Methicillin Resistant Staphylococcus aureus Pulmonary Infections in Children

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1 Commentary Methicillin Resistant Staphylococcus aureus Pulmonary Infections in Children Ashlesha Kaushik 1 * and Helen Kest 2 * 1 Pediatric Infectious Disease, Unity Point Clinic and Siouxland Medical Education Foundation; Department of Pediatrics, University of Iowa Carver College of Medicine, USA 2 Pediatric Infectious Disease, Department of Pediatrics, St. Joseph s Children s Hospital, USA *Corresponding Authors: Ashlesha Kaushik, UnityPoint Clinic, 319 Sergeant Square Dr, Sergeant Bluff, IA 51054, USA, Tel: ; Fax: ; ashleshakaushik@gmail.com; Ashlesha.Kaushik@ UnityPoint.org Helen Kest, 703, Main Street, Paterson, NJ 07503, USA, KestH@ sjhmc.org First Published October 29, 2018 Copyright: 2018 Ashlesha Kaushik and Helen Kest. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2

2 Introduction Staphylococcus aureus is ubiquitous and can cause infections ranging from skin and skin structure infections to life threatening invasive disease. Methicillin Resistant Staphylococcus aureus (MRSA) is resistant to most beta-lactam antibiotics and has fewer therapeutic options for management. MRSA infections are associated with significant morbidity and mortality. S. aureus is known to colonize around 30% to 50% of healthy children and adults. S aureus is one of the most common causes of ventilator associated pneumonia (VAP) and nosocomial pneumonia in children and is the second most common cause of health careassociated bacteremia [1]. MRSA VAP is associated with increased length of hospitalization, increased requirement of intensive care, and healthcare costs thus leading to substantial economic burden [2,3]. It has been shown that absence of MRSA colonization has a negative predictive value of >90% for development of MRSA VAP, and the presence of S. aureus colonization has been shown to be associated with a 15-fold greater risk of developing pneumonia, thus showing that colonization usually heralds development of MRSA pneumonia [4-6]. Pathogenesis In MRSA strains, resistance to β-lactam antibiotics is conferred by the acquisition of meca gene that encodes for PBP2a, that has reduced affinity for β-lactam antibiotics compared to native PBP molecules and allows cell wall synthesis to proceed even in the presence of β-lactam antibiotics [7]. The meca gene is located on staphylococcal chromosome cassette mec (SCC mec) which is a mobile genetic element. Eleven SCC mec elements have been sequenced and SCC mec types I to III generally are found in healthcare-associated MRSA (HA- MRSA) strains, while types IV and V generally are found in community-associated MRSA (CA-MRSA) strains [7]. Types IV and V are known to be transferred from strain to strain easily, because of their 3

3 small size. MRSA strains expressing the luks-pv and lukf-pv genes encoding for Panton Valentine leucocidin (PVL) have been associated with necrotizing pneumonia, and empyema. Pulmonary manifestations have been especially reported with PVL producing clones, and PVL expression has been shown to confer a poor prognosis [8-10]. PVL expressing strains have been linked with increased risk of thrombosis, thromboembolism and high fatality rates in children and adolescents with necrotizing pneumonia [7,11,12]. MRSA can cause rapidly progressive pneumonia after inhalation of the organism, aspiration from the upper respiratory tract or seeding of the lungs during bacteremia. MRSA pneumonia is commonly associated with mechanical ventilation. Most cases occur in previously healthy children and viral infections like influenza predispose to pneumonia by MRSA possibly by inhibition of T-helper cells and TH17 responses [11]. Other conditions predisposing to increased risk for severe disease by MRSA include diabetes mellitus, malignancy, prematurity, chronic lung disease, foreign body, immunocompromising conditions, and transplantation [1,7]. Lung abscesses can develop as a complication of aspiration, pneumonia or bacteremia. Clinical Manifestations and Complications of MRSA Pulmonary Infections MRSA can cause a range of serious pulmonary infections in children, and MRSA infections of the lung can be localized or extensive. Severe pulmonary disease with S. aureus among young infants has been reported [13,14]. MRSA infections of the pleuro-pulmonary tissue can manifest as pneumonia, abscesses and empyema, multiple abscesses/cavities, necrotizing pneumonia and rarely empyema necessitatis where the pleural infection spreads outside of the pleural space to involve the soft tissues of the chest wall. Destruction of lung parenchyma resulting in multiple small, thin-walled cavities is typical of necrotizing pneumonia [11,12]. Bacteremia occurs in the majority of cases of disseminat- 4

4 ed MRSA disease (75%) and has been reported in about 12% to over 25% of the patients with primary MRSA pneumonia [13,15,16]. Pleural effusion and empyema are seen with almost 90% of pulmonary infections [7]. Empyema and bronchopleural fistulae often accompany necrotizing pneumonia. Pneumatocele formation arising from destruction of intra-alveolar septa leading to cavitations is a common occurrence, seen in more than 50% of infections [7]. About 25-50% of pulmonary infections are complicated by spontaneous pneumothorax, pyopneumothorax and hydropneumothorax [7,12]. Septic pulmonary embolism as a complication of septic thrombophlebitis can be associated with MRSA focal or disseminated disease. High mortality rates for PVL+ S. aureus necrotizing pneumonia, ranging from 30-75% have been reported [17,18]. Patients with MRSA bloodstream infections and disseminated disease are usually severely ill with hemodynamic instability and need aggressive fluid, vasopressor and respiratory support. Presenting features of pneumonia include fever, cough, and rapid breathing which can rapidly progress to severe respiratory distress. In patients with pneumonia, localizing signs of consolidation include dullness to percussion, decreased breath sounds, and/or bronchial breathing and increased whispered pectoriloquy, while dullness to percussion, decreased breath sounds, and decreased whispered pectoriloquy may be present in patients with pleural effusion [11,19]. Patients with necrotizing pneumonia by PVL-producing MRSA clones are clinically sicker with high fever (>39C), and a greater risk of hemoptysis, complications like purpura fulminans, and rapid progression to severe acute respiratory distress syndrome (ARDS) [11]. Patients with lung abscesses commonly present with fever, cough, chest pain, dyspnea, loss of appetite, and weight loss. Radiographically, MRSA pulmonary infections can have findings ranging from alveolar infiltrates to large consolidations. Chest radiographs reveal presence of cavities, pleural fluid, mediastinal shift, and abscesses [7,11,12]. Computed tomography (CT) of the chest is preferred as the diagnostic modality for lung abscesses to assess magnitude [7]. 5

5 Microbiologic Diagnosis Staphylococcus aureus appears as gram positive cocci on Gram stain and isolation of bacteria from culture of sterile body fluids (blood or pleural fluid) establishes the diagnosis. Several molecular methods in the microbiology laboratory can identify Staphylococcus aureus and MRSA and the approved assays for detection include Nonamplified assays, like peptide nucleic acid fluorescent in situ hybridization (PNA-FISH); nucleic acid amplification tests, such as BD GenOhm Staph SR (BD Molecular diagnostics) and Xpert MRSA/SA BC (Cepheid) [1]. Matrix-assisted laser desorption ionization timeof-flight mass spectrometry (MALDI-TOF) can also help in rapid identification of S. aureus. Treatment Aggressive supportive care often needing admission to the intensive care unit, oxygen and ventilator support with appropriate antimicrobials with or without surgical drainage are the mainstays of therapy for MRSA pulmonary infections. Guidelines for treatment of MRSA infections have been outlined by the Infectious Diseases Society of America (IDSA). According to the IDSA guidelines, vancomycin is the preferred antimicrobial for MRSA pneumonia in children [15]. In non-bacteremic, clinically stable patients, clindamycin, a lincosamide antibiotic that inhibits bacterial protein synthesis, is an alternative, provided the MRSA strain is susceptible and clindamycin resistance rate is low (< 10%). The dosing for intravenous clindamycin is mg/kg/dose IV every 6 to 8 hours with transition to oral therapy at a dose of 40 mg/kg/day. Vancomycin is a glycopeptide antibiotic which is bactericidal and acts by inhibiting synthesis and assembly of bacterial cell wall. Vancomycin is recommended at a dose of 15 mg/kg/ dose intravenously every 6 hourly (to maintain vancomycin serum through concentrations between 15 and 20 ug/ml) for serious infections like bacteremia and pneumonia. Linezolid, an oxazolidinone antibiotic, which is also a protein synthesis inhibitor, is an alternative drug. The antimicrobial is administered at 10 mg/kg/dose every 8 hourly for children younger than 12 years of age and 600 mg orally or intravenously twice daily for children older than 12 years [15]. 6

6 Ceftaroline is a new fifth generation cephalosporin, and is FDA-approved for MRSA skin and skin structure infections in children. Ceftaroline has bactericidal activity against MRSA and has been shown to be effective in MRSA pneumonia in adults, but has not yet been approved for use in MRSA invasive disease in children [20,21]. Daptomycin is not recommended for treating MRSA lung infections as it is rendered inactive due to surfactant binding [15]. A total duration of antibiotic therapy ranging from 7 21 days is usually recommended for adults with MRSA pneumonia, depending on the clinical response and the total duration of antibiotics is guided by the clinical course in children with pneumonia. In patients with MRSA pneumonia complicated by empyema, drainage procedures and concomitant antimicrobial therapy are recommended [15]. Early surgical intervention with techniques like Video-Assisted Thoracoscopic Surgery (VATS) have been shown to be beneficial [11]. Similarly, empyema necessitatis requires treatment with antimicrobial therapy and surgical drainage. Lung abscesses without accompanying empyema can usually be treated with antibiotics alone, although percutaneous surgical drainage may be needed in some instances [7,22]. Bronchopleural fistulae may require prolonged drainage, and sometimes surgical management to seal the fistulae [11]. Prognosis Patients with MRSA pulmonary infections usually need intensive care and have associated high morbidity. Patients with necrotizing pneumonia by PVL producing clones have been associated with severe disease and high fatality rates [17,18]. Presence of pulmonary hemorrhage, leucopenia and erythroderma in necrotizing pneumonia by PVL-expressing Staphylococcus aureus, have been shown to be predictors of mortality [17], and severe leucopenia is a risk factor for severe disease and high mortality in children and young adults [13,18]. 7

7 Conclusions MRSA pulmonary infections in children can be localized or occur in conjunction with disseminated MRSA disease. MRSA infections of the lung particularly, necrotizing pneumonia and its complications can be severe and cause significant mortality. Early recognition and appropriate management is crucial for improved patient outcomes. References 1. American Academy of Pediatrics. Staphylococcus aureus In: Kimberlin DW, Brady MT, Jackson MA, Long SS, editors. Red Book: 2018 Report of the Committee on Infectious Diseases, 31st edn. Itasca: American Academy of Pediatrics. 2018: Eagye KJ, Nicolau DP, Kuti JL. Impact of superinfection on hospital length of stay and costs in patients with ventilatorassociated pneumonia. Semin Respir Crit Care Med. 2009; 30: Shorr AF, Tabak YP, Gupta V, Johannes RS, Liu LZ, et al. Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care. 2006; 10: R Burnham JP, Kollef MH. Prevention of Staphylococcus aureus Ventilator-Associated Pneumonia: Conventional Antibiotics Won t Cut It. Clin Infect Dis. 2017; 64: Langsjoen J, Brady C, Obenauf E, Kellie S. Nasal screening is useful in excluding methicillin-resistant Staphylococcus aureus in ventilator-associated pneumonia. Am J Infect Control 2014; 42: Paling FP, Wolkewitz M, Bode LG, Klein Klouwenberg PMC, Ong DSY, et al. Staphylococcus aureus colonization at ICU admission as a risk factor for developing S. aureus ICU pneumonia. Clin Microbiol Infect 2017; 23:

8 7. Long SS, Prober CG, Fischer M, editors. Staphylococcus aureus. In Principles and Practice of Pediatric Infectious Diseases, 5th edn. Philadelphia: Elsevier Saunders. 2017; Francis JS, Doherty MC, Lopatin U, Johnston CP, Sinha G, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005; 40: Gillet-Vittori L, Afanetti M, Dupont A, Gondon E, Dupont D. Life-threatening Panton-Valentine leukocidin-associated staphylococcal infections in children. A broad spectrum of clinical presentations. Arch Pediatr. 2014; 21: Ebert MD, Sheth S, Fishman EK. Necrotizing pneumonia caused by community-acquired methicillin-resistant Staphylococcus aureus: an increasing cause of mayhem in the lung. Emerg Radiol. 2009; 16: Spencer DA, Thomas MF. Necrotising pneumonia in children. Paediatr Respir Rev. 2014; 15: Masters IB, Isles AF, Grimwood K. Necrotizing pneumonia: an emerging problem in children? Pneumonia (Nathan). 2017; 9: Doudoulakakis AG, Bouras D, Drougka E, Kazantzi M, Michos A, et al. Community-associated Staphylococcus aureus pneumonia among Greek children: epidemiology, molecular characteristics, treatment, and outcome. Eur J Clin Microbiol Infect Dis. 2016; 35: Chartrand SA, McCracken GH Jr. Staphylococcal pneumonia in infants and children. Pediatr Infect Dis. 1982; 1:

9 15. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive Summary. Clin. Infect. Dis. 2011; 52: Shorr AF, Zilberberg MD, Micek ST, Kollef MH. Outcomes associated with bacteremia in the setting of methicillinresistant Staphylococcus aureus pneumonia: a retrospective cohort study. Crit Care. 2015; 19: Gillet Y, Vanhems P, Lina G, Bes M, Vandenesch F, et al. Factors predicting mortality in necrotizing communityacquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin. Clin Infect Dis. 2007; 45: Khanafer N, Sicot N, Vanhems P, Dumitrescu O, Meyssonier V, et al. Severe leukopenia in Staphylococcus aureusnecrotizing, community-acquired pneumonia: risk factors and impact on survival. BMC Infect Dis. 2013; 13: Sarkar M, Madabhavi I, Niranjan N, Dogra M. Auscultation of the respiratory system. Ann Thorac Med. 2015; 10: Karki A, Thurm C, Cervellione K. Experience with ceftaroline for treatment of methicillin-resistant Staphylococcus aureus pneumonia in a community hospital. J Community Hosp Intern Med Perspect. 2017; 7: Yim J, Molloy LM, Newland JG. Use of Ceftaroline Fosamil in Children: Review of Current Knowledge and its Application. Infect Dis Ther. 2017; 6: Monteiro R, Alfaro TM, Correia L, Simão A, Carvalho A, et al. Lung abscess and thoracic empyema: retrospective analysis in an internal medicine department. Acta Med Port. 2011; 24:

UCSF guideline for management of suspected hospital-acquired or ventilatoracquired pneumonia in adult patients

Background/methods: UCSF guideline for management of suspected hospital-acquired or ventilatoracquired pneumonia in adult patients This guideline establishes evidence-based consensus standards for management