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Population characteristics

Of the 511 subjects in the initial cohort, 87 individuals (17.0 %) experienced at
least one SSTI, as described elsewhere 6]. Two subjects from the cohort had no follow-up time after the initial SSTI, so 85
subjects were included in the analysis reported in this study. The demographics of
this cohort are shown in Table 1. The 85 subjects contributed 118.3 person-years of follow-up, with subjects censored
at loss to follow-up or at the time of recurrent SSTI.

Table 1. Baseline characteristics of individuals who did and did not develop a recurrent SSTI
during the study period

Of the initial SSTIs, 50 (58.8 %) were abscesses, 27 (31.8 %) were furuncles, and
8 (9.4 %) were cellulitides. Incision and drainage of the initial SSTI was performed
in 28 cases (32.9 %). Only 23/85 initial SSTIs were associated with culture data,
one of which was culture-negative. S. aureus was an identified pathogen in 15 initial SSTIs, and MRSA in 11 of these. Pseudomonas aeruginosa was the only other pathogen identified in more than one patient, having been identified
in 3 SSTIs. All cultures were from an infected skin site.

Of the 85 initial SSTIs, 20 (23.5 %) were treated with combination antimicrobial drug
therapy. The most common combination used was ciprofloxacin and clindamycin, used
in 3 patients (3.5 % of all patients, 15 % of patients receiving combination therapy).
Of the 65 who did not receive combination antimicrobial drug therapy, 20 (23.5 % of
all initial SSTIs) received a beta-lactam, 21 (24.7 %) received clindamycin, 8 (9.4 %)
received trimethoprim-sulfamethoxazole, 5 (5.9 %) received a fluoroquinolone, 2 (2.4 %)
received vancomycin, and 3 (3.5 %) received no antimicrobial drug therapy. Whether
or not antimicrobial drug therapy was prescribed for the initial SSTI was not documented
in the medical records of six (7.1 %) patients. As documented in the medical record,
no subject underwent attempts at decolonization after the initial SSTI.

A total of 30 subjects among the 85 who had follow-up (35.3 %) experienced at least
one recurrent SSTI during follow-up. Using Kaplan-Meier methods, the estimated proportion
of individuals who would have experienced a recurrent SSTI if all individuals had
been followed for one year was 29.2 % (95 % CI 20.3 %-41.0 %), while the 3-year risk
was 47.0 % (95 % CI 34.4 %-61.6 %). Figure 1 shows the estimated Kaplan-Meier cumulative incidence of SSTIs over time. The incidence
of second SSTI was 253.6 SSTIs/1000 person-years (95 % CI 166.8-385.7). Fourteen subjects
experienced multiple recurrences (16.5 % of all subjects with initial SSTI; 46.7 %
of subjects with at least one recurrence).

Fig. 1. Kaplan-Meier curve demonstrating the cumulative risk of recurrent SSTI over time with
95 % confidence intervals

A number of variables assessed as potential risk factors for SSTIs were time-varying.
These variables were therefore not assumed to be present throughout the follow-up
period; instead, they were calculated as present or absent on each day of follow-up.
For example, 79.8 % of follow-up time accrued to individuals on Medicaid, 1.6 % to
individuals with a catheter, 24.7 % to individuals taking trimethoprim-sulfamethoxazole
prophylaxis, and 12.0 % to individuals taking azithromycin prophylaxis. Highly active
antiretroviral therapy (HAART) was being given 77.1 % of the time, and the cohort
had an HIV VL??1000 copies/mL on 60.0 % of days. The diagnosis of certain comorbid
conditions was assessed similarly, with 14.6 % of follow-up time occurring in subjects
with diabetes, and 7.8 % with cancer (Table 2).

Table 2. Proportion of patient-days with exposure to time-varying covariates

Characteristics of recurrent SSTIs

The median recurrent SSTI occurred at 144 days after the initial SSTI (interquartile
range [IQR], 89–377). Trimethoprim-sulfamethoxazole prophylaxis was being taken by
5/30 subjects (16.7 %) at the time of SSTI, and 3/6 (50 %) individuals with CD4+ count??200
cells/mm
³
at the time of SSTI were taking trimethoprim-sulfamethoxazole. The median CD4+ count
at the time of recurrent SSTI was 403.5 (IQR 239–529), and the median VL was 1475
copies/mL (IQR undetectable-27800). We found that 26/30 (86.7 %) SSTI recurrences
occurred in patients with CD4+ count??100 cells/mm
³
. Of the recurrent infections, 17 were abscesses (56.7 %), 9 were cellulitis (30.0 %),
and 3 were furuncles (10.0 %), and the type of SSTI was undocumented in one case.
13 of 30 (43.3 %) recurrent infections met Centers for Disease Control and Prevention
(CDC) criteria for a community-associated SSTI (CA-SSTI) 18]. The primary reason that an SSTI was not classified as a CA-SSTI was hospitalization
within the prior year, which was the case in 12/30 (40.0 %) patients.

Culture data were only obtained for 8 of the recurrent SSTIs, and of those, 6 of the
8 (75 %) were confirmed S. aureus infections, with 4 of the 6 (67 %) being MRSA. Of those 4 infections, 3 were clindamycin-susceptible
MRSA, and all four were susceptible to trimethoprim-sulfamethoxazole. Of the 6 culture-proven
S. aureus infections, only 1 MRSA SSTI met CDC criteria for being a CA-SSTI. The other two
SSTIs were caused by Proteus and a coagulase negative staphylococcus species. Three
of the six recurrent SSTIs caused by S. aureus were associated with culture data for the initial SSTI; all three initial SSTIs were
caused by S. aureus as well. In two patients, both infections were causes by MRSA, and in one patient,
both infections were causes by MSSA.

Therapy in cases of recurrent SSTI was with a beta-lactam in five cases (16.7 %),
combination therapy in seven cases (23.3 %), clindamycin in four cases (13.3 %), TMP-SMX
in three cases (10 %), levofloxacin in one case (3.3 %), and vancomycin in one case
(3.3 %). Five patients (16.7 %) received no systemic antibacterial therapy, and antibiotic
therapy was not documented in four cases (13.3 %).

Predictors of Recurrent SSTI

The results of univariate Cox regression with possible predictors of SSTI are listed
in Table 3. At any given time point, the presence of an intravascular catheter (HR 4.62; 95 %
confidence intervals [CI] 1.08-19.7; p?=?0.04), chronic liver disease (HR 2.89; 95 % CI 1.00-8.35, p?=?0.05), and lymphedema (HR 4.12; 95 % CI 1.24-14.1; p?=?0.02) were associated with an increased risk of recurrent SSTI, while African-American
race was associated with decreased risk of recurrent SSTI (HR 0.34; 95 % CI 0.11-1.00;
p?=?0.05).

Table 3. Predictors of risk of recurrent SSTI in univariate and multivariate Cox regression
models

Predictors with p??0.2 were candidates for the final multivariate Cox model, which was developed by
a forward selection algorithm. Significant predictors as well as theoretical concerns
led to the choice of our final model for multivariate regression. For example, we
found a strong association between lymphedema and intravenous drug use (IVDU) in our
cohort; we accordingly only included IVDU in the final model to avoid collinearity.
Similarly, although gonorrhea was a strong statistical predictor of recurrent SSTI
in several preliminary multivariate models, we found that models including gonorrhea
were overly influenced by the single subject with a history of gonorrhea during follow
up with recurrent SSTI (out of two subjects with a history of gonorrhea during follow
up). Accordingly, gonorrhea was not included in the final model as it was felt that
the data were inadequate to allow for a multivariable analysis including this predictor.
Risk factors for recurrent SSTI in the final multivariable Cox regression model were
non-hepatitis liver disease (HR 3.44; 95 % CI 1.02-11.5; p?=?0.05), the presence of an intravenous catheter (HR 6.50; 95 % CI 1.47-28.7; p?=?0.01), and a history of intravenous drug use (HR 2.80; 95 % CI 1.02-7.65; p?=?0.05); African-American race remained associated with a decreased risk (HR 0.17;
95 % CI 0.05-0.54; p??0.01). A trend was present for HIV viral load ?1000 copies/mL as an independent
risk factor for recurrent SSTI (HR 2.21; 95 % CI 0.99-4.94; p?=?0.05), which was nearly statistically significant. A Cox-Snell residual plot demonstrated
that the model fit the data well (plot not shown).

As a sensitivity analysis, we repeated the above analyses but used 30-, 60-, 90- and
365-day recent averages for a number of the above time-varying factors, without significant
change in the results (data not shown). Similarly, we used linearly extrapolated CD4+
counts and HIV VLs and found that point estimates did not change significantly. As
a final sensitivity analysis, we used CD4+ count of 200 as an alternative cutoff,
without significant change in the results.