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Influenza With Community-Associated Methicillin-Resistant Staphylococcus Aureus Pneumonia
SPECIAL FEATURE
Patient-Centered Focused Review
Influenza With Community-Associated Methicillin-Resistant Staphylococcus Aureus Pneumonia Chia-Wei Liu, MD1, Shih-Ping Lin, MD1,2, Wei-Yao Wang, MD3 and Yen-Hsiang Huang, MD1,4,5,6 1
Department of Internal Medicine and 2 Division of Infectious Diseases, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China; 3 Department of Internal Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan, Republic of China; 4 Department of Critical Care Medicine and 5 Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China; 6 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China ABSTRACT Patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia have poor clinical outcomes and high frequency of mortality, especially in patents with postinfluenza infection. Herein, we report a case of community-acquired pneumonia with multiple organ failure in a 51-year-old patient with initial presentation of flu-like symptoms. The influenza rapid test from the specimen of nasopharyngeal swab was positive for type B influenza virus and was confirmed by real-time polymerase chain reaction. Gram stain of bronchoalveolar lavage fluid revealed gram positive cocci in group. Both sputum and blood culture yielded MRSA. We identified the CA-MRSA was staphylococcal cassette chromosome mec type IV strain carried Panton-Valentine leukocidin gene. The patient made a complete recovery following an 8-week treatment course of linezolid and was discharged with independent daily activity. According to our experience, linezolid may be a reasonable treatment choice for CA-MRSA pneumonia due to the virulence of exotoxins. Key Indexing Terms: Community-associated methicillin-resistant Staphylococcus aureus; Influenza; Linezolid; PantonValentine leucocidin. [Am J Med Sci 2019;358(4):289–293.]
INTRODUCTION
C
ommunity-acquired pneumonia (CAP) is a leading infectious cause of hospitalization and mortality worldwide. The most common bacterial pathogen in CAP is Streptococcus pneumonia (S. pneumonia), and Staphylococcus aureus (S. aureus) is also frequently detected in CAP.1 The international, multicenter global initiative for meticillin-resistant Staphylococcus aureus pneumonia study demonstrated that the prevalence of hospitalized CAP caused by S. aureus was about 6.0%, and methicillin-resistant S. aureus (MRSA) accounted for 3.0%.2 According to the global initiative for meticillin-resistant Staphylococcus aureus pneumonia study, there were 3 independent risk factors associated with MRSA CAP, including previous MRSA infection or colonization, recurrent skin infection and severe pneumonia disease.2 Patients with MRSA CAP had higher pneumonia severity scores, higher intensive care unit (ICU) admission rate, higher in-hospital mortality, higher invasive mechanical ventilation use rate and longer hospital length of stay than patients with non-MRSA CAP.3 Additionally, in patients with influenza infection, S. aureus and S. pneumonia were the most common coinfection
bacterial pathogens isolated from respiratory culture. A previous study showed that during the influenza season, the mortality rate was 40% in patients with CAP caused by methicillin-susceptible S. aureus and was about 50% in CAP patients with MRSA. Importantly, in patients with laboratory-confirmed influenza, an extremely high mortality rate of up to 90% was noted when coinfection with S. aureus was present.4 Herein, we present a case of type B influenza with community-associated MRSA (CAMRSA) pneumonia, complicated by bacteremia, septic shock, acute kidney injury and acute respiratory distress syndrome, who survived due to successful treatment with linezolid.
CASE PRESENTATION A 51-year-old male, who was a hepatitis B carrier with smoking history of 1 pack per day for more than 20 years and had quit 3 years ago, suffered from cough with whitish sputum, fever and chills for 3 days. Accompanying symptoms included general malaise, poor appetite and muscle soreness. Then, progressive shortness of breath and chest tightness developed, and flu-like
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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symptoms became worse. Thus, he visited a local regional hospital for help. Influenza rapid test from the specimen of nasopharyngeal swab was checked, and the result was positive for type B influenza virus. Oseltamivir was prescribed immediately. Chest radiography (CXR) showed multiple alveolar patches over bilateral lung fields which was compatible with pneumonia (Figure 1a). Because the respiratory pattern deteriorated with accessory muscle use and severe hypoxia, endotracheal intubation was performed with mechanical ventilator support. Owing to the rapid decline of his clinical condition, he was transferred to our hospital, a tertiary medical center, for further intensive care. At our emergency department, physical examination revealed body temperature of 35.5°C, heart rate of 114 beats/minute, respiratory rate of 12 breaths/minute, blood pressure of 70/39 mmHg and oxygen saturation of 95%. The patient was on a mechanical ventilator with 100% fraction of inspired oxygen (FiO2) support. CXR demonstrated progressive alveolar patches over multiple lobes (Figure 1b). The 2 plain films (Figure 1a and b) were taken just three hours apart. Laboratory data revealed
white blood cell count of 1,620/uL with band form 6%, C-reactive protein of 12.18 mg/dL, creatinine of 1.45 mg/ dL and lactate of 37.3 mg/dL. Real-time polymerase chain reaction (RT-PCR) from the specimen of nasopharyngeal swab confirmed the diagnosis of type B influenza virus infection. The patient received aggressive fluid resuscitation with high-dose norepinephrine drip for septic shock. Levofloxacin and peramivir were prescribed for influenza with severe CAP. After he was admitted to the ICU, bronchoalveolar lavage was performed. The gram stain revealed gram positive cocci in group. Thus, we shifted antibiotic treatment to linezolid due to the concern about the possibility of MRSA, because the follow-up arterial blood gas result showed that the PaO2/FiO2 ratio had decreased to 122. The patient underwent treatment in the prone position. Septic shock worsened and development of metabolic acidosis with lactic acidosis (lactate level, 71.4 mg/dL) was noted, and hence the patient was given continuous renal replacement therapy on day 2 after admission. Sputum culture and bronchoalveolar lavage fluid culture both yielded MRSA. On day 4, the patient was returned
FIGURE 1. a, The chest radiography (CXR) demonstrated alveolar patch over bilateral lung fields. b, Rapid progression of pneumonia within three hours. c and d, CXR on day 11 and day 15 showed multiple cavitary lesions.
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FIGURE 2. Computed tomography revealed multiple consolidation with cavitation over bilateral upper and lower lobes.
to the supine position due to improvement of oxygenation. On day 5, the patient’s clinical condition was relatively stable, so continuous renal replacement therapy and vasopressors were discontinued. On the same day, blood cultures yielded MRSA, and the result of antibiotic susceptibility testing was the same as that of sputum and bronchoalveolar lavage fluid culture. The drug susceptibility test by agar dilution according to Clinical Laboratory Standards Institute for the blood MRSA isolate showed minimum inhibitory concentration ≥8 ug/mL and minimum inhibitory concentration = 1 ug/mL against oxacillin and vancomycin, respectively.5 Based on the results of culture studies and the difference of lung penetration between vancomycin and linezolid, the patient was kept on linezolid. During the period of hospitalization, the follow-up CXR showed multiple cavitary lesions over bilateral lung fields (Figure 1c and d). Computed tomography revealed multilobar consolidation with cavitation, the
typical image presentation of staphylococcal pneumonia (Figure 2). Due to prolonged use of mechanical ventilation, percutaneous tracheostomy was performed on day 18. On day 27, T-piece resuscitator was applied and he was transferred to an ordinary ward on day 36. Serial CXR demonstrated gradual improvement of pneumonia patch (Figure 3a and b). The patient received antibiotic treatment with linezolid for 8 weeks. On day 61, he was discharged under stable condition, could communicate clearly and was capable of walking without assistance. The last CXR disclosed neartotal resolution of bilateral lung lesions (Figure 3c). Additionally, the MRSA blood isolate was identified as staphylococcal cassette chromosome mec (SCCmec) type IV by multiplex PCR designed by Kondo et al.6 Panton-Valentine leucocidin (PVL) encoded by pvl was confirmed by PCR. Therefore, the diagnosis of CAMRSA with genotype of SCCmec IV and pvl was established.
FIGURE 3. Serial chest radiography during admission: a, Day 36. b, Day 50. c, Day 61.
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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DISCUSSION MRSA infections are a growing public health concern. The prevalence of CAP caused by S. aureus was 1.6-6.0%, and MRSA was identified in approximately 0.7-3% of cases.2,3,7 The risk factors for MRSA CAP include younger age, previous MRSA infection or colonization, recurrent skin infections, severe pneumonia disease, chronic hemodialysis and preceding influenza or influenza-like illness.2,3,7,8 Patients with MRSA CAP had a poorer prognosis than those with non-S. aureus CAP, including longer invasive mechanical ventilator use, a greater rate of ICU admission and higher in-hospital mortality.3 Cases of CAP caused by S. aureus increase during influenza season.3 Bacterial coinfection mostly occurs within 6 days after influenza virus infection and the most common coinfection species are S. aureus and S. pneumoniae.9 During the influenza season, among patients with S. aureus CAP, most of the pathogens were MRSA, ranging from 79 to 88%.4,11 Importantly, the majority of mortality cases of staphylococcal pneumonia resulted from MRSA (80%).10 In patients coinfected with influenza and MRSA, the morality rate was about 90%, and low white blood cell count was associated with poor prognosis.4 Methicillin-resistance is mediated by penicillin-binding protein 2a, which is encoded by mecA gene. The mecA gene is located on the SCCmec.11 The most common strain of CA-MRSA is SCCmec type IV which was associated with the carriage of PVL.4,7,10 PVL, a staphylococcal exotoxin, destroys the cell membranes of neutrophils, monocytes and macrophages by cytolytic pore-forming activity, and cytokines are released to cause tissue necrosis and abscess formation.12 Compared with the PVL-negative strain, the lethality rate in patients with PVL-positive strain was higher, and S. aureus with PVL toxin caused rapidly progressive, hemorrhagic and necrotizing pneumonia.13 In addition, airway bleeding, erythrodema 224 hours after admission, and leukopenia were predictive factors of fatal outcome.14 Currently, the treatment of MRSA is primarily concerned with hospital-acquired MRSA (HA-MRSA). A systemic review including 9 randomized trials with a total of 4,026 patients, compared linezolid and vancomycin in patients with hospital acquired pneumonia (HAP), and found no statistical differences in mortality, clinical response, microbiological eradication, thrombocytopenia and renal failure.15 Other prospective randomized controlled trials for MRSA HAP revealed higher clinical response and lower nephrotoxicity in the linezolid group, but there was no difference in 60-day mortality.16 The aforementioned trials assessed the outcomes of HAMRSA pneumonia treatment. Previous case reports demonstrated successful treatment by linezolid and vancomycin in patients with CA-MRSA pneumonia.17 Although the clinical practice guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend vancomycin or linezolid or 292
clindamycin for CA-MRSA pneumonia, little evidence was found regarding treatment choice for CA-MRSA pneumonia.18 Some genetic and phenotypic differences exist between CA-MRSA and HA-MRSA. Compared with HAMRSA, the characteristics of CA-MRSA include younger age, minority population, greater prevalence of SCC mec type IV, higher frequency of PVL virulence factor, predominance of the USA-300 and USA-400 strains and rare multidrug resistance.12 The treatment choice may be different for CA-MRSA and HA-MRSA. An in vitro study demonstrated that antibiotics, such as linezolid and clindamycin, whose mechanism of action involves inhibition of protein synthesis, could attenuate PVL production in a CA-MRSA strain.19 In a murine model of postinfluenza CA-MRSA pneumonia, the linezolid treatment group had lower numbers of neutrophils in the bronchoalveolar lavage fluid, reduced levels of PVL toxin in lungs, as well as decreased levels of chemokines and cytokines, which protected mice from acute lung injury, compared to animals receiving vancomycin.20 Based on the above-mentioned studies, antibiotics that inhibit protein synthesis as their chief mechanism of action may be considered when treating CA-MRSA pneumonia. However, we need more clinical evidence and research in humans, especially randomized clinical trials, to make a conclusion about the difference of clinical benefits between linezolid and vancomycin in patients with CAMRSA pneumonia. In the present case, our patient had an underlying disease, namely hepatitis B, but he also contracted CAMRSA pneumonia with the risk factor of preceding influenza. During the period of hospitalization, he suffered from multiple organ failure, including septic shock, acute kidney injury and acute respiratory distress syndrome. He was placed on an invasive mechanical ventilator for four weeks, and he was admitted to the ICU for 5 weeks. Leukopenia occurred at the beginning, and hemoptysis was noted during hospitalization. Although many risk factors indicated a poor prognosis in this patient, he fortunately survived. We attribute the successful outcome to early identification of the pathogen and early treatment with effective antibiotics. In the ICU, advanced techniques, such as PCR-based assay, are needed for rapid detection of pathogens and to check antibiotic susceptibility. According to previous studies, MRSA-nasal screening had high specificity and negative predictive value for MRSA pneumonia, especially in patients with CAP.21,22 Above methods can facilitate adequate antibiotics to be prescribed as soon as possible, thereby potentially increasing the probability of a full recovery.
CONCLUSIONS Physicians should always be alert to the possibility of CA-MRSA coinfection in patients with postinfluenza pneumonia. In such cases, it is important to consider the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 358 NUMBER 4 OCTOBER 2019
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presence of cytolytic toxins such as PVL, and thus linezolid is a reasonable choice of treatment. 13.
AUTHOR CONTRIBUTIONS Conception and design of study done by S.P.L. and Y.H.H. Acquisition of data by C.W.L. and S.P.L. Analysis and/or interpretation of data by C.W.L., W.Y.W. and Y.H.H. Drafting the manuscript was done by C.W.L. and S.P.L. The manuscript was critically revised for important intellectual content by W.Y.W. and Y.H.H. Approval of the version of the manuscript to be published by C.W.L., S.P.L., W.Y.W. and Y.H.H.
REFERENCES 1. Jain S, Self WH, Wunderink RG, et al. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med. 2015;373:415–427. 2. Aliberti S, Reyes LF, Faverio P, et al. Global initiative for meticillin-resistant Staphylococcus aureus pneumonia (GLIMP): an international, observational cohort study. Lancet Infect Dis. 2016;16:1364–1376. 3. Self WH, Wunderink RG, Williams DJ, et al. Staphylococcus aureus community-acquired pneumonia: prevalence, clinical characteristics, and outcomes. Clin Infect Dis. 2016;63:300–309. 4. Kallen AJ, Brunkard J, Moore Z, et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med. 2009;53:358–365. 5. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 28th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2018. 6. Kondo Y, Ito T, Ma XX, et al. Combination of multiplex PCRs for staphylococcal cassette chromosome mec type assignment: rapid identification system for mec, ccr, and major differences in junkyard regions. Antimicrob Agents Chemother. 2007;51(1):264–274. 7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Prevalence of methicillin-resistant staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis. 2012;54:1126–1133. 8. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008;46(Suppl 5): S378–S385. 9. Chertow DS, Memoli MJ. Bacterial coinfection in influenza: a grand rounds review. JAMA. 2013;309(3):275–282. 10. Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12:894–899. 11. Sligl WI, Marrie TJ. Severe community-acquired pneumonia. Crit Care Clin. 2013;29(3):563–601. 12. Barton M, Hawkes M, Moore D, et al. Guidelines for the prevention and management of community-associated methicillin-resistant
14.
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Staphylococcus aureus: a perspective for Canadian health care practitioners. Can J Infect Dis Med Microbiol. 2006;17(Suppl C):4c–24c. Gillet Y, Issartel B, Vanhems P, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet. 2002;359:753–759. Gillet Y, Vanhems P, Lina G, et al. Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin. Clin Infect Dis. 2007;45: 315–321. Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospitalacquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open. 2013;3:(10) e003912. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54:621–629. Takigawa Y, Fujiwara K, Saito T, et al. Rapidly progressive multiple cavity formation in necrotizing pneumonia caused by community-acquired methicillin-resistant staphylococcus aureus positive for the PantonValentine leucocidin gene: a case report. Intern Med. 2019;58(5):685–691. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillinresistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18–e55. Stevens DL, Ma Y, Salmi DB, et al. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007;195:202– 211. Bhan U, Podsiad AB, Kovach MA, et al. Linezolid has unique immunomodulatory effects in post-influenza community acquired MRSA pneumonia. PloS One. 2015;10:(1) e0114574. Rimawi RH, Ramsey KM, Shah KB, et al. Correlation between methicillin-resistant Staphylococcus aureus nasal sampling and S. aureus pneumonia in the medical intensive care unit. Infect Control Hosp Epidemiol. 2014;35(5):590–593. Parente DM, Cunha CB, Mylonakis E, et al. The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: a diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis. 2018;67(1):1–7.
Submitted April 10, 2019; accepted July 31, 2019. Conflict of Interest: The authors have no financial or other conflicts of interest to disclose. Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. Correspondence: Yen-Hsiang Huang, MD, Department of Critical Care Medicine, Taichung Veterans General Hospital, No.1650, Sect. 4, Taiwan Boulevard, Taichung 407, Taiwan, Republic of China. (E-mail: [email protected]).
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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Patient-Centered Focused Review
Influenza With Community-Associated Methicillin-Resistant Staphylococcus Aureus Pneumonia Chia-Wei Liu, MD1, Shih-Ping Lin, MD1,2, Wei-Yao Wang, MD3 and Yen-Hsiang Huang, MD1,4,5,6 1
Department of Internal Medicine and 2 Division of Infectious Diseases, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China; 3 Department of Internal Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan, Republic of China; 4 Department of Critical Care Medicine and 5 Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China; 6 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China ABSTRACT Patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia have poor clinical outcomes and high frequency of mortality, especially in patents with postinfluenza infection. Herein, we report a case of community-acquired pneumonia with multiple organ failure in a 51-year-old patient with initial presentation of flu-like symptoms. The influenza rapid test from the specimen of nasopharyngeal swab was positive for type B influenza virus and was confirmed by real-time polymerase chain reaction. Gram stain of bronchoalveolar lavage fluid revealed gram positive cocci in group. Both sputum and blood culture yielded MRSA. We identified the CA-MRSA was staphylococcal cassette chromosome mec type IV strain carried Panton-Valentine leukocidin gene. The patient made a complete recovery following an 8-week treatment course of linezolid and was discharged with independent daily activity. According to our experience, linezolid may be a reasonable treatment choice for CA-MRSA pneumonia due to the virulence of exotoxins. Key Indexing Terms: Community-associated methicillin-resistant Staphylococcus aureus; Influenza; Linezolid; PantonValentine leucocidin. [Am J Med Sci 2019;358(4):289–293.]
INTRODUCTION
C
ommunity-acquired pneumonia (CAP) is a leading infectious cause of hospitalization and mortality worldwide. The most common bacterial pathogen in CAP is Streptococcus pneumonia (S. pneumonia), and Staphylococcus aureus (S. aureus) is also frequently detected in CAP.1 The international, multicenter global initiative for meticillin-resistant Staphylococcus aureus pneumonia study demonstrated that the prevalence of hospitalized CAP caused by S. aureus was about 6.0%, and methicillin-resistant S. aureus (MRSA) accounted for 3.0%.2 According to the global initiative for meticillin-resistant Staphylococcus aureus pneumonia study, there were 3 independent risk factors associated with MRSA CAP, including previous MRSA infection or colonization, recurrent skin infection and severe pneumonia disease.2 Patients with MRSA CAP had higher pneumonia severity scores, higher intensive care unit (ICU) admission rate, higher in-hospital mortality, higher invasive mechanical ventilation use rate and longer hospital length of stay than patients with non-MRSA CAP.3 Additionally, in patients with influenza infection, S. aureus and S. pneumonia were the most common coinfection
bacterial pathogens isolated from respiratory culture. A previous study showed that during the influenza season, the mortality rate was 40% in patients with CAP caused by methicillin-susceptible S. aureus and was about 50% in CAP patients with MRSA. Importantly, in patients with laboratory-confirmed influenza, an extremely high mortality rate of up to 90% was noted when coinfection with S. aureus was present.4 Herein, we present a case of type B influenza with community-associated MRSA (CAMRSA) pneumonia, complicated by bacteremia, septic shock, acute kidney injury and acute respiratory distress syndrome, who survived due to successful treatment with linezolid.
CASE PRESENTATION A 51-year-old male, who was a hepatitis B carrier with smoking history of 1 pack per day for more than 20 years and had quit 3 years ago, suffered from cough with whitish sputum, fever and chills for 3 days. Accompanying symptoms included general malaise, poor appetite and muscle soreness. Then, progressive shortness of breath and chest tightness developed, and flu-like
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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Liu et al
symptoms became worse. Thus, he visited a local regional hospital for help. Influenza rapid test from the specimen of nasopharyngeal swab was checked, and the result was positive for type B influenza virus. Oseltamivir was prescribed immediately. Chest radiography (CXR) showed multiple alveolar patches over bilateral lung fields which was compatible with pneumonia (Figure 1a). Because the respiratory pattern deteriorated with accessory muscle use and severe hypoxia, endotracheal intubation was performed with mechanical ventilator support. Owing to the rapid decline of his clinical condition, he was transferred to our hospital, a tertiary medical center, for further intensive care. At our emergency department, physical examination revealed body temperature of 35.5°C, heart rate of 114 beats/minute, respiratory rate of 12 breaths/minute, blood pressure of 70/39 mmHg and oxygen saturation of 95%. The patient was on a mechanical ventilator with 100% fraction of inspired oxygen (FiO2) support. CXR demonstrated progressive alveolar patches over multiple lobes (Figure 1b). The 2 plain films (Figure 1a and b) were taken just three hours apart. Laboratory data revealed
white blood cell count of 1,620/uL with band form 6%, C-reactive protein of 12.18 mg/dL, creatinine of 1.45 mg/ dL and lactate of 37.3 mg/dL. Real-time polymerase chain reaction (RT-PCR) from the specimen of nasopharyngeal swab confirmed the diagnosis of type B influenza virus infection. The patient received aggressive fluid resuscitation with high-dose norepinephrine drip for septic shock. Levofloxacin and peramivir were prescribed for influenza with severe CAP. After he was admitted to the ICU, bronchoalveolar lavage was performed. The gram stain revealed gram positive cocci in group. Thus, we shifted antibiotic treatment to linezolid due to the concern about the possibility of MRSA, because the follow-up arterial blood gas result showed that the PaO2/FiO2 ratio had decreased to 122. The patient underwent treatment in the prone position. Septic shock worsened and development of metabolic acidosis with lactic acidosis (lactate level, 71.4 mg/dL) was noted, and hence the patient was given continuous renal replacement therapy on day 2 after admission. Sputum culture and bronchoalveolar lavage fluid culture both yielded MRSA. On day 4, the patient was returned
FIGURE 1. a, The chest radiography (CXR) demonstrated alveolar patch over bilateral lung fields. b, Rapid progression of pneumonia within three hours. c and d, CXR on day 11 and day 15 showed multiple cavitary lesions.
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FIGURE 2. Computed tomography revealed multiple consolidation with cavitation over bilateral upper and lower lobes.
to the supine position due to improvement of oxygenation. On day 5, the patient’s clinical condition was relatively stable, so continuous renal replacement therapy and vasopressors were discontinued. On the same day, blood cultures yielded MRSA, and the result of antibiotic susceptibility testing was the same as that of sputum and bronchoalveolar lavage fluid culture. The drug susceptibility test by agar dilution according to Clinical Laboratory Standards Institute for the blood MRSA isolate showed minimum inhibitory concentration ≥8 ug/mL and minimum inhibitory concentration = 1 ug/mL against oxacillin and vancomycin, respectively.5 Based on the results of culture studies and the difference of lung penetration between vancomycin and linezolid, the patient was kept on linezolid. During the period of hospitalization, the follow-up CXR showed multiple cavitary lesions over bilateral lung fields (Figure 1c and d). Computed tomography revealed multilobar consolidation with cavitation, the
typical image presentation of staphylococcal pneumonia (Figure 2). Due to prolonged use of mechanical ventilation, percutaneous tracheostomy was performed on day 18. On day 27, T-piece resuscitator was applied and he was transferred to an ordinary ward on day 36. Serial CXR demonstrated gradual improvement of pneumonia patch (Figure 3a and b). The patient received antibiotic treatment with linezolid for 8 weeks. On day 61, he was discharged under stable condition, could communicate clearly and was capable of walking without assistance. The last CXR disclosed neartotal resolution of bilateral lung lesions (Figure 3c). Additionally, the MRSA blood isolate was identified as staphylococcal cassette chromosome mec (SCCmec) type IV by multiplex PCR designed by Kondo et al.6 Panton-Valentine leucocidin (PVL) encoded by pvl was confirmed by PCR. Therefore, the diagnosis of CAMRSA with genotype of SCCmec IV and pvl was established.
FIGURE 3. Serial chest radiography during admission: a, Day 36. b, Day 50. c, Day 61.
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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DISCUSSION MRSA infections are a growing public health concern. The prevalence of CAP caused by S. aureus was 1.6-6.0%, and MRSA was identified in approximately 0.7-3% of cases.2,3,7 The risk factors for MRSA CAP include younger age, previous MRSA infection or colonization, recurrent skin infections, severe pneumonia disease, chronic hemodialysis and preceding influenza or influenza-like illness.2,3,7,8 Patients with MRSA CAP had a poorer prognosis than those with non-S. aureus CAP, including longer invasive mechanical ventilator use, a greater rate of ICU admission and higher in-hospital mortality.3 Cases of CAP caused by S. aureus increase during influenza season.3 Bacterial coinfection mostly occurs within 6 days after influenza virus infection and the most common coinfection species are S. aureus and S. pneumoniae.9 During the influenza season, among patients with S. aureus CAP, most of the pathogens were MRSA, ranging from 79 to 88%.4,11 Importantly, the majority of mortality cases of staphylococcal pneumonia resulted from MRSA (80%).10 In patients coinfected with influenza and MRSA, the morality rate was about 90%, and low white blood cell count was associated with poor prognosis.4 Methicillin-resistance is mediated by penicillin-binding protein 2a, which is encoded by mecA gene. The mecA gene is located on the SCCmec.11 The most common strain of CA-MRSA is SCCmec type IV which was associated with the carriage of PVL.4,7,10 PVL, a staphylococcal exotoxin, destroys the cell membranes of neutrophils, monocytes and macrophages by cytolytic pore-forming activity, and cytokines are released to cause tissue necrosis and abscess formation.12 Compared with the PVL-negative strain, the lethality rate in patients with PVL-positive strain was higher, and S. aureus with PVL toxin caused rapidly progressive, hemorrhagic and necrotizing pneumonia.13 In addition, airway bleeding, erythrodema 224 hours after admission, and leukopenia were predictive factors of fatal outcome.14 Currently, the treatment of MRSA is primarily concerned with hospital-acquired MRSA (HA-MRSA). A systemic review including 9 randomized trials with a total of 4,026 patients, compared linezolid and vancomycin in patients with hospital acquired pneumonia (HAP), and found no statistical differences in mortality, clinical response, microbiological eradication, thrombocytopenia and renal failure.15 Other prospective randomized controlled trials for MRSA HAP revealed higher clinical response and lower nephrotoxicity in the linezolid group, but there was no difference in 60-day mortality.16 The aforementioned trials assessed the outcomes of HAMRSA pneumonia treatment. Previous case reports demonstrated successful treatment by linezolid and vancomycin in patients with CA-MRSA pneumonia.17 Although the clinical practice guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend vancomycin or linezolid or 292
clindamycin for CA-MRSA pneumonia, little evidence was found regarding treatment choice for CA-MRSA pneumonia.18 Some genetic and phenotypic differences exist between CA-MRSA and HA-MRSA. Compared with HAMRSA, the characteristics of CA-MRSA include younger age, minority population, greater prevalence of SCC mec type IV, higher frequency of PVL virulence factor, predominance of the USA-300 and USA-400 strains and rare multidrug resistance.12 The treatment choice may be different for CA-MRSA and HA-MRSA. An in vitro study demonstrated that antibiotics, such as linezolid and clindamycin, whose mechanism of action involves inhibition of protein synthesis, could attenuate PVL production in a CA-MRSA strain.19 In a murine model of postinfluenza CA-MRSA pneumonia, the linezolid treatment group had lower numbers of neutrophils in the bronchoalveolar lavage fluid, reduced levels of PVL toxin in lungs, as well as decreased levels of chemokines and cytokines, which protected mice from acute lung injury, compared to animals receiving vancomycin.20 Based on the above-mentioned studies, antibiotics that inhibit protein synthesis as their chief mechanism of action may be considered when treating CA-MRSA pneumonia. However, we need more clinical evidence and research in humans, especially randomized clinical trials, to make a conclusion about the difference of clinical benefits between linezolid and vancomycin in patients with CAMRSA pneumonia. In the present case, our patient had an underlying disease, namely hepatitis B, but he also contracted CAMRSA pneumonia with the risk factor of preceding influenza. During the period of hospitalization, he suffered from multiple organ failure, including septic shock, acute kidney injury and acute respiratory distress syndrome. He was placed on an invasive mechanical ventilator for four weeks, and he was admitted to the ICU for 5 weeks. Leukopenia occurred at the beginning, and hemoptysis was noted during hospitalization. Although many risk factors indicated a poor prognosis in this patient, he fortunately survived. We attribute the successful outcome to early identification of the pathogen and early treatment with effective antibiotics. In the ICU, advanced techniques, such as PCR-based assay, are needed for rapid detection of pathogens and to check antibiotic susceptibility. According to previous studies, MRSA-nasal screening had high specificity and negative predictive value for MRSA pneumonia, especially in patients with CAP.21,22 Above methods can facilitate adequate antibiotics to be prescribed as soon as possible, thereby potentially increasing the probability of a full recovery.
CONCLUSIONS Physicians should always be alert to the possibility of CA-MRSA coinfection in patients with postinfluenza pneumonia. In such cases, it is important to consider the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 358 NUMBER 4 OCTOBER 2019
Influenza With Community Acquired Pneumonia
presence of cytolytic toxins such as PVL, and thus linezolid is a reasonable choice of treatment. 13.
AUTHOR CONTRIBUTIONS Conception and design of study done by S.P.L. and Y.H.H. Acquisition of data by C.W.L. and S.P.L. Analysis and/or interpretation of data by C.W.L., W.Y.W. and Y.H.H. Drafting the manuscript was done by C.W.L. and S.P.L. The manuscript was critically revised for important intellectual content by W.Y.W. and Y.H.H. Approval of the version of the manuscript to be published by C.W.L., S.P.L., W.Y.W. and Y.H.H.
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Submitted April 10, 2019; accepted July 31, 2019. Conflict of Interest: The authors have no financial or other conflicts of interest to disclose. Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. Correspondence: Yen-Hsiang Huang, MD, Department of Critical Care Medicine, Taichung Veterans General Hospital, No.1650, Sect. 4, Taiwan Boulevard, Taichung 407, Taiwan, Republic of China. (E-mail: [email protected]).
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