Associated Outcomes of Different Intravenous Antibiotics Combined with 2% Mupirocin Ointment in the Treatment of Pediatric Patients with Staphylococcal Scalded Skin Syndrome

Introduction

Staphylococcal Scalded Skin Syndrome (SSSS) is a desquamative disease caused by the production of Exfoliative Toxin A (ETA) and Exfoliative Toxin B (ETB) by Staphylococcus aureus (S. aureus).¹ It primarily affects newborns and children under the age of five with very rare cases reported in adults.² The susceptibility to SSSS is related to the inability to metabolize ETA and ETB in the kidney and low titers of antibodies against ETA or ETB in children.³ Recent epidemiological studies have reported an increase in the morbidity of SSSS, with estimates suggesting that the incidence of SSSS in children is approximately 7.67 per million every year in the US⁴ and 696.4 per million in China.⁵

Children with SSSS typically present with several skin signs, including disseminated erythema, baggy blister-like lesions, and epidermal detachment.⁶ Consequently, a series of complications occur, including deprivation of body fluids, electrolyte abnormalities, and hypothermic and secondary infections such as septicemia and ethmyphitis, etc.^6,7 It is important to use intravenous antibiotics as quickly as possible to treat SSSS.⁸ Current recommendations for the treatment of SSSS remain controversial. As clindamycin can inhibit the synthesis of toxins that mediate the lysis of the granular layer in the skin, it is recommended by some researchers for the treatment of SSSS.^9,10 However, some studies have demonstrated that clindamycin does not improve clinical outcomes.^2,11,12 For example, some experts have found that clindamycin monotherapy does not significantly reduce hospital length for patients with SSSS.^2,12 Another retrospective analysis by Gray et al revealed that clindamycin does not improve patient prognosis.¹ Penicillinase-resistant penicillins and cephalosporins are recommended for the empiric management of SSSS. Anti-methicillin-resistant S. aureus (MRSA) was considered if the prevalence of MRSA was high in the communities or if the patients failed to improve after empiric administration of cephalosporins or penicillinase-resistant penicillins.¹¹ Mupirocin ointment is one of the most effective topical antibiotics used to clear nasal S. aureus strains, including methicillin-susceptible S. aureus (MSSA) and MRSA. Mupirocin prevents protein and RNA synthesis by inhibiting isoleucyl-tRNA synthetase, which ultimately leads to bacterial death.¹³ Mupirocin has also been reported to eliminate MRSA.¹⁴ The number of cases of MRSA skin infections treated with mupirocin has increased over the past decade.¹⁵ Mupirocin can also be applied externally to treat SSSS.¹⁶

With China’s aging population presenting significant challenges to its healthcare system, the government aims to maximize health outcomes while minimizing medical costs. To reduce the disease burden, total medical costs are strictly controlled.¹⁷ Therefore, selecting effective low-cost antibiotics for treating SSSS is crucial. To the best of our knowledge, there is a lack of data on the outcomes of pediatric patients with SSSS treated with anti-MSSA intravenous antibiotics along with topical mupirocin. Here, we compared the days of the treatment duration and costs among different intravenous antibiotic groups in combination with topical 2% mupirocin ointment. Furthermore, the antimicrobial susceptibility of S. aureus and the factors influencing treatment duration for different intravenous antibiotics were investigated.

Patients and Methods

Study Population

We conducted a retrospective study using data from pediatric patients with SSSS who were admitted to the Department of Dermatology, The First Affiliated Hospital of Gannan Medical University, between January 1, 2012, and December 31, 2022. This study adhered to the principles of the Declaration of Helsinki of the World Medical Association and ethics approval was granted by the Ethics Committee of the First Affiliated Hospital of Gannan Medical University (No. 2019100). All legal guardians provided written informed consent for the publication of their data. The SSSS cases were identified by reviewing electronic medical records using the International Classification of Diseases, ninth revision code 695.81, or tenth revision code L00.x00. A total of 400 patients were identified. We have included 253 patients meeting diagnostic criteria based on clinical manifestations. Excluded were 147 patients with comorbidities or complications (n=69), transferred to pediatrics (n=31), or not administered antibiotics in the present study (n=47) (Figure 1). The diagnostic criteria were based on the following clinical manifestations: erythema, bullae, and scaling on the skin with a positive Nikolsky sign and tenderness; radial fissuring in the periorificial area was considered a characteristic sign of SSSS, and the mucosal area was not involved (Figure 2A).^18,19

Figure 1 Study flowchart of patients and methods. Abbreviations: SSSS, Staphylococcal Scalded Skin Syndrome; S. aureus, Staphylococcus aureus.

Figure 2 Skin manifestation evolution of a patient with Staphylococcal Scalded Skin Syndrome (SSSS). (A) A patient with SSSS on admission. Skin erythema, blistering, periocular crusting, radial fissuring, exfoliating rash, and positive Nikolsky’s sign were seen on the face. (B) After 3 days of treatment, the erythema subsided, and the blisters dried up and crusted. (C) The same patient after 7 days of treatment, all the erythema resolved, and a few desquamations were left with mild pigmentation and without scarring.

The exclusion criteria were as follows: patients whose caregivers refused intravenous antibiotics; patients with comorbidities such as bacterial infection that could influence the treatment course of intravenous antibiotics; patients with severe complications such as secondary infection, sepsis, and severe dehydration; patients with diseases related to immune deficiency or impaired kidney function, and patients who were transferred to other departments. Baseline characteristics of 253 patients with SSSS were collected, including sex, age, onset days before admission, febrile status, white blood cell (WBC) count, and C-reactive protein (CRP) level. The normal range of CRP levels is 0–6 mg/L. The baseline characteristics of patients with SSSS are presented in Table 1.

Table 1 Baseline Characteristics of Pediatric Patients with SSSS (n=253)

Antibiotic Regimen Groups and Laboratory Tests

Amoxicillin–clavulanic acid (Huabei Pharmaceutical Co., Ltd. Shijiazhuang, China), or cefathiamidine (Luoxin Pharmaceutical Co., Ltd. Linyi, China) or cefuroxime (Huidisen Pharmaceutical Co., Ltd. Hanzhou, China) or ceftriaxone (Kelun Pharmaceutical Co., Ltd. Chengdu, China) were intravenously administered in 48, 82, 65, and 58 patients, respectively. The dosages of the intravenous antibiotics were according to their instructions. The doses of amoxicillin-clavulanic acid and ceftriaxone were 30mg per kilogram of body weight every 8 hours and 20mg per kilogram of body weight once a day, respectively. Cefathiamidine and cefuroxime at a dose of 20mg per kilogram of body weight every 8 hours were prescribed. Twice daily, all patients were administered 2% mupirocin ointment (China-USA SmithKline Pharmaceutical Co., Ltd. Tianjin, China) on their skin lesions. Thirteen S. aureus clinical strains were successfully cultured, and antimicrobial susceptibility tests were performed. S. aureus drug sensitivity tests of levofloxacin, erythromycin, tetracycline, clindamycin, oxacillin, penicillin G, vancomycin, and mupirocin were performed using the microdilution method. Minimum inhibitory concentration results were interpreted in accordance with Clinical and Laboratory Standards Institute guidelines and the previous publication.^20,21 The intravenous and topical application of antibiotics was withdrawn if all the erythema and bullae resolved with a few desquamations and without scarring.

Statistical Analysis

SPSS v.23.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 6.0 (Insightful Science Company, San Diego, CA, USA) were used for statistical analyses and graphing data, respectively. Data are presented as frequencies for categorical variables or (25th and 75th percentiles) for continuous variables. Pearson’s chi-square test or the Kruskal–Wallis test was used to analyze the differences in baseline characteristics among the different groups. Mann–Whitney U-test was used to compare the treatment duration of intravenous antibiotics between different age groups. Differences in the resistance rates of the eight antibiotics were compared using Cochran’s Q test. Kruskal–Wallis tests were used to compare the days of intravenous antibiotic application and total hospitalization costs among the different antibiotic groups. Univariate analysis with the Mann–Whitney U-test or Spearman’s rank correlation test was used for simple factor analysis. Covariates were adjusted using a multivariate linear regression model to analyze factors affecting the course of treatment with different intravenous antibiotics, including amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime. P <0.05 was considered statistically significant.

Results

A total of 253 pediatric patients, including 106 females and 147 males were included in the present study, most of whom were aged below 5 years (84.58%). Four types of antibiotics were administered intravenously: amoxicillin-clavulanic acid (18.97%), cefathiamidine (32.41%), cefuroxime (25.69%), and ceftriaxone (22.92%). The WBC count and CRP levels in most patients were normal. There were no significant differences in baseline characteristics among the different antibiotic groups (all p>0.05). The treatment course of intravenous amoxicillin-clavulanic acid, cefathiamidine and cefuroxime in the age groups below 60 months were significantly longer than those in the age groups equal to or above 60 months (p<0.01, Supplementary Table 1). Meanwhile, the treatment duration of the intravenous antibiotics were comparable between the other age groups (p>0.05, Supplementary Table 1). Skin manifestations at admission, three days post-treatment, and at the endpoint of antibiotic administration are presented in Figure 2A–C, respectively. Gradual resolution of skin lesions can be observed in these images. All the patients achieved full recovery by the end of the study period.

The antibiotic sensitivity results of 13 S. aureus strains are shown in Table 2 and Supplementary Table 2. There were significant differences in sensitivity rates among eight antibiotics, including levofloxacin, erythromycin, tetracycline, clindamycin, oxacillin, penicillin G, vancomycin, and mupirocin. The pairwise comparisons showed that the sensitivity rates of oxacillin (84.62%), vancomycin (100%), and mupirocin (100%) were significantly higher than those of erythromycin (0), penicillin G (0), and clindamycin (7.69%) (p<0.0001), and the sensitivity rates of oxacillin (84.62%) was comparable to those of vancomycin (100%) and mupirocin (100%) (p>0.05). Two S. aureus strains which were resistant to oxacillin were cultured from two SSSS patients who were successfully treated with intravenous amoxicillin-clavulanic acid combined with 2% mupirocin ointment. The medians of days of intravenous amoxicillin-clavulanic acid, cefathiamidine, cefuroxime, and ceftriaxone application were 7, 7, 7, and 8 days, respectively. According to the Kruskal–Wallis test, the duration of intravenous ceftriaxone application was significantly longer than amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime (p<0.01, Figure 3A). There were no significant differences in the duration among patients treated with amoxicillin-clavulanic acid, cefathiamidine, or cefuroxime (p>0.05, Figure 3A). The medians of total hospitalization costs for patients using amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime were 449.7, 502.8, and 429.9 US dollars, respectively. The total hospitalization costs for patients using cefathiamidine were significantly higher than those using amoxicillin-clavulanic acid and cefuroxime (p<0.05, Figure 3B). There were no significant differences in total hospitalization costs between the patients using amoxicillin-clavulanic acid and those treated with cefuroxime (p>0.05, Figure 3B).

Table 2 Antibiotic Sensitivity Test Results of S. aureus Isolated from Patients with SSSS (n=13)

Figure 3 Comparison of the days of treatment course and the total costs of hospitalization among different intravenous antibiotic groups. (A) The differences in the number of days of treatment course among different intravenous antibiotic groups. (B) The differences in the total costs of hospitalization among different intravenous antibiotic groups. Abbreviation: ns, non-significant. Notes: Kruskal–Wallis tests were used to compare the days of the treatment course and the total costs of hospitalization among different intravenous antibiotic applications. *p <0.05, **p <0.01,****p <0.0001.

According to the univariate analysis, age below 60 months was associated with more days of intravenous antibiotic application of amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime compared with age equal to or above 60 months (p<0.01, Table 3); WBC count was positively correlated with the days of intravenous cefathiamidine application (p<0.05, Table 3). In the multivariate linear regression model for amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime, the associations between the days of antibiotic application and patient age remained significant (β=−1.48, [95% CI: −2.29, −0.66] for amoxicillin-clavulanic acid, and β=−1.44, [95% CI: −2.06, −0.83] for cefathiamidine, and β=−0.96, [95% CI: −1.58, −0.34] for cefuroxime) (all p<0.01, Table 4). In multivariate analysis for cefathiamidine, the days of intravenous cefathiamidine application were significantly associated with WBC count (β=0.05, [95% CI: 0.01, 0.10], p<0.05) and CRP level (β=1.12, [95% CI: 0.14, 2.10], p<0.05) (Table 4).

Table 3 Univariate Analysis of Variables Affecting the Treatment Course of Different Intravenous Antibiotics in Patients with SSSS

Table 4 Multivariate Analysis of Factors Affecting the Number of Days of Intravenous Antibiotic Application in Patients with SSSS

Discussion

To our knowledge, our study is the first and the largest retrospective study to compare the days of treatment course and costs among different intravenous anti-MSSA antibiotic applications in combination with topical use of 2% mupirocin ointment and to investigate the factors affecting the intravenous antibiotic treatment course in pediatric patients with SSSS. Consistent with previous studies, most patients (84.58%) were below five years of age, and the number of male patients was nearly equal to the female patients at a ratio of 1.39:1.^6,22–24 Similar to the results previously described in some studies, 96.05% of patients had their CRP levels within the normal range.^16,25,26 The features of these patients were consistent with the typical characteristics of patients with SSSS.

Some studies have found that S. aureus strains isolated from patients with SSSS display higher rates of clindamycin resistance compared with overall S. aureus strains.^11,27,28 We found a similarly high resistance rate (92.31%) to clindamycin in S. aureus strains in our study. Therefore, we consider that the combined use of clindamycin in SSSS cases is unnecessary, and clindamycin monotherapy in patients with SSSS in our district should be avoided. Previous epidemiological studies have shown that the predominant isolates in children with SSSS are MSSA.^3,27,29 Several studies in China and Japan have reported that more than 95% of S. aureus isolates are methicillin-sensitive.^5,11,29 In line with previous studies, MSSA was the predominant pathogen identified in culture, with 84.62% of the clinical strains sensitive to oxacillin in our study.^27,28 In our study, we used amoxicillin-clavulanic acid, cefathiamidine, cefuroxime, and ceftriaxone combined with an external application of 2% mupirocin ointment for the treatment of SSSS without treatment failure. Amoxicillin-clavulanic acid is an anti-β lactamase penicillin that is commonly used to treat skin infections with MSSA.^30,31 Cefathiamidine is a first-generation cephalosporin approved by the China Food and Drug Administration for the treatment of infections caused by MSSA.^32,33 Cefuroxime is a second-generation cephalosporin antibiotic that effectively eliminates penicillinase-producing staphylococci.³⁴ Cefuroxime and β-lactamase-resistant penicillin such as amoxicillin-clavulanic acid are recommended for prompt empiric treatment of SSSS.⁶ Ceftriaxone is also considered a treatment option for MSSA infection.^35,36 However, we found that the treatment course of intravenous ceftriaxone for SSSS was longer than amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime. Previous studies have shown that it is not suitable to use a routine dose of ceftriaxone to treat MSSA infections.³⁷ Another retrospective study comparing the efficacy of cefazolin and ceftriaxone in the treatment of MSSA bacteremia revealed a higher rate of treatment failure with ceftriaxone.³⁸ We speculate that lower serum concentrations of free ceftriaxone, as a result of higher protein binding, could contribute to unsatisfactory treatment outcomes. Therefore, we do not recommend the use of intravenous ceftriaxone as an empirical regimen to treat SSSS. However, further studies are needed to confirm this hypothesis.

Recent reports have found cases of SSSS due to MRSA infection.^39,40 Therefore, some experts recommend the use of vancomycin for the empirical treatment of SSSS in districts where MRSA is the predominant strain.¹⁹ In our study, we found only two patients with SSSS infected with MRSA who were successfully treated with intravenous amoxicillin-clavulanic acid and topical mupirocin. Several studies have reported similar results showing that clinical improvement can be achieved regardless of the susceptibility of S. aureus strains.^11,26 We inferred that antibodies against exfoliative toxins might play a role in the improvement of SSSS caused by MRSA. Additionally, according to a systematic review, the prevalence of clinical S. aureus resistant to mupirocin was low, which could help eliminate MRSA in patients with SSSS.⁴¹ Moreover, the culture results of the clinical specimens could only represent the colonization of S. aureus rather than the causative organism. Further studies on the classification of S. aureus using the method of multilocus sequence typing are warranted to confirm whether there are molecular strains such as sequence types 15, 121, 2126, and 2993 that cause SSSS.²⁸

In our study, we found that the cost of cefathiamidine was higher than that of amoxicillin-clavulanic acid and cefuroxime with comparable treatment courses. We reduced the types of ancillary tests used in our study because they did not improve diagnostic precision.¹ Thus, we inferred that antibiotic costs may be the largest driver of total hospitalization cost differences among the different groups. Indeed, the price of cefathiamidine is higher than amoxicillin-clavulanic acid and cefuroxime in our country. Based on these data, amoxicillin-clavulanic acid and cefuroxime are the preferred antibiotics for the treatment of patients with SSSS.

In the final multiple linear regression model, younger age correlated with a longer duration of intravenous antibiotic treatment in the amoxicillin-clavulanate, cefathiamidine, and cefuroxime treatment groups. Low titers of antibodies against exfoliative toxins and limited capacity for renal clearance of the toxin at a young age may lead to a relatively high incidence of SSSS at a younger age.^6,23,42 Therefore, we speculate that the increased antibody titers and renal clearance capacity in older children might be favorable in the reduction of the length of intravenous antibiotic treatment course. Larger studies investigating the clinical responses of SSSS patients of different age groups are necessary.

The total WBC count is commonly used to assess the risk of serious bacterial infections. Studies have explored the role of the WBC count in evaluating the severity of infectious diseases, with some researchers reporting that treatment failure and prolonged hospital stay in patients with skin and soft tissue infections are significantly associated with a high WBC count.^43,44 Higher WBC counts on admission are also associated with a higher risk of mortality in patients with S. aureus induced infective endocarditis.⁴⁵ CRP is an acute-phase protein that is widely measured in infectious diseases, and a valuable marker of systemic inflammation, as well as a good clinical indicator of severe infections.⁴⁶ A few studies have reported that in infectious diseases, increased CRP levels are associated with an increased length of hospital stay.^47,48 CRP levels are important predictors of fatal clinical outcomes in S. aureus bacteremia.⁴⁹ The studies above demonstrated that a higher WBC count and CRP level could indicate a more severe infection, resulting in a longer duration of intravenous cefathiamidine application, which is consistent with the findings of the present study and similar with findings of our previous study.¹⁶

It is worth noting that the association between elevated WBC and CRP levels and prolonged duration was only found in the intravenous cefathiamidine group, but not in the amoxicillin-clavulanic acid and cefuroxime groups. This could be because of the small sample size of each group in our study, or it could be because some covariates, such as differential titers of antibodies against exfoliative toxins and renal clearance capacity, which could affect the treatment course, were not examined.

Our study had a few limitations. First, ours is a single-center, retrospective study with a small sample size. Second, we did not measure the anti-toxin antibiotics titers or the toxin-clearing renal clearance capacity of patients to confirm their influence on the improvement of SSSS. Third, multi-locus sequence typing on the S. aureus clinical strains were not performed. Future prospective and randomized trials are needed to evaluate the performance of the laboratory tests mentioned above.

Conclusions

Oxacillin resistance is rare, whereas the clindamycin resistance rate is high in pediatric patients with SSSS in our district. The administration of intravenous amoxicillin-clavulanic acid and cefuroxime combined with topical mupirocin was favorable in treating SSSS because of their relatively shorter intravenous treatment course compared with ceftriaxone and lower costs compared with cefathiamidine. Younger age, as well as elevated WBC count and CRP levels, may indicate that a longer treatment course with intravenous anti-MSSA antibiotics is required.