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Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma
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Original article
Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma Étiologie microbienne, profil de susceptibilité de nécrose nasopharyngée chez les patients atteints de carcinome nasopharyngé Li Wang a,1 , Jun Yang b,1 , Shi-Yi Peng c , Guo-Qing Li c , Zi-Wei Tu c,∗ a
Department of Radiotherapy, Eye Ear Nose and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, PR China Department of Radiotherapy, Medical College, Nanchang University, Nanchang, PR China c Department of Radiotherapy, Jiangxi Cancer Hospital, Medical College, Nanchang University, Nanchang, PR China b
a r t i c l e
i n f o
Article history: Received 13 April 2019 Received in revised form 10 September 2019 Accepted 13 September 2019 Keywords: Nasopharyngeal carcinoma (NPC) Postradiation nasopharyngeal necrosis (PRNN) Pathogens Drug susceptibility Antibiotics
a b s t r a c t Objective. – Postradiation nasopharyngeal necrosis (PRNN) is a notorious complication after radiotherapy that affects prognosis in patients with nasopharyngeal carcinoma (NPC). It is important for clinical doctors to realize this problem in order to cope with this severe clinical situation. The aim of our study was to assess the bacteriology of PRNN and to demonstrate the antimicrobial susceptibility pattern that should guide the clinicians towards more appropriate antibiotic use. Methods. – Sixty-nine NPC patients with PRNN in our department between March 2013 and December 2017 were retrospectively enrolled. Pathogenic culture and drug sensitivity test were performed in these 69 NPC patients with PRNN. The infection rate of Pathogens and the sensitivity of the drugs were analyzed based on these results. Results. – Sixty-nine NPC patients with PRNN were enrolled in our study. Pathogens were identified in 58 (84%) patients. Of the 58 patients, Staphylococcus aureus was isolated in 34 (58.6%) patients. And the second most common group of bacterial isolates was Pseudomonas aeruginosa. Antibiotic sensitivity showed that Levofloxacin was the highest (88.5%), followed by Ciprofloxacin (85.2%) and Gentamicin (80.3%). The only pathologic fungus was Candida albicans, about 6.8%. The positive rates of bacterial and fungal culture in PRNN patients were not significantly different from the patients’ gender, age, stage, number of radiotherapy courses (P > 0.05), but the cure rate was statistically higher in culture-negative patients in comparison with culture-positive patients (63.6% vs 20.7%, P = 0.011). Conclusion. – Our results provide an overall picture of the microbiology and drug susceptibility patterns for NPC patients with PRNN and could help implement guidelines for more rational treatment and improve therapeutic outcome. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2020 Societ rights reserved.
r é s u m é Mots clés : Carcinome du nasopharynx (CPN) Nécrose nasopharyngée postradiation (PRNN) Pathogènes Sensibilité aux médicaments Antibiotiques
Objet. – La nécrose nasopharyngée postradiation (PRNN) est une complication notoire après la radiothérapie chez les patients atteints de carcinome du nasopharynx (CPN) Il est important que les cliniciens réalisent ce problème pour faire face à cette situation clinique grave. Notre étude visait à évaluer la bactériologie de la PRNN et à démontrer le profil de sensibilité aux antimicrobiens qui devrait guider les cliniciens vers une utilisation plus appropriée des antibiotiques. Patients et méthodes. – Nous avons analysé rétrospectivement les 69 PRNN chez les patients atteints de NPC traités dans notre service. Soixante-neuf patients atteints de NPC PRNN dans notre service entre mars 2013 et décembre 2017 ont été inscrits rétrospectivement. Le test de sensibilité à la culture et aux
∗ Corresponding author. E-mail address: [email protected] (Z.-W. Tu). 1 The author equally contributes to this work. https://doi.org/10.1016/j.canrad.2019.09.008 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2020 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008
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médicaments a été réalisé chez ces 69 patients atteints de PRNN. Le taux d’infection des agents pathogènes et la sensibilité des médicaments ont été analysés sur la base de ces résultats. Résultats. – Soixante neuf PRNN chez les patients atteitns de NPC ont été inclus dans notre étude. Des agents pathogènes ont été identifiés chez 58 patients (84 %). Sur ces 58 patients, Staphylococcus aureus a été isolé chez 34 patients (58,6 %). Pseudomonas aeruginosa était la souche la plus élevée (88,5 %), suivie de la ciprofloxacine (85,2 %) et de la gentamicine (80,3 %), la sensibilité aux antibiotiques étant la plus élevée (80,5 %). Le seul champignon pathologique était Candida albicans, environ 6,8 %. La culture fongique chez les patients atteints de PRNN ne différait pas significativement du sexe, de l’âge, du stage et du nombre de cycles de radiothérapie (p > 0,05), mais le taux de guérison était statistiquement plus élevé chez les patients à culture négative que chez les patients à culture-positive (63,6 % vs 20,7 %, p = 0,011). Conclusion. – Nos résultats fournissent une image globale de la microbiologie et des schémas de sensibilité aux médicaments des patients atteints de PRNN et pourraient aider à mettre en œuvre des directives pour un traitement plus rationnel et améliorer les résultats thérapeutiques. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2020 Societ ´ ´ droits reserv es.
1. Introduction Nasopharyngeal carcinoma (NPC) is a common malignancy in Southeast Asia, with a peak annual incidence approaching 30 per 100,000 persons [1]. Radiotherapy has been the mainstay treatment for NPC [2]. Complications related to radiation therapy have been well documented in many studies, which include otitis media with effusion, xerostomia, temporal lobe necrosis, dysphagia, trismus and so on [3–7]. Among them, postradiation nasopharyngeal necrosis (PRNN) is one of the most serious late effects for NPC radiotherapy with the representative signs of headache, foul odor and intermittent bleeding [8,9]. According to the literature, the incidence of PRNN reached 22.9% for reirradiation patients [10]. PRNN not only severely reduces the patients’ quality of life (QoL), but even threatens the life of patients, when the internal carotid artery is involved. Hua et al. reported that the cure rate of PRNN is only 28.6% (8/28) and 9 patients (9/28, 32.1%) with exposed internal carotid artery died of sudden nasopharyngeal massive bleeding [11]. Although the standard treatments are not well defined, the surgical approaches and conservative treatments such as antibiotics and daily nasopharynx irrigation seem to be able to benefit the patients [12,13]. To improve the sensitivities of antibiotic drugs and effectiveness of the treatments, the use of antibiotics in the treatment of PRNN should be based on the results of culture and drug sensitivity test. Despite the advances in management of PRNN, a definitive microbial etiology is not usually available. In this paper, we aimed to evaluate the bacteriology of PRNN and demonstrate the antimicrobial susceptibility pattern so as to provide clinical evidences for reasonable application of antibiotics.
headache and foul odor. All patients underwent magnetic resonance imaging (MRI) with 1.5 T system (Fig. 1C and D). Nasal endoscopy revealed necrotic tissue with gray or yellow-green purulent secretion in the nasopharynx (Fig. 1B). The nasopharyngeal biopsy and pathologic examination were obtained for all of the patients to rule out tumor recurrence or residual by nasopharyngeal endoscopy. 2.3. Pathogenic culture, isolation, identification Before starting antibiotic treatment, specimens for isolation of pathogens were collected from the nasopharynx. The nasopharyngeal cavity was exposed by the insertion of the nasopharyngoscope into the nasopharynx before the performance of any other diagnostic procedure. The nasopharyngeal necrosis secreta was collected with sterile nasopharyngeal swab, which were rotated in the nasopharynx; each swab was subsequently kept in a tube under complete aseptic condition, and sent to the clinical lab within two hours. All samples were stained with Gram stain, then plated on MacConkey agar plates, chocolate agar and blood agar, and then incubated aerobically under 5%–10% CO2 at 35◦ C for 24 h–72 h and observed for growth. Identification and antimicrobial susceptibility testing (AST) were performed using automatic microorganisms analyzer (MircroScan Walk Away 40). 2.4. Data analysis
2. Materials and methods
The data was coded, checked, entered and analyzed by SPSS version 16 for Windows. Fisher’s exact tests and Chi2 were used to compare differences between groups. In general, P < 0.05 were considered statistically significant.
2.1. Patients
3. Results
We collected the outcomes for all patients treated for postradiation nasopharyngeal necrosis in our hospital between March 2013 and December 2017, including 69 patients (52 men and 17 women). Of the 69 patients, 57 patients underwent one circle of radiotherapy and 12 patients underwent two courses of radiotherapy due to recurrent tumors, with an average age of 54 years (range 32–77 years).
3.1. Patient characteristics
2.2. Diagnosis of PRNN Patients were diagnosed through medical history, clinical presentation, physical examination, imaging studies and pathologic examination. The signs and symptoms of PRNN mainly were
Patient characteristics were detailed in Table 1. The analysis included 69 NPC patients with PRNN. There were 52 males (75.4%) and 17 females (24.6%) enrolled in our study with a median age of 54 years ranging from 32 to 77 years. Three patients (4.3%) had early (stage I and II) disease, whereas 66 patients (95.7%) had advanced (stage III and IV) disease. All patients had received radiotherapy with the total radiation dose ranged from 66 to 73 Gy (median 70 Gy) at the nasopharyngeal tumor previously. Among them, 12 patients (17.4%) had received reirradiation for relapse. The median total reirradiation dose was 64 Gy, ranging from 56 to 67 Gy. All patients received conservative treatments such as
Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008
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Fig. 1. A. Showed the status of nomal nasopharynx. B. Showed the necrotic tissue of our PRNN patient, as indicated by the red arrows. C and D. Showed the image examinations (MRI) of the PRNN patient on the sagittal and coronal scan. The red arrows show the necrotic tissue. Table 1 Characteristics of 69 NPC patients with post radiation nasopharyngeal necrosis. Patient number (n = 69)
Results of culture Positive
Sex Male Female Age > 55 < 55 Stages I II III IV Reirradiationc No Yes Outcomes Healed 19 Non-healed 50 a b c
2/t
P value
0.00
1.00b
0.08
0.78
2.96
0.41a
1.50
0.22b
6.53
0.011b
Negative
(n = 58)
(n = 11)
52 17
44 14
8 3
34 35
29 29
5 6
1 2 16 50
1 1 13 43
0 1 3 7
57 12
46 12
11 0
12 46
7 4
Fisher’s Exact Test. Continuity correction. The dose of reirradiation: 56Gy–67 Gy (median 64 Gy).
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4 Table 2 Pathogen of 58 culture-positive patients. Pathogen Single pathogen Staphylococcus aureus Pseudomonas aeruginosa Baumanii Escherichia coli Klebsiella pneumoniae Streptococcus pyogenes Citrobacter braakii Pseudomonas stutzeri Streptococcus anginosus Staphylococcus epidermidis Streptococcus viridans Candida albicans Mixed pathogens Pseudomonas aeruginosa + Streptococcus pyogenes Pseudomonas aeruginosa + Candida albicans Klebsiella pneumonia + Candida albicans
Table 3 Antibiotic sensitivity in bacterial isolates(n = 61). n
%
34 8 2 2 1 1 1 1 1 1 1 2
58.6 13.8 3.4 3.4 1.7 1.7 1.7 1.7 1.7 1.7 1.7 3.4
1 1 1
1.7 1.7 1.7
antibiotics guided by the culture results and daily nasopharynx irrigation rinsing with saline (50–100 mL each time). After treatment, the patients performed 1–2 nasopharyngoscopy every month and a magnetic resonance examination every 3 months to evaluate the healing condition. Among these patients, 19 patients (27.5%) were healed, whereas 50 patients (72.5%) were unhealed. There were no significant differences found between groups in terms of the distribution of sex, age, stage or circles of radiotherapy. 3.2. Microbial etiology Out of 69 enrolled patients, 58 patients (84%) indicated microbial etiology including 12 isolated strains. Other patients had no growth (11 patients; 16%) pathogens identified in their pharyngonasal culture. The culture-positive group included bacteria and fungus. Among 58 patients with infected PRNN, the most common pathogen was Staphylococcus aureus, which was isolated from 34 patients (58.6%). The second most common group of bacterial isolates was Pseudomonas aeruginosa (8 patients; 13.8%). And the positive rate of fungus was 6.8% (4 patients). Among the culture-positive group, dual pathogens were identified in 3 cases (4.3%). They were Pseudomonas aeruginosa + Streptococcus pyogenes, Pseudomonas aeruginosa + Candida albicans and Klebsiella pneumonia + Candida albicans, respectively. Results of the pathogenic strains were shown in Table 2. 3.3. Antibiotic susceptibility testing Among 69 NPC patients with microbial etiology, the sensitive rate of Levofloxacin was 88.5% (54 strains), followed by that of ciprofloxacin as 85.2% (52 strains), gentamicin as 80.3% (49 strains), ceftriaxone as 70.5% (43 strains). All of these pathogenic bacteria and fungus cultured in our study can totally resist macrodantin and azithromycin with a resistant rate of 100%. The full results of drug sensitivity testing for the pathogens are listed in Table 3. 3.4. Treatment outcome of PRNN Therapeutic outcomes were evaluated by nasopharyngoscopy. At this examination, 19 (27.5%) and 50 patients (72.5%) were classified as healed and non-healed, respectively. The average time for healing was 9.6 months, ranging from 2.8 to 28.1 months. Among the non-healed patients, 46 patients existed pathogenic infection, others 4 cases were negative. When comparing treatment outcomes in terms of the percentage of healed patients, the culture-negative group showed significantly better therapeutic
Antibiotics
n
%
Levofloxacin Ciprofloxacin Gentamicin Ceftriaxone Tetracycline Moxifloxacin Vancomycin Linezolid Clindamycin Amoxicillin potassium clavulanate Rifampicin Erythrocin Quinoputin/dafutin Daptomycin Oxacillin Cefepime Meropenem Ceftazidime Imipenem Tobramycin Amikacin Piperacillin/tazobactam Piperacillin Aztreonam Ticarcillin Selectrin Fluconazole Itraconazole Amphotericin B Ketoconazole Voriconazole Penicillin Chloramphenicol Gatifloxacin Ertapenem Macrodantin Azithromycin
54 52 49 43 43 38 38 38 37 36 35 35 35 35 34 18 18 17 17 17 16 15 15 13 9 5 4 4 4 4 4 3 3 3 2 0 0
88.5 85.2 80.3 70.5 70.5 62.3 62.3 62.3 60.7 59.0 57.4 57.4 57.4 57.4 55.7 29.5 29.5 27.9 27.9 27.9 26.2 24.6 24.6 21.3 14.8 8.2 6.6 6.6 6.6 6.6 6.6 4.9 4.9 4.9 3.3 0 0
outcomes than the culture-positive group (63.6% vs 20.7%, respectively; P = 0.011; Table 1). 4. Discussion PRNN is a severe late complication of radiotherapy in NPC patients. The management of PRNN is not only important but also challenging. According to the recent reported references, the pathogenic infection rate of PRNN is 68.3%–71.4% [11,14]. Now that majority of PRNN patients have concurrent nasopharyngeal infection, inevitably, the use of antibiotics is indispensable in the therapy of PRNN. Clinically, the identification of bacteriology and drug sensitivity generally require at least three workdays for PRNN patients, and that may delay treatment. Hence, updating our knowledge about the prevalence of pathogenic infections in PRNN patients is of great significance in the clinic. At present, there is no independent study on the microbial infection as a factor that may influence the prognosis of PRNN. The aim of our study is to assess the bacteriology of PRNN and to analyze the drug sensitivity patterns that should guide the clinicians towards more appropriate antibiotic use. There is a small trial about the bacteriology of PRNN in 2008 which showed Streptococcus pneumoniae as the most common bacterium (6/20, 30%), followed by Staphylococcus aureus (5/20, 25%) and Klebsiella pneumoniae at rates of 20% (4/20) [11]. Nevertheless, the numbers of patients included in their studies were small (20 cases). In the present study, we reported the bacteriology and the administration of susceptible antibiotics on a large series of patients with PRNN. Pathogens were identified in 58 (84.1%) of enrolled cases higher than reported in the literature, including bacteria and fungus. Among the pathogens, Staphylococcus aureus showed the
Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008
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highest rate of isolation (34/58, 58.6%), followed by Pseudomonas aeruginosa (8/58, 13.8%), baumanii and Escherichia coli (2/58, 3.4% each). The only pathologic fungus was Candida albicans, about 6.8% (4/58). Candida albicans is one of the most common fungi that cause superficial and systemic infections, particularly to immunosuppressive patients [15]. Hence, the most common pathogen of PRNN was bacteria, and the infection by fungi was in rare. Besides, there was only one patient with dual bacteria infection and two patients with mixed bacterial and fungal infection. It is thus clear that single pathogen was common while mixed pathogens were infrequent. Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common pathogenic bacteria of hospital and community acquisition. They can cause various infectious diseases in humans, such as skin, wound and soft-tissue infections, as well as pneumonia and endometritis, and lead to high mortality [16–18]. Similar to previous studies, our study showed Staphylococcus aureus and Pseudomonas aeruginosa were the most common pathogens in the nasopharyngeal infection. It could be that the nasopharyngeal infection belongs to community-acquired infections. The pathogenic drug sensitivity results in this study suggested levofloxacin and ciprofloxacin should be considered as the first-line of anti-infective treatment with sensitive rate of 88.5% and 82.5%, respectively. Besides, the pathologic fungal positive rate was relatively low, with only 6.8% (4 patients). So to the NPC patients with PRNN, antifungal agents may not be the preferred choice. At present, the exact etiology and mechanism of PRNN is still unknown. As Marx reported, it is the irradiation that induces hypoxic-hypovascular-hypocellular status (the “three H” principle) and impair normal collagen synthesis and cell production, which may lead to tissue breakdown and a chronic nonhealing wound [19]. Besides, microbial infection may contribute to the process of PRNN. Local infection of nasopharynx may increase the demand of energy, oxygen and other metabolites, leading to tissue breakdown and cell death [20]. According to the literature, NPC patients who receive reirradiation are more predisposed to having PRNN [21,22]. But our results showed that only 17.4% (n = 12) of the patients received reirradiation for local recurrent tumors, which was valuable to study more. Additionally, our results indicated 95.7% of patients with PRNN were advanced patients (stage III and IV). It is most likely to stem from higher radiation dose for advanced patients. According to the reports in the literature, it is known to all that internal carotid artery erosion was an independent important risk factor for the patients with PRNN [11]. In the current study, our findings showed that the difference in curative effect between infection group and non-infection group was significantly (P = 0.011). Therefore, keeping oropharynx clean and preventing infection are both of great significance to improve the efficacy of the PRNN patients. Clinically, occurrence of multidrug resistant strains closely associated with abuse of antibiotics [23]. Once the emergence of resistant strains during therapy may increase the difficulty of treatment for PRNN patients. This study investigated the microbial etiology in NPC patients with PRNN and the antimicrobial susceptibility that can provide the evidence for rational antibiotic using in the clinics. Further study is still needed on a larger cohort to establish guidelines for selecting the proper antibiotics for treatment. The treatment of PRNN may be very difficult. In general, the curative rate of PRNN was relatively low, with only 27.5% (19/69) in our result. Therefore, prophylaxis should be more important than therapy. The mechanism of PRNN will be further studied in future to reduce the incidence rates of PRNN.
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5. Conclusion This study updates our knowledge on the prevalence of microbial infections and antibiotics susceptibility in NPC patients with PRNN. Our research shows that infection impact wound healing of PRNN patients; the most frequent pathogen is Staphylococcus aureus; levofloxacin and ciprofloxacin may be considered as the first-line of anti-infective treatment to the NPC patients with PRNN. As to the low infection rate of fungus, antifungal agents may not be the preferred choice. Funding This study was supported financially by grant from the Natural Science Foundation of Shanghai (81660453 and 81802915) and the Youth fund of science and technology department of Jiangxi province (2016BAB215255). Author contributions Zi-Wei Tu made substantial contributions to the conception or design of the work, Jun Yang did data processing and supervision, Shi-Yi Peng and Guo-Qing Li carried out some data analysis and materials characterization, Li Wang helped with project supervision and designing some experiments, Zi-Wei Tu (corresponding author) supervised the work progress, helped out with the results discussion. All authors contributed to writing of manuscript. All persons who have made substantial contributions to the work reported in the manuscript, including those who provided editing and writing assistance but who are not authors, are named in the Acknowledgments section of the manuscript and have given their written permission to be named. If the manuscript does not include acknowledgments, it is because the authors have not received substantial contributions from non-authors. Disclosure of interest The authors declare that they have no competing interest. Acknowledgements We acknowledge the support of the Department of Radiation Oncology, Jiangxi Cancer Hospital. The views expressed in this publication are those of the authors. References [1] Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol 2015;33:3356–64. [2] Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, et al. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiother Oncol 2014;110:398–403. [3] Chan JY, Tsang RK, Wei WI. Morbidities after maxillary swing nasopharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck 2015;37:487–92. [4] Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for earlystage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981–91. [5] Young YH. Irradiated ears in nasopharyngeal carcinoma survivors: a review. Laryngoscope 2019;129:637–42. [6] Wang X, Ying H, Zhou Z, Hu C, Eisbruch A. Successful treatment of radiationinduced temporal lobe necrosis with mouse nerve growth factor. J Clin Oncol 2011;29:e166–8. [7] Yen TT, Lin CH, Jiang RS, Shih YT, Yen HR, Liang KL. Incidence of late-onset pneumonia in patients after treatment with radiotherapy for nasopharyngeal carcinoma: a nationwide population-based study. Head Neck 2015;37:1756–61.
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[15] Lone SA, Ahmad A. Candida auris-the growing menace to global health. Mycoses 2019;62:620–37. [16] Raafat D, Otto M, Reppschläger K, et al. Fighting Staphylococcus aureus biofilms with monoclonal antibodies. Trends Microbiol 2019;27:303–22. [17] Pragasam AK, Veeraraghavan B, Nalini E, et al. An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa. Indian J Med Microbiol 2018;36:303–16. [18] Drissa M, Amani F. Drissa H Staphylococcus aureus infective endocarditis at a tertiary Tunisian hospital. A changing profile? Egypt Heart J 2018;70:365–8. [19] Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283–8. [20] Meyer I. Infectious diseases of the jaws. J Oral Surg 1970;28:17–26. [21] Huang XM, Zheng YQ, Zhang XM, et al. Diagnosis and management of skull base osteoradionecrosis after radiotherapy for nasopharyngeal carcinoma. Laryngoscope 2006;116:1626–31. [22] Lu TX, Mai WY, Teh BS, et al. Initial experience using intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;58:682–7. [23] Xiao Y. Antimicrobial stewardship in china: systems, actions and future strategies. Clin Infect Dis 2018;67:S135–41.
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Original article
Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma Étiologie microbienne, profil de susceptibilité de nécrose nasopharyngée chez les patients atteints de carcinome nasopharyngé Li Wang a,1 , Jun Yang b,1 , Shi-Yi Peng c , Guo-Qing Li c , Zi-Wei Tu c,∗ a
Department of Radiotherapy, Eye Ear Nose and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, PR China Department of Radiotherapy, Medical College, Nanchang University, Nanchang, PR China c Department of Radiotherapy, Jiangxi Cancer Hospital, Medical College, Nanchang University, Nanchang, PR China b
a r t i c l e
i n f o
Article history: Received 13 April 2019 Received in revised form 10 September 2019 Accepted 13 September 2019 Keywords: Nasopharyngeal carcinoma (NPC) Postradiation nasopharyngeal necrosis (PRNN) Pathogens Drug susceptibility Antibiotics
a b s t r a c t Objective. – Postradiation nasopharyngeal necrosis (PRNN) is a notorious complication after radiotherapy that affects prognosis in patients with nasopharyngeal carcinoma (NPC). It is important for clinical doctors to realize this problem in order to cope with this severe clinical situation. The aim of our study was to assess the bacteriology of PRNN and to demonstrate the antimicrobial susceptibility pattern that should guide the clinicians towards more appropriate antibiotic use. Methods. – Sixty-nine NPC patients with PRNN in our department between March 2013 and December 2017 were retrospectively enrolled. Pathogenic culture and drug sensitivity test were performed in these 69 NPC patients with PRNN. The infection rate of Pathogens and the sensitivity of the drugs were analyzed based on these results. Results. – Sixty-nine NPC patients with PRNN were enrolled in our study. Pathogens were identified in 58 (84%) patients. Of the 58 patients, Staphylococcus aureus was isolated in 34 (58.6%) patients. And the second most common group of bacterial isolates was Pseudomonas aeruginosa. Antibiotic sensitivity showed that Levofloxacin was the highest (88.5%), followed by Ciprofloxacin (85.2%) and Gentamicin (80.3%). The only pathologic fungus was Candida albicans, about 6.8%. The positive rates of bacterial and fungal culture in PRNN patients were not significantly different from the patients’ gender, age, stage, number of radiotherapy courses (P > 0.05), but the cure rate was statistically higher in culture-negative patients in comparison with culture-positive patients (63.6% vs 20.7%, P = 0.011). Conclusion. – Our results provide an overall picture of the microbiology and drug susceptibility patterns for NPC patients with PRNN and could help implement guidelines for more rational treatment and improve therapeutic outcome. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2020 Societ rights reserved.
r é s u m é Mots clés : Carcinome du nasopharynx (CPN) Nécrose nasopharyngée postradiation (PRNN) Pathogènes Sensibilité aux médicaments Antibiotiques
Objet. – La nécrose nasopharyngée postradiation (PRNN) est une complication notoire après la radiothérapie chez les patients atteints de carcinome du nasopharynx (CPN) Il est important que les cliniciens réalisent ce problème pour faire face à cette situation clinique grave. Notre étude visait à évaluer la bactériologie de la PRNN et à démontrer le profil de sensibilité aux antimicrobiens qui devrait guider les cliniciens vers une utilisation plus appropriée des antibiotiques. Patients et méthodes. – Nous avons analysé rétrospectivement les 69 PRNN chez les patients atteints de NPC traités dans notre service. Soixante-neuf patients atteints de NPC PRNN dans notre service entre mars 2013 et décembre 2017 ont été inscrits rétrospectivement. Le test de sensibilité à la culture et aux
∗ Corresponding author. E-mail address: [email protected] (Z.-W. Tu). 1 The author equally contributes to this work. https://doi.org/10.1016/j.canrad.2019.09.008 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2020 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008
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médicaments a été réalisé chez ces 69 patients atteints de PRNN. Le taux d’infection des agents pathogènes et la sensibilité des médicaments ont été analysés sur la base de ces résultats. Résultats. – Soixante neuf PRNN chez les patients atteitns de NPC ont été inclus dans notre étude. Des agents pathogènes ont été identifiés chez 58 patients (84 %). Sur ces 58 patients, Staphylococcus aureus a été isolé chez 34 patients (58,6 %). Pseudomonas aeruginosa était la souche la plus élevée (88,5 %), suivie de la ciprofloxacine (85,2 %) et de la gentamicine (80,3 %), la sensibilité aux antibiotiques étant la plus élevée (80,5 %). Le seul champignon pathologique était Candida albicans, environ 6,8 %. La culture fongique chez les patients atteints de PRNN ne différait pas significativement du sexe, de l’âge, du stage et du nombre de cycles de radiothérapie (p > 0,05), mais le taux de guérison était statistiquement plus élevé chez les patients à culture négative que chez les patients à culture-positive (63,6 % vs 20,7 %, p = 0,011). Conclusion. – Nos résultats fournissent une image globale de la microbiologie et des schémas de sensibilité aux médicaments des patients atteints de PRNN et pourraient aider à mettre en œuvre des directives pour un traitement plus rationnel et améliorer les résultats thérapeutiques. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2020 Societ ´ ´ droits reserv es.
1. Introduction Nasopharyngeal carcinoma (NPC) is a common malignancy in Southeast Asia, with a peak annual incidence approaching 30 per 100,000 persons [1]. Radiotherapy has been the mainstay treatment for NPC [2]. Complications related to radiation therapy have been well documented in many studies, which include otitis media with effusion, xerostomia, temporal lobe necrosis, dysphagia, trismus and so on [3–7]. Among them, postradiation nasopharyngeal necrosis (PRNN) is one of the most serious late effects for NPC radiotherapy with the representative signs of headache, foul odor and intermittent bleeding [8,9]. According to the literature, the incidence of PRNN reached 22.9% for reirradiation patients [10]. PRNN not only severely reduces the patients’ quality of life (QoL), but even threatens the life of patients, when the internal carotid artery is involved. Hua et al. reported that the cure rate of PRNN is only 28.6% (8/28) and 9 patients (9/28, 32.1%) with exposed internal carotid artery died of sudden nasopharyngeal massive bleeding [11]. Although the standard treatments are not well defined, the surgical approaches and conservative treatments such as antibiotics and daily nasopharynx irrigation seem to be able to benefit the patients [12,13]. To improve the sensitivities of antibiotic drugs and effectiveness of the treatments, the use of antibiotics in the treatment of PRNN should be based on the results of culture and drug sensitivity test. Despite the advances in management of PRNN, a definitive microbial etiology is not usually available. In this paper, we aimed to evaluate the bacteriology of PRNN and demonstrate the antimicrobial susceptibility pattern so as to provide clinical evidences for reasonable application of antibiotics.
headache and foul odor. All patients underwent magnetic resonance imaging (MRI) with 1.5 T system (Fig. 1C and D). Nasal endoscopy revealed necrotic tissue with gray or yellow-green purulent secretion in the nasopharynx (Fig. 1B). The nasopharyngeal biopsy and pathologic examination were obtained for all of the patients to rule out tumor recurrence or residual by nasopharyngeal endoscopy. 2.3. Pathogenic culture, isolation, identification Before starting antibiotic treatment, specimens for isolation of pathogens were collected from the nasopharynx. The nasopharyngeal cavity was exposed by the insertion of the nasopharyngoscope into the nasopharynx before the performance of any other diagnostic procedure. The nasopharyngeal necrosis secreta was collected with sterile nasopharyngeal swab, which were rotated in the nasopharynx; each swab was subsequently kept in a tube under complete aseptic condition, and sent to the clinical lab within two hours. All samples were stained with Gram stain, then plated on MacConkey agar plates, chocolate agar and blood agar, and then incubated aerobically under 5%–10% CO2 at 35◦ C for 24 h–72 h and observed for growth. Identification and antimicrobial susceptibility testing (AST) were performed using automatic microorganisms analyzer (MircroScan Walk Away 40). 2.4. Data analysis
2. Materials and methods
The data was coded, checked, entered and analyzed by SPSS version 16 for Windows. Fisher’s exact tests and Chi2 were used to compare differences between groups. In general, P < 0.05 were considered statistically significant.
2.1. Patients
3. Results
We collected the outcomes for all patients treated for postradiation nasopharyngeal necrosis in our hospital between March 2013 and December 2017, including 69 patients (52 men and 17 women). Of the 69 patients, 57 patients underwent one circle of radiotherapy and 12 patients underwent two courses of radiotherapy due to recurrent tumors, with an average age of 54 years (range 32–77 years).
3.1. Patient characteristics
2.2. Diagnosis of PRNN Patients were diagnosed through medical history, clinical presentation, physical examination, imaging studies and pathologic examination. The signs and symptoms of PRNN mainly were
Patient characteristics were detailed in Table 1. The analysis included 69 NPC patients with PRNN. There were 52 males (75.4%) and 17 females (24.6%) enrolled in our study with a median age of 54 years ranging from 32 to 77 years. Three patients (4.3%) had early (stage I and II) disease, whereas 66 patients (95.7%) had advanced (stage III and IV) disease. All patients had received radiotherapy with the total radiation dose ranged from 66 to 73 Gy (median 70 Gy) at the nasopharyngeal tumor previously. Among them, 12 patients (17.4%) had received reirradiation for relapse. The median total reirradiation dose was 64 Gy, ranging from 56 to 67 Gy. All patients received conservative treatments such as
Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008
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Fig. 1. A. Showed the status of nomal nasopharynx. B. Showed the necrotic tissue of our PRNN patient, as indicated by the red arrows. C and D. Showed the image examinations (MRI) of the PRNN patient on the sagittal and coronal scan. The red arrows show the necrotic tissue. Table 1 Characteristics of 69 NPC patients with post radiation nasopharyngeal necrosis. Patient number (n = 69)
Results of culture Positive
Sex Male Female Age > 55 < 55 Stages I II III IV Reirradiationc No Yes Outcomes Healed 19 Non-healed 50 a b c
2/t
P value
0.00
1.00b
0.08
0.78
2.96
0.41a
1.50
0.22b
6.53
0.011b
Negative
(n = 58)
(n = 11)
52 17
44 14
8 3
34 35
29 29
5 6
1 2 16 50
1 1 13 43
0 1 3 7
57 12
46 12
11 0
12 46
7 4
Fisher’s Exact Test. Continuity correction. The dose of reirradiation: 56Gy–67 Gy (median 64 Gy).
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4 Table 2 Pathogen of 58 culture-positive patients. Pathogen Single pathogen Staphylococcus aureus Pseudomonas aeruginosa Baumanii Escherichia coli Klebsiella pneumoniae Streptococcus pyogenes Citrobacter braakii Pseudomonas stutzeri Streptococcus anginosus Staphylococcus epidermidis Streptococcus viridans Candida albicans Mixed pathogens Pseudomonas aeruginosa + Streptococcus pyogenes Pseudomonas aeruginosa + Candida albicans Klebsiella pneumonia + Candida albicans
Table 3 Antibiotic sensitivity in bacterial isolates(n = 61). n
%
34 8 2 2 1 1 1 1 1 1 1 2
58.6 13.8 3.4 3.4 1.7 1.7 1.7 1.7 1.7 1.7 1.7 3.4
1 1 1
1.7 1.7 1.7
antibiotics guided by the culture results and daily nasopharynx irrigation rinsing with saline (50–100 mL each time). After treatment, the patients performed 1–2 nasopharyngoscopy every month and a magnetic resonance examination every 3 months to evaluate the healing condition. Among these patients, 19 patients (27.5%) were healed, whereas 50 patients (72.5%) were unhealed. There were no significant differences found between groups in terms of the distribution of sex, age, stage or circles of radiotherapy. 3.2. Microbial etiology Out of 69 enrolled patients, 58 patients (84%) indicated microbial etiology including 12 isolated strains. Other patients had no growth (11 patients; 16%) pathogens identified in their pharyngonasal culture. The culture-positive group included bacteria and fungus. Among 58 patients with infected PRNN, the most common pathogen was Staphylococcus aureus, which was isolated from 34 patients (58.6%). The second most common group of bacterial isolates was Pseudomonas aeruginosa (8 patients; 13.8%). And the positive rate of fungus was 6.8% (4 patients). Among the culture-positive group, dual pathogens were identified in 3 cases (4.3%). They were Pseudomonas aeruginosa + Streptococcus pyogenes, Pseudomonas aeruginosa + Candida albicans and Klebsiella pneumonia + Candida albicans, respectively. Results of the pathogenic strains were shown in Table 2. 3.3. Antibiotic susceptibility testing Among 69 NPC patients with microbial etiology, the sensitive rate of Levofloxacin was 88.5% (54 strains), followed by that of ciprofloxacin as 85.2% (52 strains), gentamicin as 80.3% (49 strains), ceftriaxone as 70.5% (43 strains). All of these pathogenic bacteria and fungus cultured in our study can totally resist macrodantin and azithromycin with a resistant rate of 100%. The full results of drug sensitivity testing for the pathogens are listed in Table 3. 3.4. Treatment outcome of PRNN Therapeutic outcomes were evaluated by nasopharyngoscopy. At this examination, 19 (27.5%) and 50 patients (72.5%) were classified as healed and non-healed, respectively. The average time for healing was 9.6 months, ranging from 2.8 to 28.1 months. Among the non-healed patients, 46 patients existed pathogenic infection, others 4 cases were negative. When comparing treatment outcomes in terms of the percentage of healed patients, the culture-negative group showed significantly better therapeutic
Antibiotics
n
%
Levofloxacin Ciprofloxacin Gentamicin Ceftriaxone Tetracycline Moxifloxacin Vancomycin Linezolid Clindamycin Amoxicillin potassium clavulanate Rifampicin Erythrocin Quinoputin/dafutin Daptomycin Oxacillin Cefepime Meropenem Ceftazidime Imipenem Tobramycin Amikacin Piperacillin/tazobactam Piperacillin Aztreonam Ticarcillin Selectrin Fluconazole Itraconazole Amphotericin B Ketoconazole Voriconazole Penicillin Chloramphenicol Gatifloxacin Ertapenem Macrodantin Azithromycin
54 52 49 43 43 38 38 38 37 36 35 35 35 35 34 18 18 17 17 17 16 15 15 13 9 5 4 4 4 4 4 3 3 3 2 0 0
88.5 85.2 80.3 70.5 70.5 62.3 62.3 62.3 60.7 59.0 57.4 57.4 57.4 57.4 55.7 29.5 29.5 27.9 27.9 27.9 26.2 24.6 24.6 21.3 14.8 8.2 6.6 6.6 6.6 6.6 6.6 4.9 4.9 4.9 3.3 0 0
outcomes than the culture-positive group (63.6% vs 20.7%, respectively; P = 0.011; Table 1). 4. Discussion PRNN is a severe late complication of radiotherapy in NPC patients. The management of PRNN is not only important but also challenging. According to the recent reported references, the pathogenic infection rate of PRNN is 68.3%–71.4% [11,14]. Now that majority of PRNN patients have concurrent nasopharyngeal infection, inevitably, the use of antibiotics is indispensable in the therapy of PRNN. Clinically, the identification of bacteriology and drug sensitivity generally require at least three workdays for PRNN patients, and that may delay treatment. Hence, updating our knowledge about the prevalence of pathogenic infections in PRNN patients is of great significance in the clinic. At present, there is no independent study on the microbial infection as a factor that may influence the prognosis of PRNN. The aim of our study is to assess the bacteriology of PRNN and to analyze the drug sensitivity patterns that should guide the clinicians towards more appropriate antibiotic use. There is a small trial about the bacteriology of PRNN in 2008 which showed Streptococcus pneumoniae as the most common bacterium (6/20, 30%), followed by Staphylococcus aureus (5/20, 25%) and Klebsiella pneumoniae at rates of 20% (4/20) [11]. Nevertheless, the numbers of patients included in their studies were small (20 cases). In the present study, we reported the bacteriology and the administration of susceptible antibiotics on a large series of patients with PRNN. Pathogens were identified in 58 (84.1%) of enrolled cases higher than reported in the literature, including bacteria and fungus. Among the pathogens, Staphylococcus aureus showed the
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highest rate of isolation (34/58, 58.6%), followed by Pseudomonas aeruginosa (8/58, 13.8%), baumanii and Escherichia coli (2/58, 3.4% each). The only pathologic fungus was Candida albicans, about 6.8% (4/58). Candida albicans is one of the most common fungi that cause superficial and systemic infections, particularly to immunosuppressive patients [15]. Hence, the most common pathogen of PRNN was bacteria, and the infection by fungi was in rare. Besides, there was only one patient with dual bacteria infection and two patients with mixed bacterial and fungal infection. It is thus clear that single pathogen was common while mixed pathogens were infrequent. Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common pathogenic bacteria of hospital and community acquisition. They can cause various infectious diseases in humans, such as skin, wound and soft-tissue infections, as well as pneumonia and endometritis, and lead to high mortality [16–18]. Similar to previous studies, our study showed Staphylococcus aureus and Pseudomonas aeruginosa were the most common pathogens in the nasopharyngeal infection. It could be that the nasopharyngeal infection belongs to community-acquired infections. The pathogenic drug sensitivity results in this study suggested levofloxacin and ciprofloxacin should be considered as the first-line of anti-infective treatment with sensitive rate of 88.5% and 82.5%, respectively. Besides, the pathologic fungal positive rate was relatively low, with only 6.8% (4 patients). So to the NPC patients with PRNN, antifungal agents may not be the preferred choice. At present, the exact etiology and mechanism of PRNN is still unknown. As Marx reported, it is the irradiation that induces hypoxic-hypovascular-hypocellular status (the “three H” principle) and impair normal collagen synthesis and cell production, which may lead to tissue breakdown and a chronic nonhealing wound [19]. Besides, microbial infection may contribute to the process of PRNN. Local infection of nasopharynx may increase the demand of energy, oxygen and other metabolites, leading to tissue breakdown and cell death [20]. According to the literature, NPC patients who receive reirradiation are more predisposed to having PRNN [21,22]. But our results showed that only 17.4% (n = 12) of the patients received reirradiation for local recurrent tumors, which was valuable to study more. Additionally, our results indicated 95.7% of patients with PRNN were advanced patients (stage III and IV). It is most likely to stem from higher radiation dose for advanced patients. According to the reports in the literature, it is known to all that internal carotid artery erosion was an independent important risk factor for the patients with PRNN [11]. In the current study, our findings showed that the difference in curative effect between infection group and non-infection group was significantly (P = 0.011). Therefore, keeping oropharynx clean and preventing infection are both of great significance to improve the efficacy of the PRNN patients. Clinically, occurrence of multidrug resistant strains closely associated with abuse of antibiotics [23]. Once the emergence of resistant strains during therapy may increase the difficulty of treatment for PRNN patients. This study investigated the microbial etiology in NPC patients with PRNN and the antimicrobial susceptibility that can provide the evidence for rational antibiotic using in the clinics. Further study is still needed on a larger cohort to establish guidelines for selecting the proper antibiotics for treatment. The treatment of PRNN may be very difficult. In general, the curative rate of PRNN was relatively low, with only 27.5% (19/69) in our result. Therefore, prophylaxis should be more important than therapy. The mechanism of PRNN will be further studied in future to reduce the incidence rates of PRNN.
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5. Conclusion This study updates our knowledge on the prevalence of microbial infections and antibiotics susceptibility in NPC patients with PRNN. Our research shows that infection impact wound healing of PRNN patients; the most frequent pathogen is Staphylococcus aureus; levofloxacin and ciprofloxacin may be considered as the first-line of anti-infective treatment to the NPC patients with PRNN. As to the low infection rate of fungus, antifungal agents may not be the preferred choice. Funding This study was supported financially by grant from the Natural Science Foundation of Shanghai (81660453 and 81802915) and the Youth fund of science and technology department of Jiangxi province (2016BAB215255). Author contributions Zi-Wei Tu made substantial contributions to the conception or design of the work, Jun Yang did data processing and supervision, Shi-Yi Peng and Guo-Qing Li carried out some data analysis and materials characterization, Li Wang helped with project supervision and designing some experiments, Zi-Wei Tu (corresponding author) supervised the work progress, helped out with the results discussion. All authors contributed to writing of manuscript. All persons who have made substantial contributions to the work reported in the manuscript, including those who provided editing and writing assistance but who are not authors, are named in the Acknowledgments section of the manuscript and have given their written permission to be named. If the manuscript does not include acknowledgments, it is because the authors have not received substantial contributions from non-authors. Disclosure of interest The authors declare that they have no competing interest. Acknowledgements We acknowledge the support of the Department of Radiation Oncology, Jiangxi Cancer Hospital. The views expressed in this publication are those of the authors. References [1] Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol 2015;33:3356–64. [2] Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, et al. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiother Oncol 2014;110:398–403. [3] Chan JY, Tsang RK, Wei WI. Morbidities after maxillary swing nasopharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck 2015;37:487–92. [4] Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for earlystage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981–91. [5] Young YH. Irradiated ears in nasopharyngeal carcinoma survivors: a review. Laryngoscope 2019;129:637–42. [6] Wang X, Ying H, Zhou Z, Hu C, Eisbruch A. Successful treatment of radiationinduced temporal lobe necrosis with mouse nerve growth factor. J Clin Oncol 2011;29:e166–8. [7] Yen TT, Lin CH, Jiang RS, Shih YT, Yen HR, Liang KL. Incidence of late-onset pneumonia in patients after treatment with radiotherapy for nasopharyngeal carcinoma: a nationwide population-based study. Head Neck 2015;37:1756–61.
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Please cite this article in press as: Wang L, et al. Microbial etiology, susceptibility profile of postradiation nasopharyngeal necrosis patients with nasopharyngeal carcinoma. Cancer Radiother (2020), https://doi.org/10.1016/j.canrad.2019.09.008