Risk Factors of Infectious Complications After Endobronchial Ultrasound-Guided Transbronchial Biopsy

Abstract

BackgroundInfectious complications after endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS-TBB) are serious in that they may delay or change scheduled subsequent therapy. The aim of this study was to identify risk factors for infection after EBUS-GS-TBB.Research QuestionWhat are the risk factors for infection after EBUS-GS-TBB?Study Design and MethodsWe retrospectively reviewed the medical records of 1,045 consecutive patients who had undergone EBUS-GS-TBB for peripheral lung lesions between January 2013 and December 2017 at Fujita Health University Hospital. We evaluated the following risk factors for infectious complications after EBUS-GS-TBB: relevant patient characteristics (age and comorbidities), lesion size, CT scan features of target lesion (intratumoral low-density areas [LDAs] and cavitation), stenosis of responsible bronchus observed by bronchoscopy, and laboratory data before EBUS-GS-TBB (WBC count and C-reactive protein concentration).ResultsForty-seven of the study patients developed infectious complications (24 with pneumonia, 14 with intratumoral infection, three with lung abscess, three with pleuritis, and three with empyema), among whom the complication caused a delay in cancer treatment in 13 patients, cancellation of cancer treatment in seven patients, and death in three patients. Multivariate analysis showed that cavitation (P = .007), intratumoral LDAs (P < .001), and stenosis of responsible bronchus observed by bronchoscopy (P < .001) were significantly associated with infectious complications after EBUS-GS-TBB. Prophylactic antibiotics had been administered to 13 patients in the infection group. Propensity matched analysis could not show significant benefit of prophylactic antibiotics in preventing post-EBUS-GS-TBB infections.InterpretationCavitation, LDAs for CT scan features of target lesions, and stenosis of responsible bronchus observed by bronchoscopy are risk factors of post-EBUS-GS-TBB infection. In the cohort, prophylactic antibiotics failed to prevent infectious complications. Infectious complications after endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS-TBB) are serious in that they may delay or change scheduled subsequent therapy. The aim of this study was to identify risk factors for infection after EBUS-GS-TBB. What are the risk factors for infection after EBUS-GS-TBB? We retrospectively reviewed the medical records of 1,045 consecutive patients who had undergone EBUS-GS-TBB for peripheral lung lesions between January 2013 and December 2017 at Fujita Health University Hospital. We evaluated the following risk factors for infectious complications after EBUS-GS-TBB: relevant patient characteristics (age and comorbidities), lesion size, CT scan features of target lesion (intratumoral low-density areas [LDAs] and cavitation), stenosis of responsible bronchus observed by bronchoscopy, and laboratory data before EBUS-GS-TBB (WBC count and C-reactive protein concentration). Forty-seven of the study patients developed infectious complications (24 with pneumonia, 14 with intratumoral infection, three with lung abscess, three with pleuritis, and three with empyema), among whom the complication caused a delay in cancer treatment in 13 patients, cancellation of cancer treatment in seven patients, and death in three patients. Multivariate analysis showed that cavitation (P = .007), intratumoral LDAs (P < .001), and stenosis of responsible bronchus observed by bronchoscopy (P < .001) were significantly associated with infectious complications after EBUS-GS-TBB. Prophylactic antibiotics had been administered to 13 patients in the infection group. Propensity matched analysis could not show significant benefit of prophylactic antibiotics in preventing post-EBUS-GS-TBB infections. Cavitation, LDAs for CT scan features of target lesions, and stenosis of responsible bronchus observed by bronchoscopy are risk factors of post-EBUS-GS-TBB infection. In the cohort, prophylactic antibiotics failed to prevent infectious complications. FOR EDITORIAL COMMENT, SEE PAGE 458Flexible fiber-optic bronchoscopy is a mainstay procedure for the diagnosis and treatment of various respiratory diseases including lung cancer, infections, and interstitial diseases. The endobronchial ultrasound (EBUS) technique, introduced to daily clinical practice and now widely used, has led to a higher diagnostic yield of lung cancer in the peripheral lung field and hilar or mediastinal lesions.1Minezawa T. Okamura T. Yatsuya H. et al.Bronchus sign on thin-section computed tomography is a powerful predictive factor for successful transbronchial biopsy using endobronchial ultrasound with a guide sheath for small peripheral lung lesions: a retrospective observational study.BMC Med Imaging. 2015; 15: 21Crossref PubMed Scopus (39) Google Scholar,2Fielding D.I. Kurimoto N. EBUS-TBNA/staging of lung cancer.Clin Chest Med. 2013; 34: 385-394Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS-TBB) is one of the most common procedures for the biopsy of peripheral lung lesions. Although it is a relatively safe procedure, transbronchial biopsy (TBB) can rarely be complicated by several postbronchoscopic adverse events, such as fever, pneumonia, infection at the biopsied site, hemorrhage, or pneumothorax.3Takiguchi H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Scholar Among these events, infectious complications after TBB constitute a serious clinical problem because they might delay the start of treatment or cause the intended treatment to be modified to a milder one. The precise mechanism of such complications is still unclear, and effective prophylaxis procedures have not been established. According to the British Thoracic Society guidelines, antibiotic prophylaxis is not recommended before bronchoscopy because it does not prevent postbronchoscopy fever or pneumonia.4Du Rand I.A. Blaikley J. Booton R. et al.British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE.Thorax. 2013; 68 suppl 1: i1-i44Crossref PubMed Scopus (380) Google Scholar Therefore, it is very important to identify the risk factors for infectious complications after TBB if and when these complications are to be avoided. Previous studies have suggested the probable risk factors for infectious complications after conventional TBB (not using the EBUS-GS system) to be older age, abnormal findings in the bronchial lumen, and CT scan features of tumors (intratumoral low-density areas [LDAs] or cavitation).3Takiguchi H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Scholar,5Fortin M. Taghizadeh N. Chee A. et al.Lesion heterogeneity and risk of infectious complications following peripheral endobronchial ultrasound.Respirology. 2017; 22: 521-526Crossref PubMed Scopus (4) Google Scholar However, few studies have focused on the incidence of and risk factors for infections after EBUS-GS-TBB. Infections after TBB may be caused by the spread of pathogens from the oral cavity and upper airways to sterile lower airways.3Takiguchi H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Scholar The aim of this study was to elucidate the potential risk factors for infectious complications after EBUS-GS-TBB in a large sample of patients. We also estimated the efficacy of antibiotics prophylaxis after EBUS-GS-TBB in the cohort. FOR EDITORIAL COMMENT, SEE PAGE 458 We retrospectively reviewed the medical records of 1,045 consecutive patients who had undergone EBUS-GS-TBB for the purpose of diagnosing lung cancer between January 2013 and December 2017 at Fujita Health University Hospital (Table 1). We investigated the following clinical factors of all patients: age, sex, smoking status, comorbidities, laboratory data before EBUS-GS-TBB including WBC counts and C-reactive protein (CRP) concentrations, CT scan features of tumors (tumor size, location, intratumoral density, and presence of cavitation), bronchoscopic findings (presence of stenosis at responsible bronchus), bronchoscopic examination time, prophylactic administration of antibiotics, and final pathologic diagnosis. The institutional review board of Fujita Health University approved this study (HM18-188).Table 1Patient Characteristics (N = 1,045)CharacteristicValueAge, y Median (range)72 (32-91) < 75671 ≥ 75374Sex Male710 Female335Smoking status Former492 Current218 Never335Comorbidities Diabetes mellitus121 Collagen vascular diseases46 Immunosuppressant use41 Other malignancies60Lesion size (long diameter), mm ≤ 20369 > 20 and ≤ 30331 > 30345Lesion location Right upper lobe336 Middle lobe67 Lower lobe244 Left upper lobe249 Lower lobe149Cavitation within the lesion Present95 Absent950LDA in the lesion Present132 Absent913Stenosis of responsible bronchus Present75 Location of stenosisSegmental53Subsegmental18More distal4 Absent970WBC count before bronchoscopy (count/μL) Median (range)6,900 (1,000-22,100)CRP before bronchoscopy (mg/dL) Median (range)1.0 (0-18.5)Bronchoscopic examination duration, min Median (range)52 (18-146)Prophylactic antibiotics administration Yes102 No943Bronchoscopic diagnosis Lung cancer and other malignancy695 Others189 Undiagnosed161Final diagnosis Adenocarcinoma536 Squamous cell carcinoma147 Others (malignancy)122 Others (benign)240Values are No. or as otherwise indicated. CRP = C-reactive protein; LDA = low-density area. Open table in a new tab Values are No. or as otherwise indicated. CRP = C-reactive protein; LDA = low-density area. After local pharyngeal anesthesia using 2% lidocaine, all patients were sedated with IV midazolam at an individually calculated dose reported elsewhere.6Ogawa T. Imaizumi K. Hashimoto I. et al.Prospective analysis of efficacy and safety of an individualized-midazolam-dosing protocol for sedation during prolonged bronchoscopy.Respir Investig. 2014; 52: 153-159Crossref PubMed Scopus (13) Google Scholar In some patients, we added IM injection of pethidine hydrochloride and/or IV dexmedetomidine hydrochloride in combination with midazolam. All bronchoscopies were performed with intrabronchial administration of 1% lidocaine. We used one of the following combinations of bronchoscopes and guide sheath kits (Olympus) according to the size of target lesions: BF-p260F or BF-p290 (working channel diameter 2.0 mm) with a K201 guide sheath kit equipped with a biopsy forceps (FB233D, outer diameter 1.5 mm) and a cytology brush (BC-204D-2010, outer diameter 1.4 mm); or BF-1T260 or BF-1TQ290 (working channel 2.8 and 3.0 mm, respectively) with a K203 guide sheath kit equipped with a biopsy forceps (FB231D, outer diameter 1.9 mm) and a cytology brush (BC-202D-2010, outer diameter 1.8 mm). TBB using EBUS with a guide sheath was performed according to the standard Kurimoto et al7Kurimoto N. Miyazawa T. Okimasa S. et al.Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically.Chest. 2004; 126: 959-965Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar method. Before the procedure, we identified the responsible bronchus of the target lesion and evaluated the CT scan bronchus sign on a thin-slice section of chest CT scan.1Minezawa T. Okamura T. Yatsuya H. et al.Bronchus sign on thin-section computed tomography is a powerful predictive factor for successful transbronchial biopsy using endobronchial ultrasound with a guide sheath for small peripheral lung lesions: a retrospective observational study.BMC Med Imaging. 2015; 15: 21Crossref PubMed Scopus (39) Google Scholar We introduced a guide sheath into the lesion via the responsible bronchus with a reusable guiding device (CC-6DR-1; Olympus) and inserted an EBUS probe via the guide sheath. After obtaining the proper EBUS findings (within or adjacent to the lesion),7Kurimoto N. Miyazawa T. Okimasa S. et al.Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically.Chest. 2004; 126: 959-965Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar we procured 12 biopsy samples and conducted bronchial brush cytology and bronchial washing. We routinely obtained 12 biopsy specimens to provide sufficient samples for molecular and histochemical analyses. Only a few patients who did not undergo these routine procedures for some reason (eg, restlessness, unstable cardiopulmonary condition) were excluded from the study. We performed EBUS-GS-TBB even if responsible bronchus was stenotic. However, when bronchial lesions contained overt epithelial lesions or presented 100% stenosis (ie, obstruction), we did not (could not) perform EBUS-GS-TBB but performed endobronchial biopsy instead. These patients who underwent endobronchial biopsy were also excluded from the study. Patients who were postbronchoscopy routinely revisited our hospital to undergo medical examination (blood test and chest radiograph) on days 5 to 7 after bronchoscopy. All patients were advised to visit us whenever they felt something unusual after being discharged from the hospital. We infectious complications after EBUS-GS-TBB as respiratory infections that within after bronchoscopy that matched the following or of respiratory for > > chest or of WBC count or CRP with before and developed or on chest or chest CT scan with of We significant WBC count and CRP as CRP was in the before the bronchoscopy, to > was to be CRP was before the bronchoscopy, an of > from the was as the WBC count was in the in and < in before the bronchoscopy, to > was to be the WBC count was to an abnormal before the bronchoscopy, an of > from the was as We infectious complications as pneumonia, intratumoral infection, lung and (Table Among we intratumoral infection as lesions with size of LDA or cavitation the by overt and/or of We lung as developed the that to LDA or was as with lung field or Values are No. or as otherwise indicated. EBUS-GS-TBB = endobronchial ultrasound-guided transbronchial biopsy with a guide = The data are presented as or counts and between of and post-EBUS-GS-TBB infection were analysis with all the used for and was to the final We presented and for post-EBUS-GS-TBB infection for analysis and the final In an to the of prophylactic antibiotics on infectious complications after we performed a matched Propensity was using that the age, lesion size, CT scan features of lesions and cavitation the stenosis of responsible bronchus observed by bronchoscopy, and laboratory data before EBUS-GS-TBB (WBC counts and CRP Propensity was performed using and with a of patients who were administered prophylactic antibiotics, were matched to the The of prophylactic antibiotic with post-EBUS-GS-TBB infection was using All were performed using the of post-EBUS-GS-TBB infections In patients developed post-EBUS-GS-TBB infections, the incidence of was of EBUS-GS-TBB The most of infection was pneumonia = by intratumoral infection = Others lung abscess, and = All patients with infections and three IV administration of Among of and with All of with and one with lung within before administration of treatment of seven patients, including these three who was because of of In 13 it was to delay the start of In > of patients with post-EBUS-GS-TBB infection were to the risk factors for post-EBUS-GS-TBB infections, we investigated clinical factors that could be to postbronchoscopy infections, including or ≥ sex, smoking status, comorbidities, CT scan findings of target lesion and LDA the stenosis of responsible bronchus WBC count and CRP before bronchoscopy, prophylactic antibiotics and final diagnosis of the lesion (Table 1). analysis that among these sex, diameter of the cavitation in the LDA in the stenosis of responsible WBC CRP and prophylactic antibiotic were potential factors (Table cavitation in the lesion LDA in the lesion and bronchoscopic findings of responsible bronchus stenosis were significantly associated with development of post-EBUS-GS-TBB infections (Table In this we with responsible in (Table in the post-EBUS-GS-TBB infection and in the who did not post-EBUS-GS-TBB of the location of bronchial stenosis or was in the post-EBUS-GS-TBB infection and the and one at and in the postbronchoscopy infection and three in the and Multivariate of for status or Diabetes Collagen vascular Immunosuppressant Other location or diameter of the lesion in the in the of responsible count before bronchoscopy before bronchoscopy diagnosis and for of Open table in a new tab and for of Prophylactic antibiotic was associated with post-EBUS-GS-TBB infection after CT of cavitation and LDA in the target and bronchoscopic of responsible bronchus stenosis in our In the study cohort, patients prophylactic In patients, antibiotics were administered after bronchoscopy, patients prophylactic antibiotics before bronchoscopy. of prophylactic antibiotics are in used antibiotics were and The of prophylactic antibiotics administration was 5 days Although the analysis did not show significant of prophylactic antibiotics with postbronchoscopy infections, the analysis was to the of antibiotics prophylaxis because this is an observational study and between patients with and prophylactic antibiotics significantly the (Table Propensity significantly The analysis did not show significant of prophylactic antibiotics with post-EBUS-GS-TBB infection We also evaluated identified during after EBUS-GS-TBB (Table We identified in 12 of of post-EBUS-GS-TBB These seven of pneumonia, three of and one of intratumoral infection. data were obtained for Among prophylactic antibiotics were administered in In had to prophylactic antibiotics of Prophylactic of Prophylactic are No. who prophylactic antibiotics who developed post-EBUS-GS-TBB Median of of prophylactic antibiotics is 5 days = = = = = = = = = for of other Open table in a new tab for Prophylactic Prophylactic = = Prophylactic = = scan findings size LDA in the of responsible data before EBUS-GS-TBB WBC count are CRP are and for of Values are Open table in a new tab of were from samples obtained after post-EBUS-GS-TBB infection. were and and = = = = = = = = = = = = = = = = = = = = not = for of other Open table in a new tab Values are No. who prophylactic antibiotics who developed post-EBUS-GS-TBB Median of of prophylactic antibiotics is 5 days = = = = = = = = = for of other and for of All were from samples obtained after post-EBUS-GS-TBB infection. were and and = = = = = = = = = = = = = = = = = = = = not = for of other According to the British Rand I.A. Blaikley J. Booton R. et al.British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE.Thorax. 2013; 68 suppl 1: i1-i44Crossref PubMed Scopus (380) Google Scholar for diagnostic bronchoscopy in fever and infection after bronchoscopy relatively common N. et of fever and following flexible a Med Google Scholar The precise mechanism of postbronchoscopy infection has not been in the oral cavity or upper may be introduced to the lower by bronchoscopy. the protocol for a with could during bronchial Previous studies also suggested that pathogens are in postbronchoscopy T. S. in specimens from bronchoscopy in patients with lung Investig. PubMed Scopus Google Scholar and are most not to A. S. S. following endobronchial ultrasound-guided transbronchial 2017; PubMed Scopus Google T. N. Imaizumi K. et complications after endobronchial ultrasound-guided transbronchial for lesions of lung of Investig. PubMed Scopus Google Scholar guide sheath the of bronchial into the target However, our study showed that the incidence of post-EBUS-GS-TBB infection was not lower that of conventional bronchoscopy reported in H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Rand I.A. Blaikley J. Booton R. et al.British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE.Thorax. 2013; 68 suppl 1: i1-i44Crossref PubMed Scopus (380) Google Scholar Therefore, our study could also that of from bronchus into the peripheral lung is not the mechanism of of postbronchoscopy infection. infection is a clinical problem not because it is a serious clinical but also because this complication the subsequent H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Scholar In the patients, of with postbronchoscopy (ie, infection could not therapy. Therefore, the risk factors for postbronchoscopy infection and the incidence of this complication is one of the most important in diagnostic bronchoscopy. EBUS-GS-TBB is now a widely used for diagnosing peripheral lung lesions that is relatively safe and an diagnostic T. Okamura T. Yatsuya H. et al.Bronchus sign on thin-section computed tomography is a powerful predictive factor for successful transbronchial biopsy using endobronchial ultrasound with a guide sheath for small peripheral lung lesions: a retrospective observational study.BMC Med Imaging. 2015; 15: 21Crossref PubMed Scopus (39) Google N. Miyazawa T. Endobronchial Med. 2004; PubMed Scopus Google I. et probe endobronchial ultrasound using a guide sheath for peripheral lung lesions in Med. PubMed Scopus Google Scholar However, that post-EBUS-GS-TBB infectious complications in this study we focused on post-EBUS-GS-TBB infection with the aim of the risk factors for this In we introduced the EBUS-GS to our bronchoscopy procedure for diagnosis of peripheral lung lesions. including the study we have performed EBUS-GS-TBB for peripheral lung lesions with few We were to a large of patients in our large studies efficacy and complications in bronchoscopy peripheral lesions have been and A. et yield and complications of bronchoscopy for peripheral lung lesions. of the Med. PubMed Scopus Google Scholar and the of for J. et bronchoscopy to lung lesions in of the study.BMC Med. 2017; PubMed Scopus Google Although these studies did not on they did not infectious complications after bronchoscopy, in our we infectious complications after EBUS-GS-TBB. can on for this the being that our study might patients of clinical status and these the of our was higher that of the studies In we routinely obtained 12 biopsy specimens in all of EBUS-GS-TBB. In the the of biopsy specimens were in of biopsy increases to peripheral lesions, it might status at reason to the patient In our patients who are postbronchoscopy routinely revisited our hospital to undergo medical examination (blood and chest radiograph) on days 5 to 7 after bronchoscopy. In all patients who underwent bronchoscopy were advised to visit us whenever they felt something unusual after being discharged from the hospital. Therefore, we were to all infectious complications that after EBUS-GS-TBB. We three risk factors for post-EBUS-GS-TBB cavitation in the LDA in the and responsible bronchus could be from change of the by of from the responsible et and of cavitation on of cell lung cancer patients with Full Text Full Text PDF PubMed Scopus Google Scholar LDA the may also N. T. of CT and after for PubMed Scopus Google Scholar EBUS-GS-TBB might from the upper into the of or biopsy procedures might local in the area. it may also to responsible in of the biopsied lung lesions such as lung may the may to stenosis of the responsible forceps or a guide sheath be introduced the lesions may be to infection after the three risk factors in our study that the status of lesions may be the most important factor for post-EBUS-GS-TBB infection. et H. Hayama N. Oguma T. et al.Post-bronchoscopy pneumonia in patients suffering from lung cancer: development and validation of a risk prediction score.Respir Investig. 2017; 55: 212-218Crossref PubMed Scopus (9) Google Scholar reported that risk factors for pneumonia after bronchoscopy > and smoking status, is with our However, contained with lesions, and be because risk factors for infection after bronchoscopy be between lesions and peripheral lesions. The matched analysis could not efficacy of antibiotics prophylaxis in preventing infections. with studies the efficacy of prophylactic antibiotics after M. T. K. et clinical study to the efficacy of prophylactic antibiotics after diagnostic Med Google et of antibiotic prophylaxis on postbronchoscopy a Lung 15: PubMed Scopus Google Scholar British Rand I.A. Blaikley J. Booton R. et al.British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE.Thorax. 2013; 68 suppl 1: i1-i44Crossref PubMed Scopus (380) Google Scholar for diagnostic flexible bronchoscopy for that antibiotic prophylaxis is not before bronchoscopy for the of fever, or In postbronchoscopic fever, from such as might to the A. M. from fever after bronchoscopy and Med. PubMed Scopus Google Scholar H. of administration in of respiratory infection after bronchoscopic a PubMed Scopus Google Scholar reported on the efficacy of in the of infection after bronchoscopy, and the of an other an of Although our study does not the of antibiotics in postbronchoscopy infection patients that infection may the of prophylactic We that and be to patients diagnostic EBUS-GS-TBB with to the risk factors identified in our study. are some to this study. this is a study. However, we > EBUS-GS-TBB during the study that with infectious complications. as we our study is one of the studies to postbronchoscopic infectious complications. In our study is the to on post-EBUS-GS-TBB complications. our study could not provide to prevent post-EBUS-GS-TBB infection. We might be to the of biopsy (eg, by the of according to of the risk factors in In of safe and procedures to prevent infections is an our this study is the to the risk factors of post-EBUS-GS-TBB infection. Although we were to to prevent post-EBUS-GS-TBB infection, we were to patients at We are now studies to the of some including prophylactic antibiotics, to prevent post-EBUS-GS-TBB infections. In a retrospective analysis of 1,045 patients who underwent infectious complications after EBUS-GS-TBB in of patients. and LDAs the target lesion on CT scan and stenosis of responsible bronchus observed by bronchoscopy are risk factors for post-EBUS-GS-TBB infection. In prophylactic antibiotics failed to prevent infectious complications in our matched studies or clinical to provide effective for infection are

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