (.61–2.2)
Non-black	160	149 (93)	Ref	152	133 (88)	Ref
Largest wound dimensionc, cm	2.1 (1.5–3.0)d	…	0.85 (.60–1.2)	2.2 (1.5–3.0)d	…	0.85 (.65–1.1)
Diameter ≥ median, cm	199	188 (94)	1.2 (.52–2.8)	192	169 (88)	0.93 (.49–1.8)
Diameter < median, cm	181	169 (93)	Ref	170	151 (89)	Ref
Wound areae, cm2	3.1 (0.94–7.1)d	…	0.94 (.86–1.0)	3.1 (0.94–7.1)d	…	0.96 (.89–1.0)
Positive culturef	351	329 (94)	…	336	297 (88)	0.54 (.07–4.3)
Negative culture	17	17 (100)	…	15	14 (93)	Ref
Staphylococcus aureus isolated	257	242 (94)	1.1 (.43–2.7)	246	220 (89)	1.3 (.65–2.6)
S. aureus not isolated	111	104 (94)	Ref	105	91 (87)	Ref
MRSA isolated	193	180 (93)	0.75 (.31–1.8)	184	162 (88)	0.89 (.46–1.7)
MRSA not isolated	175	166 (95)	Ref	167	149 (89)	Ref
MSSA isolated	64	62 (97)	2.2 (.50–9.6)	62	58 (94)	2.1 (.71–6.0)
MSSA not isolated	304	284 (93)	Ref	289	253 (88)	Ref
TMP-SMX	178	167 (94)	0.96 (.41–2.2)	168	145 (86)	0.68 (.36–1.3)
Clindamycin	202	190 (94)	Ref	194	175 (90)	Ref
DOT (0–10 d), per additional day	10 (10–10)d	…	1.9 (1.6–2.2)	10 (10–10)d	…	1.6 (1.4–1.9)
>5 DOT (>15 doses)	353	344 (97)	41 (15–112)	338	311 (92)	19 (7.7–48)
≤5 DOT (≤15 doses)	27	13 (48)	Ref	24	9 (38)	Ref
>7 DOT (>21 doses)	340	332 (98)	25 (9.6–64)	325	299 (92)	8.8 (4.1–19)
≤7 DOT (≤21 doses)	40	25 (63)	Ref	37	21 (57)	Ref

Data are presented as no. (%) unless otherwise indicated.

Abbreviations: CI, confidence interval; DOT, days of therapy; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; OMFU, 1-month follow-up; OR, odds ratio; Ref, referent value; TMP-SMX, trimethoprim-sulfamethoxazole.

^aOnly treatment duration was significant, so multivariable analysis was not performed.

^bEthnicity reported as “multiple” for n = 1.

^cMedian abscess size (cm) was calculated by age group (6–11 months, 1–8 years, ≥9 years) for this determination. At TOC, overall median size was 2.1 (interquartile range [IQR], 1.5–3.0); 6–11 months, 3.0 (IQR, 2.1–3.4); 1–8 years, 2.0 (IQR, 1.5–3.0); ≥9 years, 2.5 (IQR, 1.5–3.2). At OMFU, overall median size was 2.2 (IQR, 1.5–3.0); 6–11 months, 3.0 (IQR, 2.1–3.4); 1–8 years, 2.0 (IQR, 1.5–3.0); ≥9 years, 2.5 (IQR, 1.5–3.5).

^dMedian (IQR).

^eArea was calculated using the formula for an ellipse: (length × width × π) / 4.

^fPrimary wound culture obtained but no result for n = 12 at TOC and n = 11 at OMFU.

For the size-by-treatment analysis, complete data were available for 680 participants at TOC and 652 at OMFU. For both TOC and OMFU, median abscess size (cm) across placebo and antibiotic groups was 2.5 (range, 0.2–5.0) overall; 3.0 (range, 0.2–4.5) for 6–11 months; 3.0 (range, 0.2–5.0) for 1–8 years; and 2.5 (range, 0.2–5.0) for ≥9 years. Assessed continuously, size was not associated with cure at TOC (OR, 1.1 [95% CI, .89–1.3]) or OMFU (OR, 1.1 [95% CI, .89–1.2]) between placebo and treatment groups or within antibiotic groups (see Table 1 for median and interquartile ranges for antibiotic groups). Abscess size greater than the median was not associated with cure at TOC (OR, 0.99 [95% CI, .61–1.6]) or OMFU (OR, 1.0 [95% CI, .67–1.5]). Stratifying on size, no significant interaction was observed with antibiotic treatment: at TOC, odds of cure were 4.4 (95% CI, 2.1–9.0) times higher for abscesses with diameter below the median vs 2.0 (95% CI, 1.0–4.1) times higher for abscesses equal to or above the median (Breslow-Day P = .14); at OMFU, odds were 2.3 (95% CI, 1.3–4.1) and 2.4 (95% CI, 1.3–4.4) times higher below vs equal to or above the median, respectively (Breslow-Day P = .90).

Discussion

While many providers prescribe adjunctive antibiotics after I&D of cutaneous abscesses, there is a wide variability of prescribing patterns for skin infection after I&D of cutaneous abscess [2–5]. Recent clinical trials have provided evidence to support adjunctive antibiotic use, demonstrating significantly higher likelihood of clinical cure in patients prescribed antibiotics vs those receiving placebo [6–8]. Our current analyses build upon these observations, suggesting that, in conjunction with I&D, courses of antibiotics beyond 5 or 7 days (15 or 21 doses), up to 10 days (30 doses), are associated with an increased likelihood of clinical cure of the acute infection. In addition, longer courses of treatment were significantly associated with decreased incidence of recurrent or new abscesses at approximately 6 weeks after treatment initiation, which may be due to decreasing S. aureus burden or eradicating colonization [9]. These data do not discount the importance of I&D in abscess management, but rather provide additional evidence to other recent trials [6–8], demonstrating the benefit of adjunctive antibiotics after I&D.

Abscess size has been cited as a factor considered when choosing to prescribe antibiotics after I&D. In a survey of pediatric providers, including emergency physicians, general pediatricians, and infectious disease specialists, 23% reported that their decision to prescribe antibiotics depends on abscess size and/or location [4]. In our analysis, no association between abscess size and clinical cure at (either TOC or OMFU) visits was observed, and in fact, the effect size was larger for smaller abscesses. Similarly, Talan et al evaluated the effectiveness of TMP-SMX vs placebo after I&D for SSTI treatment, assessing abscess resolution and requirement for additional antibiotics or surgical intervention 1–2 weeks and 6–8 weeks following treatment completion [8]. Compared to placebo, likelihood of cure was significantly higher in the TMP-SMX group; this effect was preserved when analyzed according to 1-cm increments in abscess cavity size (median length, 2.5 cm [range, 0.1–16.0 cm]; median width, 2.0 cm [range, 0.1–11.0 cm]) [8]. Together, these data suggest that regardless of abscess size, higher odds of cure are observed with adjunctive antibiotics, though further trials to specifically address this question are needed.

In this analysis, 23% of participants took less than the prescribed 10 days of therapy per pharmacy accounted adherence data. This potentially reflects a high degree of motivation among study participants. Despite this limitation, the odds of cure among patients receiving antibiotics were similar to the original trial [6] and the trial by Talan et al [8]. We observed lower likelihood of cure in those participants who took ≤5 and ≤7 days of antibiotics than may be expected after I&D alone. This could be due to the small sample size or it may indicate a high-risk population that would derive more benefit from antibiotic therapy with higher adherence to the prescribed course. Further investigation into strategies for risk stratification to identify which patients would derive the greatest benefit from antibiotic therapy is needed.

In summary, our secondary analysis of a large clinical trial addressing skin infection treatment found further evidence that adjunctive antibiotics, compared to I&D alone, improve short-term outcomes for patients with cutaneous abscesses. In this study and others [8], this effect exists regardless of abscess size. Prospective randomized trials are needed to determine the ideal treatment length for limited skin abscesses to maximize the clinical benefit while minimizing adverse effects of antibiotic overuse and the development of antibiotic resistance.

Notes

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health (NIH) or the Agency for Healthcare Research and Quality (AHRQ).

Financial support. The original trial was supported by a contract to the Division of Microbiology and Infectious Diseases 07-0051 team from the NIH/National Institute of Allergy and Infectious Diseases (NIAID) (grant number HHSN272200700031C to H. F. C.). The current work was supported by the NIH/NIAID (grant number K23-AI091690 to S. A. F.) and the AHRQ (grant numbers R01-HS021736 and R01-HS024269 to S. A. F.).

Potential conflicts of interest. L. M. reports grants from Merck, Genentech, Paratek, Melinta, and Theravance, outside the submitted work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.