Clinical trial NCT03673956
Conditions: Chronic Rhinosinusitis (Diagnosis)
Sponsor: Mayo Clinic
Start date: 2018-09-26; Completion date: 2021-02-01
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Researchers are trying to find out if patients develop antibiotic resistant organisms after the use of topical antibiotics in the treatment of chronic rhinosinusitis.

Detailed description:
There is a certain group of patients that has chronic rhinosinusitis that has continued even with treatment including saline and steroid nasal irrigations as well as oral steroids and antibiotics and surgery.

In these patients, the use of topical antibiotic nasal rinses may be of benefit to their disease. The use of topical antibiotic nasal rinses is commonly used as standard of care already throughout the country for refractory chronic rhinosinusitis including here at the Mayo Clinic. Our pharmacy has compounded this medication for this specific purpose. As such, this study is not aimed at a 'novel medication', but rather to investigate the efficacy of a medication already in common use but without great evidence.

The investigators are doing this research study to find out if patients develop antibiotic resistant organisms after the use of topical antibiotics in the treatment of chronic rhinosinusitis.

In addition, this study will look at the effects of topical antibiotics on patient symptoms as measured by a patient survey called the Sino-Nasal Outcomes Test (SNOT-22) and in-office an exam of the inside of their nose, including with a scope (a camera on the end of a long tube).

Arms: arm 1: Subjects with a history of chronic rhinosinusitis (CRS) who had previously undergone endonasal sinus surgery (minimum of maxillary antrostomy and anterior ethmoidectomy), will receive a trial of Mupirocin topical antibiotic rinses. Subjects will undergo a baseline assessment including an aerobic sinus bacterial culture with antibiotic sensitivity to determine baseline microbial antibiotic resistance and to direct selection of appropriate topical antibiotic therapy. arm 2: Subjects with a history of chronic rhinosinusitis (CRS) who had previously undergone endonasal sinus surgery (minimum of maxillary antrostomy and anterior ethmoidectomy), will receive a trial of Tobramycin topical antibiotic rinses. Subjects will undergo a baseline assessment including an aerobic sinus bacterial culture with antibiotic sensitivity to determine baseline microbial antibiotic resistance and to direct selection of appropriate topical antibiotic therapy. arm 3: Subjects with a history of chronic rhinosinusitis (CRS) who had previously undergone endonasal sinus surgery (minimum of maxillary antrostomy and anterior ethmoidectomy), will receive a trial of Levofloxacin topical antibiotic rinses. Subjects will undergo a baseline assessment including an aerobic sinus bacterial culture with antibiotic sensitivity to determine baseline microbial antibiotic resistance and to direct selection of appropriate topical antibiotic therapy. arm 4: Subjects with a history of chronic rhinosinusitis (CRS) who had previously undergone endonasal sinus surgery (minimum of maxillary antrostomy and anterior ethmoidectomy), will receive a trial of Vancomycin topical antibiotic rinses. Subjects will undergo a baseline assessment including an aerobic sinus bacterial culture with antibiotic sensitivity to determine baseline microbial antibiotic resistance and to direct selection of appropriate topical antibiotic therapy.
Interventions: intervention 1: Mupirocin intervention 2: Tobramycin intervention 3: Levofloxacin intervention 4: Vancomycin
Intervention descriptions: intervention 1: 30mg capsules dissolved in a standard 240mL saline irrigation rinse and self-administered through nasal saline irrigation twice per day over 30 days. intervention 2: 240mg capsules dissolved in a standard 240mL saline irrigation rinse and self-administered through nasal saline irrigation twice per day over 30 days. intervention 3: 240mg capsules dissolved in a standard 240mL saline irrigation rinse and self-administered through nasal saline irrigation twice per day over 30 days. intervention 4: 240mg capsules dissolved in a standard 240mL saline irrigation rinse and self-administered through nasal saline irrigation twice per day over 30 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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P R É CI S    
St u d y Title  
T o pical A nti bi otics i n C hr o nic R hi n osi n usitis 
O bjecti ve  
  
T he pri mar y o bjecti ve is t o s h o w t hat t he use of t o pical a nti bi otics i n t he treat me nt of 
c hr o nic r hi n osi n usitis d oes n ot lea d t o a nti bi otic resista nt or ga nis ms. T he sec o n dar y 
o bjecti ves ar e t o i n vesti gate t he effects of t o pical a nti bi otics o n patie nt s y m pt o ms as 
meas ure d b y t he v ali date d Si n o- Nasal O utc o mes Test ( S N O T - 2 2) a n d p h ysical e xa m 
e n d osc o pic fi n di n gs as d oc u me nte d b y L u n d- K e n ne d y e n d osc o pic s c ori n g s yste m. 
Desi g n a n d O utc o m es   
T his is a pr os pecti ve pil ot st u d y t o e val uate de vel o p me nt of a nti bi otic resista nce i n patie nts 
wit h c hr o nic r hi n osi n usiti s w h o are bei n g treate d wit h t o pical a nti bi otics. 
I nter ve nti o ns a n d D ur ati o n 
I nter ve nti o n i ncl u des 2 8 da ys of c ult ure directe d a nti bi otic t hera p y wit h o ne of t he f oll o wi n g 
f o ur t o pical a nti bi otics: T o bra m yci n, M u pir oci n, G e nta mici n or Le v ofl o x aci n  
   
S a m ple Size a n d P o p ul ati o n  
 
T here will be 2 0 p artici p a nts t otal i n t he st u d y a n d t he y will all recei ve t h e  i nter ve nti o n.  




T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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1  
S T U D Y O B J E C TI V E S  
1. 1  Pri m ar y O bjecti ve  
 
T he pri mar y o bjecti ve is t o descri be t he res ults of a nti bi otic resista nt or ga nis ms after t he use 
of t o pical a nti bi otics i n t he treat me nt of c hr o nic r hi n osi n usitis.  
       T he sec o n d ar y o bjecti ves are t o i n vesti gate 1) t he effects of t o pical a nti bi otics o n patie nt 
s y m pt o ms as meas ure d b y t he vali date d Si n o-Nas al O utc o mes Test ( S N O T - 2 2) a n d p h ysical 
e xa m e n d osc o pic fi n di n gs as d oc u me nte d b y L u n d- Ke n ne d y e n d osc o pic s c ori n g s yste m.  2) 
t he a d her e nce t o st u d y i nter ve nti o n  
2  
B A C K G R O U N D A N D R A TI O N A L E   
2. 1  B ac k gr o u n d o n C o n diti o n, Dise ase, or Ot her P ri m ar y St u d y F oc us 
T here is a p o p ulati o n of patie nts w h o ha ve c hr o ni c r hi n osi n usiti s t hat is refract or y t o 
ma xi mal me dical t hera p y i ncl u di n g treat me nt wit h sali ne a n d ster oi d nas al irri gati o ns as well 
as wit h oral ster oi ds a n d a nti bi otics.  
T he e vi de nce f or us e of t o pical a nti bi otics i n c urre nt literat ure is c o nflicti n g. T he fe w d o u bl e 
bli n d ra n d o mize d c o ntr ol st u dies cite d ha ve si g nifica nt li mitati o ns i ncl u di n g s mall sa m ple 
size, varia bl e i nter ve nti o n me dicati o ns a n d deli ver y met h o ds as well as varia ble o utc o mes 
meas ure d 1- 5. Ot her st u dies ha ve s h o w n t hat use of t o pical a nti bi otics i n C R S has tre n de d 
t o war d p ositi ve c ha n g e i n s y m pt o m sc ore a n d e n d osc o pic p h ysical e x a m fi n di n gs6. I n 
a d diti o n, t o pical a nti bi otics are c urre ntl y bei n g use d c o m m o nl y at t his i nstit uti o n f or patie nts 
wit h recalcitr a nt c hr o nic r hi n osi n usitis wit h g o o d cli nical a nec d ot al res ult. A well d esi g ne d 
st u d y is warrante d t o f urt her i n vesti gate t he utilit y of t o pical a nti bi otics i n c hr o nic 
r hi n osi n usitis.  
O ne c o ncer n wit h t o pical a nti bi otics li miti n g wi des prea d use is percei ve d i ncreas e d ris k of 
ca usi n g a nti bi otic resista nce . N o n -sta n d ar dize d d osa ge patter ns h as le d t o t he c o ncer n t hat 
patie nts are p ote ntiall y b ei n g treate d wit h s u bt hera p utic d osa ges. Ot hers p ost ulate t hat 
treat me nt wit h t o pical a nti bi otics a gai nst s usce pti ble bacteri a ma y  ha v e t he effect of i n d uci n g 
bi ofil m pr o d ucti o n fr o m resista nt bacteria 7. I n c o ntrast, a d v ocat es f or t o pical a nti bi otics 
e x pect t o pical deli ver y t o deli ver hi g h c o nce ntrati o ns of a nti bi otics  t o t he si n o nasal ca vit y 
w here t he y m a y pe netrat e a bacterial bi ofil m, a n d a v oi d t he syste mic effects of e nteral or 
pare nteral a nti bi otics 7. F urt her st u d y is warra nte d t o f urt her des cri be t he p ote ntial ass ociati o n 
of t o pical a nti bi otic treat me nt of t he si n o nasal ca vit y wit h a nti bi otic resista nce.  
O ur de part me nt has de vel o pe d i n c o nj u ncti o n wit h t he i nfecti o us disease d e part me nt a n d t he 
Ma y o p har mac y, a n eas y t o i m ple me nt set of t o pical a nti bi otics wit h  eas y t o use ca ps ules a n d  
set d osa ges f or us e b y o ur patie nts. T h is is a pil ot st u d y desi g ne d wit h  t he h y p ot hesis t hat 
t o pical a nti bi otics d o n ot ca use a nti bi otic resista n ce. I n a d diti o n, data will b e c ollecte d t o 
i n vesti gate s y m pt o m a n d p h ysical e xam o utc o mes i n patie nts  u n der g oi n g t o pical a nti bi otic 
t hera p y as sec o n dar y o utc o mes. T he st u d y will be  c o n d ucte d o n e xisti n g patie nts w h o w o ul d 
ot her wise recei ve treat m e nt wit h t o pical a nti bi otics as sta n dar d of care.  


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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M ore o ver, ma n y of patie nts w h o ha ve recalcitra nt c hr o nic r hi n osi n usitis are i nfecte d b y t h e 
bacteria ps e u d o m o nas aer u gi n osa. T he use of t he fl u or o q ui n ol o ne class of a nti bi otics is a 
treat me nt of c h oice f or t his pat h o ge n. I n 2 0 0 8, t he U S F o o d a n d Dr u g A d mi nistrati o n iss ue d 
a “ blac k b o x ” a d visi n g ma n ufact urers t o w ar n pr o vi ders a n d patie nts of ris k i ncreas e d ris k of 
te n di nitis, te n d o n r u pt ure, peri p heral ne ur o pat h y. A well -st u die d, via ble alt er nati ve t o oral 
fl u or o q ui n ol o ne t hat w or ks well wit h o ut t he ass ociate d ris ks is warra nte d.  
Fi nall y, p o or pe netrati o n of oral a nti bi otics t o t he si n o nasal ca vit y d ue t o t he i nfecti o n bei n g 
wit hi n a s pace  ma y li mit t he efficac y of oral a nti bi otics as a treat me nt . I n c o ntrast use of 
t o pical a nti bi otics i n a patie nt w h o has pre vi o usl y u n der g o ne si n us s ur ger y, pr o vi des a 
p ote ntiall y m ore eff ecti v e deli ver y of m e dicati o n  t o t he i nfecte d s pace8. 
2. 2  St u d y R ati o n ale 
T he i nterve nti o n al re gi me n is as f oll o ws.  
Patie nt will u n der g o pre-i nter ve nti o n nasal s wa b fr o m t he affecte d si n us t h at will be se nt f or 
gra m stai n a n d  bacterial c ult ure a n d se nsiti vities.  
If pat h o ge n i de ntifie d i n t he bacterial c ult ure is pse u d o m o nas aer u gi n osa, t o pical t o bra m yci n 
or ge nta m yci n will be assi g ne d as first li ne a ge nt  p e n di n g c ult ure pr ofiles a n d c ost fact ors. If 
t he se nsiti vities s h o w resista nce t o b ot h t o bra m yci n a n d ge nta m yci n, t he n l e v ofl o xaci n will 
be prescri be d. 
If t he pat h o ge n i d e ntifie d i n t he bacterial c ult ure is ot her t ha n pse u d o m o nas aer u gi n osa, 
m u pir oci n will be prescri be d. If t he p at h o ge n s h o ws resista nce t o m u pir oci n, t he n t he patie nt 
will be prescri be d o n e of t he ot her t hree a nti bi otics will be prescri be d p e n di n g c ult ure 
pr ofiles a n d c ost f act ors 
T he patie nt will use t he t o pical a nti bi otic t wice a da y f or 2 8 da ys. T his will be acc o m plis he d 
b y first pr ocee di n g wit h t heir n or mal nasal ri nse re gi me n as prescri be d b y t heir p h ysicia n 
(t his ma y i ncl u de sali ne al o ne, or sali ne wit h b u des o ni de).  T wice p er da y, at t he e n d of eac h 
re gi me n, t he y perf or m o n e a d diti o nal nasal sali ne ri nse usi n g t he Neil Me d si n us ri nse b ottle 
i n t he ma n ner o utli ne d o n t he pac ka gi n g i nstr ucti o ns. H o we ver, wit h t his last a d diti o nal 
nasal sali ne ri nse, t he y will o pe n t heir a nti bi otic ca ps ule a n d dr o p t he c o nte nts i nt o t he ri nse 
b ottle pri or t o ri nsi n g. 
 
K n o w n a n d p ote nti al risks are as f oll o ws:  
P ote ntial ris ks  of nasal sali ne irri gati o n is sti n gi n g se nsati o n a n d b ur ni n g 
P ote ntial ris ks  of filli n g t he nasal sali ne irri gati o n ri nse b ottle wit h water t h at is t o o h ot is 
m uc osal b ur ns 
P ote ntial ris ks of t o pical a nti bi otic a d mi nistrati o n i ncl u de l ocal prurit is a n d i nfla m mati o n  
P ote ntial ris ks of  selecti o n a nti bi otic resista nt or ga nis ms.  
P ote ntial ris k f or heari n g l oss 
3  
S T U D Y D E SI G N  
T his is a pr os pecti ve, pil ot st u d y t o i n vesti gate t he prese n ce or a bse n ce of a nti bi otic resista nt 
or ga nis ms after tr eat me nt of c hr o nic r hi n osi n usitis wit h t o pical a nti bi otics. I n a d diti o n, 
t hera peutic eff ects of t he t o pical a nti bi o tics will be i n vesti gated via assess m e nt of  patie nt 
s y m pt o ms, a n d p hysical e xa m e n d osc o pic fi n di n gs. 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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T here will be 1  st u d y gr o u p wit h 2 0 patie nts.  
T he patie nts will first u n der g o pre-i nter ve nti o n assess me nt i n t he o ut patie nt setti n g. T his 
will occ ur i n t he De p art me nt of Ot or hi n olar y n g ol o g y o n t he 1 2 t h fl o or of t he G o n da b uil di n g 
i n R oc hester, M N wit h o ne of t he staff r hi n ol o gists. Patie nts will be selecte d t o partici pate if 
t he y ha ve acti ve m uc o p ur ule nce o n t heir e n d osc o pic e xa mi nati o n.  T he ass ess me nt will 
c o nsist of 1) o btai ni n g a nasal s wa b of m u c o p ur ul e nce fr o m t he affecte d si n us t o be se nt f or 
gra m stai n, c ult ure a n d s e nsiti vit y, 2) assess me nt of patie nt s y m pt o m se verit y sc ore as 
meas ure d b y t he s elf -a d mi nistere d Si n o -Nasal O utc o mes Test ( S N O T - 2 2) s ur ve y, a n d 3) 
assess me nt of patie nt p h ysical e xa m as e val uate d b y ri gi d nasal e n d osc o p y a n d d oc u me nte d 
i n L u n d- Ke n ne d y e n d osc o pic fi n di n gs f or m.  
T he st u d y i nter ve nti o n is t he a d mi nistrati o n of c ult ure directe d t o pical a nti bi otics o ver 2 8 
da ys. T hese a nti bi otics will prescri be d t o t he patie nt i n ca ps ule f or m as c o m p o u n de d b y t he 
Ma y o Cli nic p har mac y , or s uita ble lice nse d c o m p o u n di n g p har mac y.  On e ca ps ule will 
s u bse q ue ntl y be a d de d t o a nasal sali ne irri gati o n b ottle, a n d t he patie nt will a d mi nister t his 
irri gati o n t o hi m or herself i n t he us ual fas hi o n t wice per d a y. 
- 
T he d osa ges of t h e a nti bi otic ca ps ules were det er mi ne d b y t he Ma y o Cli nic p har mac y 
tea m wit h i n p ut fr o m i nfecti o us disease, bas e d u p o n a vaila ble p u blis he d data, a n d will be 
as f oll o ws, diss ol ve d i n a sta n dar d 2 4 0 m L sali ne irri gati o n ri nse 
o  M u pir oci n: 3 0 m g 
o  T o bra m yci n: 1 9 2 m g 
o  Ge nta mici n: 1 9 2 m g  
o  Le v ofl o xaci n: 2 5 0 m g 
After t he c o m pleti o n of t he st u d y i nter ve nti o n ( wit hi n 2 1 da ys), t he patie nt will u n der g o 
p ost-i nter ve nti o n assess me nt i n t he o ut patie nt setti n g, a gai n i n t he De part me nt of 
Ot or hi n olar y n g ol o g y wit h o ne of t he staff r hi n ol o gists. T he patie nt will a gai n be assesse d 
wit h 1) nasal s wa b fr o m t he aff ecte d si n us se nt f or gra m stai n, c ult ure a n d s e nsiti vit y 2) 
S N O T - 2 2 s y m pt o m sc ores a n d 3) L u n d- Ke n ne d y e n d osc o pic e x a m sc ores.  
 
4  
S E L E C TI O N A N D E N R O L L M E N T O F P A R TI CI P A N T S   
4. 1  I ncl usi o n Criteri a  
All partici pa nts i n t he st u d y m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o partici pate 
i n t his st u d y. 
•  Male or fe m ale, bet w ee n 1 8 - 8 0 years ol d, dia g n os e d wit h c hr o nic r hi n osi n usitis 
w h o ha ve u n der g o ne pr e vi o us f u ncti o nal e n d osc o pic si n us s ur ger y i ncl u di n g at 
mi ni m u m ma xillar y a ntr ost o m y a n d a nteri or et h m oi dect o m y  
•  Acti ve m uc o p ur ule n ce o n e n d osc o pic e x a mi nati o n wit h c orres p o n di n g c ult ure 
de m o nstrati n g pat h o ge ni c bacterial gr o wt h  
•  C o m pleti o n of writte n i nf or me d c o nse nt 
•  N o pri or e nr oll me nt i nt o t his st u d y 
•  Refract or y t o ma xi mal me dical t hera p y  


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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4. 2  E xcl usi o n Criteri a  
C a n di dates meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria at baseli ne will be e x cl u de d 
fr o m st u d y partici pati o n.  
•  Patie nt has n ot ha d pri or e n d osc o pic si n us s ur ger y c o nsisti n g of at mi ni m u m 
bilateral ma xillar y a ntr ost o m y a n d a nteri or et h m oi dect o m y  
•  Patie nt is c urre ntl y bei n g treate d wit h oral a nti bi otics  
•  Patie nt has bee n treate d wit h oral or t o pical a nti bi otics wit hi n t he past 1 4 da ys 
•  Partici pati o n i n a n i n vesti gati o nal dr u g st u d y si m ulta ne o usl y wit h 
partici pati o n i n t his st u d y  
•  C o nc urre nt use of oral st er oi ds 
•  Aller g y t o T o bra m yci n, M u pir oci n, Ge nta mici n a n d Le v ofl o xaci n  
•  K n o w n t o c urr e ntl y be pre g na nt 
 
4. 3  St u d y E nr oll m e nt Pr oce d ures  
Garr et C h o b y, M D or st u d y staff will c o nse nt a n d e nr oll p ote ntial partici pa nts fr o m t he 
p o ol of pri nci pal a n d c o- i n vesti gat ors patie nts. 
 
Recr uit me nt will ta ke place i n G o n da 1 2 Ot or hi n olar y n g ol o g y de part me nt d uri n g t he 
patie nt's cli nical visit.  
 
T here will be n o scree ni n g l o g or ot her d oc u me ntati o n of reas o ns of i neli gi bilit y. 
 
T he c o nse nt a n d e nr oll me nt  pr ocess will occ ur i n a pri vate patie nt r o o m o n G o n da 1 2. 
W he n t he c o ns ulta nt has c o m plete d disc ussi n g differe nt treat me nt o pti o ns  wit h t he 
patie nt, a n d t he patie nt a n d t he p h ysicia n ha ve d eci de d o n t o p urs ue treat me nt wit h 
t o pical a nti bi otics, t he st u d y staff me m ber will i nf or m t he patie nt t hat he/s he meets t he 
criteria f or t his st u d y a n d descri be t he st u d y t o t he patie nt. T otal ti me of disc ussi o n is 
e x pecte d t o b e 1 0 mi n ute s. T he patie nt will be gi ve n a de q u ate ti me t o deci d e w het her or 
n ot t o partici pate i n t he st u d y.  
 
T he patie nt will be i nf or me d b y t he st u d y staff m e m ber of t he p ossi ble ris ks a n d be nefits 
of partici pati o n a n d st u d y staff me m ber will rei nf orce t hat t his is a decisi o n o nl y t he 
patie nt ca n ulti matel y ma ke. T he st u d y staff me m b er  will als o i nf or m t he patie nt t hat 
decli ni n g partici pati o n i n t he st u d y will i n n o wa y affect t he q ualit y or d urati o n of t heir 
care.  O nl y patie nts w h o ca n c o nse nt f or t he msel v es will be e nr olle d i n t his st u d y. 
 
If t he p ote ntial partici p a nt is a w o me n a ge 1 8- 5 0, t he Ma y o Cli nic “Pre -Pr o ce d ure 
Pre g na nc y Reas o na bl y E xcl u de d G ui de ( P R E G)” will be a d mi nistere d. If pre g na nc y is 
reas o na bl y e xcl u de d acc or di n g t o t he g ui de, t he patie nt will q ualif y f or e nr oll me nt. If t he 
patie nt is f o u n d t o be pre g na nt, s he will be e xcl u d e d fr o m t he st u d y.  
 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
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5  
S T U D Y I N T E R V E N TI O N S    
5. 1  I nter ve nti o ns, A d mi nistr ati o n, a n d D ur ati o n  
T he pre-i nter ve nti o n assess me nt will occ ur d uri n g t he e nr oll me nt visit as part of r o uti ne 
cli nical car e. O nce t he r es ults of t he gra m stai n, c ult ure a n d se nsiti vities are k n o w n, t he 
patie nt will be prescri b e d t he a p pr o priat e t o pical a nti bi otic f or t he st u d y. T he y will be 
n otifie d of t he res ult of t he gra m stai n, c ult ure a n d se nsiti vities as well as t heir pe n di n g 
prescri pti o n via a p h o n e call or ot her electr o nic m ea ns, as per st u d y s u bject prefere nce. 
T he i nter ve nti o n will ta ke o ver t he c o urse of 2 8 d a ys as t he patie nt uses t h e me dicati o n as 
a n o ut patie nt. T her e will be o nl y o ne 2 8 da y d urati o n st u d y i nter ve nti o n a d mi nistere d 
after t he e nr oll me nt visit . T here will be n o m o dificati o ns t o t his st u d y i nter ve nti o n.  
 
5. 2  H a n dli n g of St u d y I nter ve nti o ns  
After c o m plet i o n of t he i nter ve nti o n, t he patie nt will prese nt f or p ost-i nter v e nti o n 
assess me nt i n t he De part me nt of Ot or hi n olar y n g ol o g y o n t he 1 2t h fl o or of t he G o n da 
b uil di n g i n R oc hester, M N wit h o ne of t he staff r hi n ol o gists. T his assess me nt will be 
e xactl y t he sa me as t he pre -i nter v e nti o n assess me nt. S pecificall y, t his assess me nt will 
c o nsist of 1) o btai ni n g a nasal s wa b of m u c o p ur ul e nce fr o m t he affecte d si n us t o be se nt 
f or gra m stai n, c ult ur e a n d se nsiti vit y, 2) assess me nt of patie nt s y m pt o m se verit y sc ore as 
me as ure d b y t he s elf- a d mi nistere d Si n o -Nasal O utc o mes Test ( S N O T - 2 2) s ur ve y, a n d 3) 
assess me nt of patie nt p h ysical e xa m as e val uate d b y ri gi d nasal e n d osc o p y a n d 
d oc u me nte d i n L u n d- K e n ne d y e n d osc o pic fi n di n gs f or m.  
5. 3  C o nc o mit a nt I nter ve nti o ns 
5. 3. 1  All o we d I nter v e n ti o ns 
A n y a d diti o nal me dicati o ns prescri be d t o t he p atie nt as part of t heir o n g oi n g t hera p y f or 
c hr o nic r hi n osi n usitis i ncl u di n g nasal sali ne irri gati o ns, ster oi d irri gati o ns, or t o pical 
s pra ys. 
5. 3. 2  Re q uire d I nter v e nti o ns  
N o ne 
5. 3. 3   Pr o hi bite d I nter v e nti o ns 
Patie nts will be e xcl u de d if t he y are prescri be d c o nc o mita nt oral ster oi ds  
5. 4  A d here nce Assess m e nt  
Defi niti o n of a d her e nce t o st u d y i nter ve nt i o n will st u d y s u bject attestati o n t hat t he y 
c o m plete d at least 4 8 / 5 6 d osa ges of nas al sali ne irri gati o n wit h t o pical a nti bi otic a n d 
prese ntati o n f or o n e p ost-i nter ve nti o n assess me nt. Patie nt will rec or d t o pical a nti bi otic 
use i n a dail y l o g. T his l o g will be use d b y t he i n vesti gat ors t o assess a d here nce.  T h ese 
a vaila ble e n d p oi nts will be ta ke n a n d i n c or p orate d i nt o a nal ysis.   
 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
9 
6  
S T U D Y P R O C E D U R E S  
6. 1  
Sc he d ule of E v al u ati o ns  
 
Pre -I nter v e nti o n assess m e nt: t o be c o m plete d bef ore starti n g i nter ve nti o n 
•  Nasal s wa b: O btai n  s w a b fr o m affecte d si n us a n d se n d f or gra m stai n, c ult ure a n d 
se nsiti vity  
•  Patie nt s y m pt o m e val uati o n as assesse d b y S N O T - 2 2 s y m pt o m sc ores  
•  Patie nt e n d osc o pic p h ysical e xa m as assesse d b y  L u n d- Ke n ne d y e n d osc o pic e xa m 
sc ores.  D o c u me ntati o n p h ot os will als o be o btai ne d wit h t w o e n d osc o pic p h ot os 
per si de, o ne fr o m t he hea d of t he i nferi or t ur bi nat e i nt o t he nasal ca vit y a n d o ne 
fr o m t he hea d of t he mi d dle t ur bi nate t o war ds t he mi d dle meat us. 
 
P ost- I nter v e nti o n assess me nt: t o occ ur aft er t he c o m pleti o n of t he 2 8 da ys of i nter ve nti o n 
wit h t o pical a nti bi otics  
•  Nasal s wa b: O btai n s w a b fr o m affecte d si n us a n d se n d f or gra m stai n, c ult ure a n d 
se nsiti vit y  
•  Patie nt s y m pt o m e val uati o n as assesse d b y S N O T - 2 2 s y m pt o m sc ores  
•  Patie nt e n d osc o pic p h ysical e xa m as assesse d b y  L u n d- Ke n ne d y e n d osc o pic e xa m 
sc ores.  D o c u me ntati o n p h ot os will als o be o btai ne d wit h t w o e n d osc o pic p h ot os 
per si de, o ne fr o m t he hea d of t he i nferi or t ur bi nat e i nt o t he nasal ca vit y a n d o ne 
fr o m t he hea d of t he mi d dle t ur bi nate t o war ds t he mi d dle meat us. 
 
6. 2  Descri pti o n of E v al u ati o ns  
6. 2. 1  Scree ni n g E val u ati o n  
C o nse nti n g Pr oce d ure 
T here will be a si n gle i nf or me d c o nse nt f or m t hat descri bes b ot h t he scree ni n g a n d 
st u d y pr oce d ur es. 
 
Garr et C h o b y M D  or st u d y staff will c o nse nt p ote ntial partici pa nts fr o m t he p o ol of 
pri nci pal i n vesti gat or’s a n d c o-i n vesti gat ors’ patie nts. W he n t he staff m e m ber  has 
c o m plete d disc ussi n g t he i nter ve nti o n wit h t he patie nt, t he pr o vi der will i nf or m t he 
patie nt t hat he/s he meets t he crit eria f or t his st u d y. T otal ti me of disc ussi o n is 
e x pecte d t o b e 1 0 mi n utes. T he patie nt will be gi ve n ti me t o deci de if t he y w o ul d li ke 
t o partici pate i n t he st u d y.  
 
D oc u me ntati o n of si g ne d c o nse nt will be mai ntai ne d t hr o u g h m o nit ori n g b y Garr et 
C h o b y M D a n d st u d y staff a n d/ or E N T C o m mittee . T he d oc u me nt ati o n will be ke pt 
i n a sec ur e, l oc ke d ca bi n et i n t he De part me nt of Ot or hi n olar y n g ol o g y’s Researc h 
office  o nl y accessi ble t o PI a n d st u d y staff.  
 
 
Scree ni n g   
Scree ni n g will be bas e d o n pr oce d ures t hat are part of sta n dar d p atie nt care, a n d 
t heref or e, i nf or me d c o ns e nt will n ot be o btai ne d b y st u d y staff pri or t o scree ni n g 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 0 
patie nts.  P ote ntial partici pa nts will c o me fr o m t he p o ol of patie nts dia g n ose d wit h 
c hr o nic r hi n osi n usiti s t hat t he pri nci pal i n vesti gat or a n d c o-i n v esti gat or c o ns ulta nts 
ha ve treate d.  
Scree ni n g e v al uati o n  f or patie nts i n b ot h gr o u ps i ncl u des:  
•  Patie nt De m o gra p hics  
•  Dia g n osis of c hr o nic r hi n osi n usitis 
•  Assess me nt of s y m pt o m sc ore wit h S N O T - 2 2 s ur ve y 
•  P h ysical E xa mi nati o n -I n v ol ves e xa mi nati o n of t h e patie nts bilateral nas al 
ca vities a n d para nas al si n uses wit h ri gi d e n d osc o p y 
•  Pre - Pr oce d ure Pre g n a nc y Reas o na bl y E xcl u de d G ui de ( P R E G) 
 
If t he p ote ntial partici p a nt is a w o me n a ge 1 8- 5 0, t he Ma y o Cli nic “Pre -Pr o ce d ure 
Pre g na nc y Reas o na bl y E xcl u de d G ui de ( P R E G)” will be a d mi nistere d. If pre g na nc y 
is reas o na bl y e x cl u de d acc or di n g t o t he g ui de, t he patie nt will q ualif y f or e nr oll me nt. 
If t he patie nt is f o u n d t o be pre g na nt, s h e will be e xcl u de d fr o m t he st u d y.  
 
T he st u d y staff will re vie w t hese tests fr o m t he patie nt’s me dical rec or ds t o deter mi ne 
eli gi bilit y.  Ti me pri or t o e nr oll me nt wit hi n w hic h t he scree ni n g tests a n d e v al uati o ns 
m ust be perf or me d is wit hi n 2 8 da ys of st u d y e nr oll me nt.  
6. 2. 2  E nr oll me nt a n d Baseli ne  
E nr oll me nt 
 
E nr oll me nt will be defi ne d as t he date all scree ni n g criteria are met a n d i n di vi d ual 
a grees t o p artici pate. T h ere will be a si n gle i nf or m e d c o nse nt f or m f or b ot h scree ni n g 
a n d st u d y pr oce d ures. E nr oll me nt a n d scree ni n g will be c o n d ucte d d uri n g t he sa me 
visit.  
T he criteri a use d f or i ncl usi o n a n d e xcl usi o n will be c ollecte d fr o m t he pati e nt o n t his 
date usi n g t he f oll o wi n g tests: 
•  me dicati o n rec o n ciliati o n  
•  Re vie w of me dical rec or d  
 
6. 2. 3  P ost- treat me nt assess me nt 
P ost- treat me nt assess me nt m ust be perf or me d aft er t he c o m pleti o n of t he i nter ve nti o n 
 
 
7  
S A F E T Y A S S E S S M E N T S   
7. 1  S pecific ati o n of S afet y P ar a meters  
 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 1 
Safet y will be assesse d f or a d mi nistrati o n  of t o pical a nti bi otic via nasal irri gati o n t hat 
is t he s u bject of t he i nter ve nti o n u n der i n vesti gati o n. Assess me nt will i ncl u de details 
of a n y a d verse r eacti o n  at t he site of irri gati o n.  
7. 2  Met h o ds a n d Ti mi n g f or Assessi n g, Rec or di n g, a n d A n al yzi n g S afet y 
P ar a m eters  
Assess me nt  of a d verse r eacti o n  at t he p ost-i nter ve nti o n visit.  
7. 3  A d verse E ve nts  a n d Seri o us A d verse E ve nts  
A n  a d verse e v e nt  (A E ) is ge nerall y defi ne d as a n y  u nfa v ora bl e a n d u ni nte n de d 
dia g n osis, s y m pt o m, si g n (i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y n dr o me or 
disease w hic h eit her occ urs d uri n g t he st u d y, ha vi n g bee n a bse nt at baseli n e, or if 
prese nt at bas eli ne, a p pears t o w orse n. A d verse e v e nts are t o b e rec or de d re gar dless 
of t heir relati o ns hi p t o t he st u d y i nter ve nti o n.    
 
A seri o us a d verse e v e nt (S A E ) is ge nerall y defi ne d as a n y u nt o w ar d me di cal 
occ urr e nce t hat res ults i n deat h, is life t hreat e ni n g, re q uires i n patie nt h os pit alizati o n 
or pr ol o n gati o n o f e xisti n g h os pitalizati o n, res ults i n persiste nt or si g nifica nt 
disa bilit y/i nca pacit y, or is a c o n ge nital a n o mal y . 
N o seri o us a d verse e v e nt o ut of c hara cter wit h nas al irri gati o ns  is e x pecte d.  
A d verse e ve nts ca pt ure d d uri n g i nter val cli nical visit are ca pt ure d as u ns oli cite d 
e ve nts, b ut if patie nt re p orts b y calli n g PI directl y usi n g n u m ber o n t he c o nse nt f or m 
it will be ca pt ure d as a s olicite d e ve nt. T he e v e nts will be rec or d e d as s uc h s o t hat 
t here are n o d o u ble c ollecti o n s yste ms.  
If t here ar e a n y a d v erse e ve nts or seri o us a d v erse e ve nts  re p ort e d b y t he patie nt t o t he 
c o-i n vesti gat ors at a n y p oi nt p ost-i nter ve nti o nal pr oce d ure t hr o u g h o ut t he st u d y, t he 
Pri nci pal I n v esti gat or will be n otifie d wit hi n 2 4 h o urs.  
7. 4  
Re p orti n g Pr oce d ures  
 
If t here ar e a n y a d v erse e ve nts or seri o us a d v erse e ve nts  re p ort e d b y t he patie nt t o t he 
c o-i n vesti gat ors at a n y p oi nt ( p ost-i nter ve nti o nal pr oce d ure) t hr o u g h o ut t h e st u d y, t he 
Pri nci pal I n v esti gat or wi ll be n otifie d wit hi n 2 4 h o urs. T he c o -i n v esti gat or will rec or d 
t he occ urre nce i n t he pati e nt’s researc h file wit hi n 2 4 h o urs of re p ort of t he i nci de nt. 
Decisi o n of rel ate d ness a n d se verit y will be ma de b y t he Pri nci ple I n vesti gat or. 
Details of t he a d v erse e v e nt will be mai ntai ne d i n t he Re p orta ble E ve nt Trac ki n g L o g 
f or t his st u d y. 
7. 5  
F oll o w- u p f or A d verse E ve nts  
A d verse e ve nts i n v ol vi n g i nfecti o n will be f oll o we d u p wit h a p pr o priate treat me nt 
i n v ol vi n g w o u n d c ult ures, br oa d s pectr u m a nti bi otics, a n d narr o w s pectr u m o nce t he 
s pecies is i de ntifie d. F oll o w u p will c o nti n ue as nee de d (ac ute d e bil itati n g e ve nt), 
u ntil res ol uti o n f or c hr o nic A D fr o m t he o cc urre n ce of a d v erse e ve nt. 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 2 
8  
I N T E R V E N TI O N DI S C O N TI N U A TI O N  
  
 
Partici pa nts  ma y wit h dra w v ol u ntaril y fr o m partici pati o n i n t he st u d y at a n y ti me a n d f or 
a n y reas o n. Partici pa nts s h o ul d c o nti n ue t o be f oll o we d, wit h t heir per missi o n, after st u d y 
i nter ve nti o n has bee n a d mi nistere d .  
 
Re place me nt of p artici pa nts w h o disc o nti n ue earl y is all o we d. T he partici p a nts w h o are 
re place d will n ot be c o u nte d i n t he st u d y a n d re place me nt ca n occ ur if parti ci pa nts  d o n ot 
c o m plete t he at least 4 8 / 5 6 d osa ges of i nter v e nti o n wit h t o pical a nti bi otics .  
 
 It is vital t o c ollect saf et y data o n a n y s u bject dis c o nti n ue d d ue t o a n A E or S A E. I n a n y 
case, e v er y eff ort will  be ma de t o u n derta k e pr ot oc ol-s pecifie d safet y f oll o w- u p 
pr oce d ur es. If v ol u ntar y wit h dra wal occ urs, t he s u bject will  be as ke d t o c o nti nue 
sc he d ule d e v al uati o ns, c o m plete a n e n d-of -st u d y e val uati o n, a n d be gi v e n a p pr o priate 
care u n d er me di cal s u per visi o n u ntil t he s y m pt o ms of a n y A E res ol ve or t h e s u bject’s 
c o n diti o n bec o mes sta ble.  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S     
9. 1  Ge ner al Desi g n Iss ues  
T his will be pr os pecti ve si n gle ar m pil ot st u d y. We pr o p ose e nr olli n g 4 0 patie nts i n t his 
st u d y.  
Meas ure of s uccess is p ost- treat me nt assess me nt wit h nasal s wa b se nt f or gra m stai n, 
c ult ure a n d se nsiti vit y. 
9. 2  S a m ple Size a n d R a n d o miz ati o n 
We pr o p ose e nr olli n g 4 0 patie nts i n t his st u d y. Si nce t his st u d y is a pil ot st u d y w here we 
ai m t o descri be t he r es ults a n d c ollect data f or f ut ure lar g er st u d y, sa m ple si ze calc ulati o n 
is n ot re q uire d. 
9. 3  I nteri m a n al yses a n d St o p pi n g R ules  
Safet y fi n di n gs t hat w o ul d te m p oraril y s us pe n d e nr oll me nt a n d/ or st u d y i nter ve nti o n u ntil 
a safet y r e vie w is c o n v e n e d ( eit her r o uti ne or a d h oc ) t o deter mi ne w het her t he st u d y 
s h o ul d c o nti n ue per pr ot oc ol, pr ocee d wit h ca uti o n, be f urt her i n v esti gate d, be 
disc o nti n ue d, or be m o difie d a n d t he n pr o cee d are as f oll o ws: 
  - N u m ber of S A Es o v erall 
  -N u m ber of o cc u rre nces of a partic ul ar t y pe of S A E 
  -Se vere A Es/reacti o ns  
  -I ncr ease d fre q u e nc y of e ve nts 
S uc h fi n di n gs are pr ese nt e d t o t he Data a n d Safet y M o nit ori n g B oar d ( D S M B) statisticia n 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 3 
to re vie w t he e v e nts b y gr o u p t o deter mi ne w h et her t here are statistical as well as cli nical 
c o ncer ns. T h e statisticia n re p orts his fi n di n gs t o a cl ose d sessi o n of t he D S M B ( or t o t he 
Safet y Officer a n d/ or NI A.) T he fi n di n gs are use d t o deter mi ne w hat ste ps will be ta ke n.  
 
9. 4  O utc o m es  
9. 4. 1  Pri mar y O utc o me  
P ost treat me nt assess me nt of prese nce of a nti bi otic resista nt or ga nis m as ass esse d b y 
nasal s wa b se nt f or gra m stai n, c ult ure a n d se nsiti vit y  
9. 4. 2  Sec o n dar y o utc o mes   
T he sec o n d ar y o utc o mes are meas ure me nt of patie nt s y m pt o ms as meas ure d b y t he 
vali date d Si n o- Nasal O ut c o mes Test ( S N O T - 2 2)  a n d p h ysical e xa m e n d os c o pic fi n di n gs 
as d oc u me nte d b y L u n d- Ke n ne d y e n d os c o pic sc ori n g s yste m  
 
9. 5  D at a A n al yses 
St atistic al Met h o ds  
 
C o nti n u o us patie nt c haracters  will  be  s u m marize d  wit h  mea ns  a n d  sta n dar d  
de viati o ns f or feat ur es t hat are a p pr o xi mat el y n or mall y distri b ute d a n d wit h me dia ns, 
i nter q uartile ra n g es, a n d ra n ges ot her wise.  Cate g orical feat ures will be s u m marize d 
wit h fre q ue n c y c o u nts a n d perce nt a ges.   
 
Pri mar y e n d p oi nt: 
N u m ber a n d pr o p orti o n of patie nts w h o de vel o pe d a nti bi otic resista nce or ga nis m will 
be s u m marize d. 9 5 % c o nfi de nce i nter vals will be pr o vi de d f or t he pr o p orti o n. 
 
           Sec o n dar y e n d p oi nt:  
1)   S N O T - 2 2 s y m pt o m sc ores a n d L u n d- Ke n ne d y e n d osc o pic e xa m sc ore will be 
s u m marize d as mea n (sta n dar d de viati o n) a n d me dia n (ra n g e). 
  
   
 2). Defi niti o n of a d here n ce t o st u d y i nter ve nti o n will be t o c o m plete 2 5 of 2 8 da ys 
of t o pical a nti bi otics a n d atte n d t he pre- i nter ve nti o n / e nr oll me nt visit as well as t he 
p ost-i nter ve nti o n assess me nt visit. N u m ber a n d pr o p orti o n of patie nts wit h 
a d here n ce will be re p orte d.  
3) A u di o metric data will be s u m marize d as a mea n (sta n dar d de viati o n) a n d me dia n 
(ra n ge) 
 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 4 
1 0  
D A T A C O L L E C TI O N A N D Q U A LI T Y A S S U R A N C E  
1 0. 1  D at a C ollecti o n F or ms 
Inf o r mati o n will be c ollecte d o n Case Re p ort F or ms ( C R Fs) b y st u d y staff.  Partici pa nt 
C R Fs will be ke pt i n a l oc ke d ca bi net i n t he D e p art me nt of Ot or hi n olar y n g ol o g y a n d o nl y 
st u d y staff will ha ve access t o t his ca bi net t o mai ntai n c o nfi de ntialit y of partici pa nt 
rec or ds.  
 
Data Ma na g e me nt  
All data is c hec k e d f or c o m plete ness a n d f or acc urac y o n dat a ra n g es.   
Data c ollecti o n f or ms will be or ga nize d i n t he f oll o wi n g cate g ories: 
  - E nr oll me nt / Pre-i nter ve nti o n assess me nt 
  - P ost-i nter ve nti o n assess me nt 
            Data will be c ollecte d a n d st ore d usi n g e x cel file.  
 
1 0. 2  Q u alit y Ass ur a nce  
1 0. 3. 1  
Trai ni n g 
C o -i n vesti gat ors will be briefe d o n t he st u d y pri m ar y a n d sec o n dar y o bjecti ves, t he 
st u d y desi g n a n d all i nf or mati o n i n t his pr ot oc ol will be re vie we d i n pers o n b y t he 
Pri nci pal I n v esti gat or .  
1 0. 3. 2  Q ualit y C o ntr ol C o m mittee  
E N T  Resear c h C o m mittee  is t he st u d y c o ntr ol c o m mittee. Jeffre y J a n us, M D is C hair 
of t his C o m mittee.  
1 0. 3. 3  Pr ot oc ol De viati o ns 
Pr ot oc ol de viati o ns will be ca pt ure d b y t he PI or st u d y staff at t he ti me of o cc urre nce, 
d uri n g s ur ger y or d uri n g f oll o w u p. I nf or mati o n o n de viati o n will be d oc u me nte d. 
T he st u d y will o nl y use data t hat is c o here nt wit h pr ot o c ol. 
1 1  
P A R TI CI P A N T  RI G H T S A N D C O N FI D E N TI A LI T Y   
1 1. 1  I nstit uti o n al Re vie w B o ar d (I R B) Re vie w 
T his pr ot oc ol a n d t he i nf or me d c o nse nt d oc u m e nt a n d a n y s u bse q ue nt m o dificati o ns will 
be re vie w e d a n d a p pr o ve d b y t he I R B.    
1 1. 2  I nf or m e d C o nse nt F or m 
A si g ne d c o nse nt f or m will be o btai ne d fr o m eac h  partici pa nt.   Partici pa nts w h o  ca n n ot 
c o nse nt f or t he msel v es will n ot be e nr olle d i n t his st u d y. T he c o nse nt f or m will descri be 
t he p ur p ose of t he st u d y, t he pr oce d ures t o be f oll o we d, a n d t he ris ks a n d be nefits of 
partici pati o n . A c o p y will be gi ve n t o eac h p artici pa nt a n d t his fact will be d oc u me nte d i n 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 5 
t he partici pa nt’s r ec or d.  
1 1. 3  P artici p a nt C o nfi de nti alit y  
All rec or ds will be ke pt i n a l oc ke d file ca bi net.  All c o m p uter e ntr y a n d n et w or ki n g 
pr o gra ms will be d o ne b y eit her t he Pri nci pal I n v esti gat or or St u d y Staff usi n g sec ure 
l o gi n i nf or mati o n o nl y. Inf or mati o n will n ot be release d wit h o ut writte n per missi o n of t he 
partici pa nt, e xce pt as necessar y f or m o nit ori n g b y I R B, t he F D A, O H R P . 
1 1. 4  St u d y Disc o nti n u ati o n  
T he st u d y ma y be disc o nti n ue d at a n y ti me b y t he I R B, t he NI A, t he O H R P, t he F D A, or 
ot her g o ver n me nt a ge nci es as part of t h eir d uties t o e ns ure t hat researc h partici pa nts are 
pr otecte d.  
1 2  
P U B LI C A TI O N O F R E S E A R C H FI N DI N G S  
P u blicati o n of t he res ults of t his trial will be g o ve r ne d b y t he p olicies a n d pr oce d ures 
de vel o pe d b y t he E N T R esear c h C o m mittee.  A n y prese ntati o n, a bstract, or ma n uscri pt 
wi ll be ma de a vaila ble f or re vie w t o t he m b y PI pri or t o s u b missi o n . 
 
 


T o pic al A nti bi otics i n C hr o nic R hi n osi n usitis  
1 6 
 
1 3  
 
Refere nces  
 
1.   
Wei J L, S y kes KJ, J o h ns o n P, He J, Ma y o M S. Safet y a n d efficac y of o n ce-dail y nasal 
irri gati o n f or t he treat me nt of pe diatric c hr o nic r hi n osi n usitis. L ary n g osc o pe. Se p 
2 0 1 1; 1 2 1( 9): 1 9 8 9- 2 0 0 0. 
2.  
Jer vis- Bar d y J, B oase S, Psaltis A, F ore ma n A, W or mal d PJ. A ra n d o mize d trial of 
m u pir oci n si n o nasal ri nses vers us sali ne i n s ur gicall y recal citra nt sta p h yl o c occal c hr o nic 
r hi n osi n usitis. L ary n g osc o pe. Oct 2 0 1 2; 1 2 2( 1 0): 2 1 4 8- 2 1 5 3. 
3.  
Desr osiers M Y, Salas - Pr at o M. Treat me nt of c hr o nic r hi n osi n usitis refract or y t o ot her 
treat me nts wit h t o pical a nti bi otic t hera p y deli vere d b y mea ns of a lar ge-p article 
ne b ulizer: r es ults of a c o ntr olle d trial. Ot ol ary n g ol He a d Neck S ur g. Se p 
2 0 0 1; 1 2 5( 3): 2 6 5- 2 6 9. 
4.   
Vi deler WJ, v a n Dr u n e n C M, Reits ma J B, F o k ke ns WJ. Ne b ulize d b acitraci n/c oli m yci n: 
a treat me nt o pti o n i n recalcitra nt c hr o nic r hi n osi n usitis wit h Sta p h yl oc occ us a ure us? A 
d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d, cr oss- o ver pil ot st u d y. R hi n ol o gy. J u n 
2 0 0 8; 4 6( 2): 9 2- 9 8. 
5.   
S y kes D A, Wils o n R, C ha n K L, Mac k a y I S, C ole PJ. Relati ve i m p orta nce of a nti bi otic 
a n d i m pr o ve d cleara n ce i n t o pical treat me nt of c hr o nic m uc o p ur ule nt r hi n osi n usitis. A 
c o ntr olle d st u d y. L a ncet ( L o n d o n, E n gl a n d). A u g 1 6 1 9 8 6; 2( 8 5 0 3): 3 5 9- 3 6 0. 
6.   
Lee V S, Da vis G E. C ult ure-directe d t o pical a nti bi otic treat me nt f or c hr o nic 
r hi n osi n usitis. A m J R hi n ol Aller gy. N o v 1 2 0 1 6; 3 0( 6): 4 1 4- 4 1 7. 
7.   
Bars ha k M B, D ura n d M L. T he r ole of i nfecti o n a n d a nti bi otics i n c hr o nic r hi n osi n usitis. 
L ary n g osc o pe i nvesti g ative ot ol ary n g ol o gy. Fe b 2 0 1 7; 2( 1): 3 6- 4 2. 
8.   
Lia n g J, La ne A P. T o pical Dr u g Deli ver y f or C hr o nic R hi n osi n usitis. C urre nt 
ot or hi n ol ary n g ol o gy re p orts. Mar 1 2 0 1 3; 1( 1): 5 1- 6 0.