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Letters to the Editor
“African American” were identified through the UIC Cerner Medical Systems. Those with an ICD-9/10 code of SCD were excluded from this cohort. The African American cohort of 16,000 patients used in our analyses were chosen by propensity score, matched to the SCD cohort at a 50:1 ratio for age, sex, and follow-up time using the Matchit R analytic software package by the nearest-neighbor matching algorithm.10
Baseline characteristics at the time of study initiation were compared by MDR status using the Kruskal-Wallis and Chi-square or Fisher’s exact test for linear and cate- gorical variables, respectively. Median and interquartile range (IQR) are provided. A final multivariate logistic regression model was fit by stepwise variable selection of variables with P<0.1 in the univariate analysis, adjusting for the following covariates: age, sex, sickle cell geno- type, and hydroxyurea use. Fisher’s exact test was used to compare MDR status between SCD and AA patients for each specific antimicrobial-organism pair. Relative risk (RR) was calculated as the ratio of the proportional resistance between the SCD and AA groups. Survival was analyzed by MDR status using Kaplan-Meier curves and Cox Proportional Hazards models, adjusting for the fol- lowing covariates: age, sex, SCD genotype, and hydrox- yurea use. For patients lost to follow-up, MDR status and survival were censored at the date of last known contact. The survival time was defined as the period between January 1, 2017 and either the date of patient’s death or last known encounter up to April 14, 2020.
Baseline characteristics of the SCD and AA cohort were similar for age, sex, and follow-up time (Online Supplementary Table S2). Between January 1, 2017 and April 14, 2020, we observed 176 non-recurrent positive cultures, defined as not occurring within 30 days of a pre- vious culture with an identical organism and source,11 in 77 of 320 (24.1%) SCD patients (Online Supplementary Table S3). The total infection rate in SCD patients was 205.0 infections per 1,000-person-years. We observed 3,968 non-recurrent positive cultures in 2,075 of 16,000 (13.0%) AA patients, for a total infection rate of 92.8 infections per 1,000-person-years (P<0.001).
An MDR infection was observed in 27.3% (21 of 77) of SCD and 33.3% (692 of 2,075) of AA patients (P=0.3) with an infection. Baseline differences in the SCD patients by MDR status are provided in Table 1. There were no SCD adults on penicillin prophylaxis during the study period. Female sex (OR 5.9, 95% Confidence Interval [CI]: 1.6–21.7; P=0.007) and central venous catheter placement (OR 4.3, 95%CI: 1.6–11.5; P=0.004) were independently associated with an increased MDR infection risk and PPSV23 vaccination was associated with a reduced risk (OR 0.2, 95%CI: 0.1–0.6; P=0.003), adjusting for age, SCD genotype and hydroxyurea use.
Antimicrobial resistance patterns for antimicrobial- organism pairs in SCD patients are provided in Figure 1A and Online Supplementary Table S4. Antimicrobial resist- ance was observed in 11.4% (135 of 1,050) of unique Escherichia coli infections, including 26.1% (23 of 88 test- ed) resistant to levofloxacin, 22.7% (20 of 88 tested) to sulfamethoxazole-trimethoprim, and 2.4% (2 of 82 test- ed) to nitrofurantoin. Klebsiella pneumoniae and Pseudomonas aeruginosa were highly resistant to several antibiotic groups, with the exception of amikacin and imipenem for Klebsiella pneumoniae and amikacin for Pseudomonas aeruginosa. Oxacillin-resistant Staphylococcus aureus was observed in 53.8% of infections. Both coagu- lase-negative Staphylococcus epidermidis and Staphylococcus species were highly resistant to most antibiotic groups except for vancomycin. We observed
only one Staphylococcus pneumoniae infection, which was resistant to penicillin.
A comparison of resistance patterns between SCD and AA patients are provided in Figure 1B. Escherichia coli infections were less commonly resistant, while Klebsiella pneumoniae and Pseudomonas aeruginosa infections were typically more resistant to antibiotics in SCD versus AA patients.
During the 3-year study period, 14 of 320 (4.4%) SCD patients died; ten of 299 (3.3%) without and four of 21 (19.0%) with an. MDR infection (Figure 1C). Sepsis was a contributing factor to the cause of mortality in eight of ten deaths with a known etiology. Developing an MDR infection was an independent risk factor for death (Hazard Ratio [HR] 4.9, 95%CI: 1.5–16.4; P=0.009), adjusting for age, sex, SCD genotype and hydroxyurea use.
In the era of penicillin prophylaxis, we observed higher rates of infection but a similar prevalence of MDR infec- tions in SCD adults compared to AA. This suggests that penicillin prophylaxis may be altering colonization and infection patterns but not drug resistance patterns for gram-positive infections in SCD adults. Vaccination with PPSV23 reduces exposure to antimicrobial drugs and is associated with less resistance to erythromycin, trimethoprim-sulfamethoxazole, and cephalosporins in the general population.12 We observed high rates of resist- ance to trimethoprim-sulfamethoxazole and erythromy- cin in gram-positive bacterial infections. Furthermore, vaccination with PPSV23 was associated with a 5-fold lower risk of having an MDR infection. In the general population, approximately 20–67% of central-line associ- ated infections are MDR infections.13 In our cohort, cen- tral venous catheter line placement, which is often required for pain management or for exchange transfu- sion therapy in SCD, was associated with a 4-fold greater risk of developing an MDR infection. Alternative strate- gies for administering pain medications, such as inhaled routes, and better implementation of protective meas- ures, such as the use of chlorhexidine for skin prepara- tion, avoiding femoral vein catheters, and the use of anti- septic barrier caps,14 may help reduce MDR infection rates in SCD. The association of female sex with a higher MDR infection rate may be due to the increased risk for urinary tract infections in females. Other potential bio- logical differences, such as the effects of sex hormones and X-chromosome genes on immune response regula- tion, may also be contributing to the observed differ- ences.15
Limitations of our study include being a single-center study and not taking into account the specific antimicro- bial therapies used to treat the infections. Investigating the effects of socioeconomic status and health behavior may highlight modifiable risk factors to improve vaccina- tion rates in SCD. Health care utilization is a likely con- tributor to developing antibiotic resistance, and therapies that reduce hospitalizations may be another approach to reduce MDR infections. Future strategies to reduce the spread of antibiotic resistance, such as greater implemen- tation of PPSV23 and strategies to reduce central venous catheter placement, may help decrease the morbidity and early mortality observed in SCD.
Andrew Srisuwananukorn,1 Jin Han,1,2 Rasha Raslan,3 Michel Gowhari,1 Faiz Hussain,1 Franklin Njoku,1
Robert E. Molokie,1,4 Victor R. Gordeuk1 and Santosh L. Saraf1
1Sickle Cell Center, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 2Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL,
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