Effectiveness of adjunctive clindamycin in β-lactam antibiotic-treated patients with invasive β-haemolytic streptococcal infections in US hospitals: a retrospective multicentre cohort study

Abstract

Background: Clindamycin is strongly recommended as an adjunctive treatment to β-lactam antibiotics in patients with severe invasive group A β-haemolytic streptococcal (iGAS) infections. However, there is little evidence of a benefit in the use of clindamycin in humans, and its role, if any, in treating patients with invasive non-group A/B β-haemolytic streptococcal (iNABS) infections is unclear.

Methods: For this retrospective multicentre cohort study, we used a dataset from patients in the Cerner Health Facts database, which contains electronic health-based data from 233 US hospitals. We queried the Cerner Health Facts database for inpatients (no age restriction) admitted to hospital in 2000-15, with any clinical cultures positive for β-haemolytic streptococcal taxa of interest, and who had received β-lactam antibiotics within 3 days either side of culture sampling. This group of patients was then queried for those who had also received intravenous or oral clindamycin within 3 days either side of culture sampling. Patients were excluded if they had polymicrobial growth or clindamycin non-susceptible isolates, received linezolid, or had missing variable data needed for analysis. Patients were categorised by Lancefield group (iGAS or iNABS); β-lactam antibiotic-treated patients who had received clindamycin were propensity-matched (1:2) to those who did not receive clindamycin separately for iGAS and iNABS cohorts, and logistic regression was then used to account for residual confounding factors. The primary outcome was the adjusted odds ratio (aOR) of in-hospital mortality in propensity-matched patients treated with adjunctive clindamycin versus those not treated with clindamycin in the iGAS and iNABS infection cohorts.

Findings: We identified 1956 inpatients with invasive β-haemolytic streptococcal infection who had been treated with β-lactam antibiotics across 118 hospitals (1079 with iGAS infections and 877 with iNABS infections). 459 (23·4%) of these patients had received adjunctive clindamycin treatment (343 [31·7%] patients with iGAS infections and 116 [13·2%] patients with iNABS infections). The effect of adjunctive clindamycin therapy on in-hospital mortality differed significantly and showed the opposite trend in iGAS and iNABS infection cohorts (p=0·013 for an interaction). In the iGAS cohort, in-hospital mortality in propensity-matched patients who received adjunctive clindamycin (18 [6·5%] of 277 patients) was significantly lower than in those who did not (55 [11·0%] of 500 patients; aOR 0·44 [95% CI 0·23-0·81]). This survival benefit was maintained even in patients without shock or necrotising fasciitis (six [2·6%] of 239 patients treated with adjunctive clindamycin vs 27 [6·1%] of 422 patients not treated with adjunctive clindamycin; aOR 0·40 [0·15-0·91]). By contrast, in the iNABS infection cohort, in-hospital mortality in propensity-matched patients who received adjunctive clindamycin (ten [9·8%] of 102) was higher than in those who did not (nine [4·6%] of 193), but this difference was not significant (aOR 2·60 [0·94-7·52]). Several subset analyses found qualitatively similar results.

Interpretation: Real-world data suggest that increased use of adjunctive clindamycin for invasive iGAS infections, but not iNABS infections, could improve outcomes, even in patients without shock or necrotising fasciitis.

Funding: Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Disease.

Figure 1. Selection of patients with invasive β-haemolytic streptococcal infections

*The database was queried for inpatents (aged ≥18 years) with any clinical culture samples displaying monomicrobial growth of select β-haemolytic species (appendix p 3), filtered on the basis of receiving β-lactam antibiotics within 3 days either side of culture sampling with or without clindamycin treatment. †Patients could have met more than one exclusion criterion. ‡No patients were treated with tedizolid.

Figure 2. Clindamycin use among patients with invasive β-haemolytic streptococcal infections

*Includes mediastinitis, orchitis or epididymitis, parapharyngeal abscess, periapical abscess, peritonsillar abscess, retropharyngeal abscess, abscess of the mediastinum, and abscess of the salivary gland. Calculated by use of an electronic health record-based adaption of the original Sequential Organ Failure Assessment (appendix p14).

Figure 3. Distribution of propensity scores (2:1 match) in the invasive group A β-haemolytic streptococcal infection cohort (A) and the invasive non-group A/B β-haemolytic streptococcal infection cohort (B)

Propensity scores were calculated from a logistic regression associated with receipt of clindamycin as a binary outcome to the matching variables (shown in the table) used as predictors for 1956 individuals. From the model, a fitted probability (propensity score) for each patient was calculated to estimate the likelihood of receiving adjunctive clindamycin based on their covariate profile of matching variable values. The propensity scores are visualised on the logit scale.

Figure 4. OR of in-hospital mortality in patients with invasive group A β-haemolytic streptococcal infection treated with versus without adjunctive clindamycin

The ORs (95% CIs) of in-hospital mortality in the primary analysis, by propensity matching and adjustment status, and in subgroup analyses of propensity-matched patients in the invasive group A β-haemolytic streptococcal infection cohort. OR=odds ratio. NA=not applicable. *Adjusted for proven invasive β-haemolytic streptococcal infection, vasopressor-dependent shock, and intensive care unit status. †All subgroup analyses were propensity-matched. ‡Too few deaths in patients with probable invasive β-haemolytic streptococcal infection alone precluded reliable assessment of the effect of clindamycin on mortality.

Figure 5. OR of in-hospital mortality in patients with invasive non-group A/B β-haemolytic streptococcal infection treated with versus without adjunctive clindamycin

The ORs (95% CIs) of in-hospital mortality in the primary analysis, by propensity matching and adjustment status, and in subgroup analyses of propensity-matched patients in the invasive group A β-haemolytic streptococcal infection cohort. OR=odds ratio. *Adjusted for proven invasive β-haemolytic streptococcal infection, vasopressor-dependent shock, and intensive care unit status. †All subgroup analyses were propensity-matched.