Multi-Site Infections Caused by Methicillin-Resistant Staphylococcus Aureus in a Six-Year Old Girl: A Rare Case Report

Background Community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen that leads to severe outcomes, especially in pediatric patients with multiple site infections. Case presentation: We report a case of a multiple organ and life-threatening infection caused by CA-MRSA in a 6-year-old girl who manifested sepsis, myelitis, purulent arthritis, purulent meningitis, hydropericardium, pneumonia, and empyema. The girl exhibited good response to the combination therapy of linezolid and rifampicin after treatment with vancomycin failed due to delay in achieving target serum concentration. We performed pleural effusion and hydropericardium effusion drainage and treated left lower limb infection using interdisciplinary approaches.

and empyema. The girl exhibited good response to the combination therapy of linezolid and rifampicin after treatment with vancomycin failed due to delay in achieving target serum concentration. We performed pleural effusion and hydropericardium effusion drainage and treated left lower limb infection using interdisciplinary approaches.

Conclusion
This case highlights the need to be aware of CA-MRSA infection, which requires accurate diagnosis, identi cation of site infection, appropriate antibiotic treatment, and surgical debridement.

Background
Staphylococcus aureus (S. aureus) is one of the main pathogens of community-and hospital-acquired infections and can cause a wide variety of infectious diseases, including mild skin and soft tissue infections, endocarditis, osteomyelitis, and fatal pneumonia [1,2]. Moreover, based on the sensitivity to antibiotic drugs, S. aureus can be categorized into methicillin-resistant S. aureus (MRSA) and methicillinsensitive S. aureus (MSSA). Based on the original source, MRSA is classi ed into community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA) [3,4]. MRSA infections lead to higher mortality than MSSA [5,6] and delay in active antimicrobial therapy further worsens the outcomes. In the last decade, rates of CA-MRSA infection have increased steadily, while HA-MRSA infection rates have generally declined [7]. CA-MRSA typically presents as skin and soft tissue infection, but invasive infection such as septicopyemia may also occur, which can lead to serious or even fatal consequences, especially in children. Patients with CA-MRSA infections tend to be younger, and often, are otherwise healthy.
Notably, CA-MRSA can acquire drug resistance genes, and its resistance has increased over time, making CA-MRSA treatment challenging. In a retrospective study based on 208 cases of community-acquired S. aureus mediated septicopyemia, 136 cases had CA-MRSA infection and 12 deaths were attributed to the CA-MRSA infections [8].
MRSA prevalence is estimated at < 50% in most countries, with several countries reporting prevalence of < 25%. However, the prevalence and epidemiology of MRSA have been constantly changing, with novel MRSA clones being reported in different geographical regions. MRSA prevalence has been increasing since the early 2000s and several reports have come different countries [9]. Even with the ongoing development of new antibiotics and advances in infection prevention, MRSA remains a challenging pathogen with persistently high mortality [10]. The mortality rate of systemic infection caused by MRSA is more than 50%, which has become a worldwide problem in clinical and community anti-infective treatment [3,11]. It has been estimated that the treatment failure rate of complicated MRSA bloodstream infections is as high as 40% [12]. The prognosis of a single site MRSA infections is relatively better.
However, multiple site infections caused by MRSA are rare, are di cult to treat, and lead to high mortality rates. Here, we report a pediatric patient who suffered from sepsis, myelitis, purulent arthritis, purulent meningitis, hydropericardium, pneumonia, and empyema. The child exhibited good response to the therapy and had a good recovery.

Case Presentation
The patient was a 6-year-old girl without a family history of immunode ciency. The girl suffered from left anklebone fracture due to trauma and received plaster xation on January 14, 2019. Two days later, she was febrile with the temperature of 38.0 ℃, accompanied by systemic pain, cough, dyspnea, chest tightness, headache, and pain in left foot. She had local swelling and was unable to walk. Blood and hydropericardium cultures were positive for MRSA and she was treated with intravenous meropenem combined with vancomycin. However, the treatment was not effective and the condition of the patient gradually aggravated. She was transferred to our hospital for further treatment in pediatric ICU on January 24, 2019. After admission, the child presented dyspnea, which could not be alleviated by nasal catheter oxygenation. Chest-enhanced Computed tomography (CT) revealed bilateral pneumonia and large amount of pleural effusion ( Fig. 1a-b). Closed thoracic drainage was performed, and specimens were sent for culture. Chest tube was removed after seven days. Further auscultation revealed weakened pulmonary moist rales and cardiac sound, while echocardiography revealed moderate amounts of hydropericardium and cardiac insu ciency. We performed pericardiocentesis and found hydropericardium to have yellow turbidity with ocs. Approximately 100 mL pericardial uid was drained daily during the rst two weeks, and the volume decreased gradually. The pericardial drainage tube was removed on the 26th day and pericardial uid was sent for culture. Before administering anti-infective treatment, blood and bone marrow were also sent for culture. The child had been suffering from high fever with a temperature of 40°C and had headache. Investigations at the other hospital showed that cerebrospinal uid (CSF) had 1233 × 10 6 leukocytes/L, glucose under 1.1 mmol/L, protein at 1470 mg/L, and chloride at 116.3 mmol/L. Investigation revealed purulent meningitis. After admission to our hospital, CSF investigation on January 27, 2019 showed 12.0 × 10 6 leukocytes/L, glucose at 2.5 mmol/L, protein at 500 mg/L, and chloride at 130 mmol/L. CSF culture showed absence of bacteria or fungi. However, next-generation sequencing (NGS) analysis revealed presence of S. aureus (Fig. S1). Purulent meningitis was under control due to the administration of anti-infection treatment at the other hospital. As a result, the examination of nervous system did not show any obvious abnormalities, and the magnetic resonance imaging (MRI) of the cranium was normal. However, the laboratory ndings including complete blood cells count revealed high level of white cells (white blood cell count of 13.9 × 10 9 /L, with 78.3% neutrophils, 16.4% lymphocytes, and 3.7% monocytes), while the C-reactive protein (CRP) was 111 mg/L. Therefore, antibiotic treatment of vancomycin (15 mg/kg per dose every 6 hours) combined with rifampicin was administered. Once vital signs leveled off, MRI of the lower extremity was performed, which demonstrated osteomyelitis (Fig. 1c-d). Results of marrow, blood, pleural effusion, and hydropericardium cultures eventually con rmed MRSA infection after one week. Next, multi-locus sequence typing (MLST) and S. aureus-speci c staphylococcal protein A (spa) typing were performed to identify the strain. Tests for Staphylococcal cassette chromosome mec (SCCmec) typing and MRSA toxin identi cation were also performed. The test results revealed that the sequence type (ST) was ST-59, the spa type was t437, and the SCCmec typing was type IV. In addition, the strain tested positive for pantonvalentine leukocidin (PVL) and staphylococcal enterotoxin genes, including seb, sek, and seq.
On day 8 after hospitalization, the child still had fever and the in ammatory index including CRP and procalcitonin (PCT) remained signi cantly higher than normal. Meanwhile, left foot and knee had tenderness with obvious local swelling, increased local temperature, and restricted movement. Orthopedists performed debridement of the left ankle ( Fig. 3a-d) and left knee, retained drainage after the surgery (Fig. 1d), and changed dressing regularly per the orthopedic recommendations. After the operation, the child still had a high fever; complete blood count showed WBC of 16.5 × 10 9 /L, while CRP was 122 mg/L, revealing that the infection was not under control even on day 11 of antibiotic treatment.
Vancomycin trough was routinely monitored, with a concentration of up to 7.4 µg/mL, which did not reach the effective range. Hence, vancomycin was discontinued and treatment with linezolid combined with rifampicin was started (Fig. 2b). Thus, the patient was treated for 45 days with intravenous linezolid combined with rifampicin following vancomycin treatment. The patient's condition gradually improved and WBC count and CRP level returned to normal, indicating that clinical treatment was effective (Fig. 2a). The chest CT showed a signi cant improvement in bilateral pneumonia, pleural effusion, and hydropericardium ( Fig. 1c-d). MRI of left lower extremity showed that wide T2WI high signal had not improved, but cystic uid was absorbed (Fig. 1g-h). Eventually, the patient was discharged on the 57th day of admission. The child and her guardian provided written consent for reporting this case.

Discussion
MRSA has become one of the most important pathogens of recent time. The organism is transmitted in both healthcare and community settings and is the leading cause of bacteremia, endocarditis, skin and soft tissue infections, bone and joint infections, and hospital-acquired infections. Studies have reported that MRSA can cause psoitis, multiple venous thromboses [13], empyema necessitans [14], acute epiglottitis [15], fatal necrotizing pneumonia [16], sepsis with bilateral pneumonia, osteomyelitis, and septic arthritis of the knee [17], all of which achieved good therapeutic results after relevant treatment. However, treatment of multi-system infections caused by MRSA is di cult, and therefore, its mortality rate remains high. No case reports have described MRSA infections leading to sepsis, osteomyelitis, purulent arthritis, hydropericardium, septic meningitis, pneumonia, and empyema. Here, we report a child who suffered from all clinical symptoms mentioned above and yet exhibited good response to the therapy. Such a typical case of MRSA infection has never been reported in literature. Here, we share our experience for clinicians to improve the success rate of treatment in future similar clinical scenarios.
We explored the reasons which may have caused the severe infections in this child. The causative strain was identi ed as ST59-SCCmec IV-t437, which was the most common CA-MRSA increasing in Shanghai, China [18][19][20]. Rates of CA-MRSA infections have increased signi cantly during the past 30 years worldwide. S. aureus can produce several types of exotoxins with varying effects. PVL is one of the synergohymenotropic exotoxins produced by S. aureus and belongs to pore-forming toxin family. Most CA-MRSA carry the gene encoding PVL. The association of PVL with an enhanced in ammatory response, pus-forming lesions, necrotizing pneumonia, skin infections, and other severe infections that often require surgical intervention is well documented in otherwise healthy children [21]. In our case, we con rmed that the strain was PVL-positive, which also explained the potential cause of the severe infection in the child.
MRSA is not only resistant to β-lactam antibiotics, but also to other antimicrobial agents such as aminoglycosides, quinolones, and macrolides. Infections caused by MRSA have been regarded clinically challenging and have attracted extensive attention from domestic as well as foreign experts. Vancomycin has long been considered the rst-line antibiotic treatment for invasive MRSA infection, including both HA-MRSA and CA-MRSA. However the use of vancomycin is limited because of its shortcomings such as the slow bactericidal activity, increased minimum inhibitory concentrations (MICs), reduced activity against bio lm-forming pathogens, and poor tissue penetration [22]. Several researchers have shown that subtherapeutic trough vancomycin concentration is the main reason of treatment failure. Vancomycin treatment failed in our patient due to the delay in achieving target serum concentration. we monitored the vancomycin trough dynamically up to 7.4 µg/mL, while the guideline recommends the trough level to be 15-20 µg/mL, which could not be reached in our case. Since vancomycin is mainly excreted in urine, renal function is the most important determining factor for vancomycin pharmacokinetics. Augmented renal clearance (ARC) is associated with reduced β-lactam plasma concentrations and Yang Chu et al showed its impact on clinical outcomes [23]. Creatinine clearance (CLcr) of more than 130 mL.min − 1 is termed high CLcr [24]. ARC patients are signi cantly younger, and exhibit a higher CLcr and glomerular ltration rate. The patients with high Ccr show signi cantly lower trough vancomycin concentrations in the same dosing regimen. Here, our patient was young and showed the CLcr within 120-130 mL.min − 1 .
We speculate that the reason of low vancomycin valley concentration may be related to CLcr. Clinical practice guidelines for the treatment of refractory MRSA bacteremia and vancomycin treatment failure lack consensus. We started linezolid after vancomycin treatment failed. A previous study [25] showed that linezolid had the highest inhibitory effect on S. aureus. On the 7th day after starting linezolid treatment, in ammatory biomarker CRP decreased from 120 to 85 mg/L and the body temperature also decreased signi cantly. Further, pulmonary in ammation and pericardial effusion were evidently absorbed, indicating that antibiotic treatment was effective. Finally, the child was discharged 57 days after admission. We followed up the child after discharge. While movement of her left leg has a slightly limp, the child is otherwise normal.

Conclusion
In summary, since clinical practice guidelines for the treatment of refractory MRSA bacteremia and vancomycin treatment failure lack consensus, antibacterial treatment should be adjusted according to the clinical e cacy; moreover, timely control of focal infection is the key to successful clinical outcome.

Disclosure statement
No potential con ict of interest is reported by the authors.