treatment of chronic rhinosinusitis using erythromycin phonophoresis

CASE REPORT

Treatment of chronic rhinosinusitis usingerythromycin phonophoresis

Noureddin Nakhostin Ansari1, PhD, PT Mojtaba Fathali2, MD Soofia Naghdi3, PhD, PTJim Bartley4, FRACS and Mohammad Saeed Rastak5, MSc, PT

1Associate Professor, Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences,Tehran, Iran2Surgeon and Specialist in Ear, Nose and Throat, School of Rehabilitation, Tehran University of Medical Sciences,Tehran, Iran3Assistant Professor, Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences,Tehran, Iran4Surgeon and Specialist in Ear, Nose and Throat, Institute of Biomedical Technologies, Auckland University ofTechnology, Auckland, New Zealand5Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran

ABSTRACT

Bacterial biofilms have been implicated in many chronic infective diseases, including chronic rhinosinusitis (CRS).Therapeutic ultrasound enhances the breakdown of bacterial biofilms and is clinically effective in CRS treatment,while phonophoresis has also been utilized for antibiotic delivery through the skin. The objective of this case reportis to describe the results of a novel treatment, erythromycin phonophoresis, in a woman with CRS. A 31-year-oldwoman with a 7-month history of CRS refractory to conventional medical management was treated with erythromy-cin phonophoresis to both maxillary sinuses. Individual sinus symptom severity was assessed and sinus CT scanswere obtained both pretreatment and posttreatment. After treatment, the total sinusitis symptom score improvedfrom 12 to 0 and the CT scan showed almost complete disease resolution. At 5-month follow-up, the patientreported sustained improvement. Erythromycin phonophoresis has potential as an effective treatment for CRS.

INTRODUCTION

Bacteria exist in two forms of planktonic or sophisti-cated communities called biofilms. Biofilms havebeen defined as a “structured community of bacterialcells enclosed in a self-produced polymeric matrix andadherent to an inert or living surface” (Costerton,Stewart, and Greenberg, 1999). Biofilm is composedof biopolymers, principally polysaccharides as well asprotein and nucleic acid. The biofilm protects itsinhabitants against environmental and biologicalthreats (Dunne, 2002). Bacteria within biofilms are

associated with many chronic infective diseases,including chronic rhinosinusitis (CRS) (Al-Mutairiand Kilty, 2011; Dworniczek et al, 2009).

In the laboratory setting, ultrasound (US) can break-down bacterial biofilms (Bartley and Young, 2009).Based on these observations, Bartley and Young(2009) hypothesized that therapeutic US had a poten-tial role in CRS treatment. Several clinical studieshave shown that therapeutic US is effective in the man-agement of both acute rhinosinusitis and CRS (Ansari,Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi,and Jalaie, 2007; Ansari, Fathali, Naghdi, andHasson, 2010; Ansari et al, 2012; Høsøien, Lund,and Vasseljen, 2010; Naghdi, Ansari, and Farhadi,2008; Nakhostin Ansari, Naghdi, and Farhadi, 2004;Rocha et al, 2011; Young,Morton, and Bartley, 2010).

Therapeutic US is one of the most widely usedphysical modalities in physical therapy (PT) and has

Address correspondence toDrNoureddinNakhostinAnsari,Departmentof Physiotherapy, School of Rehabilitation, Tehran University of MedicalSciences, Tehran, Iran. E-mail: [email protected]

Accepted for publication 15 June 2012

Physiotherapy Theory and Practice, 29(2):159–165, 2013Copyright © Informa Healthcare USA, Inc.ISSN: 0959-3985 print/1532-5040 onlineDOI: 10.3109/09593985.2012.714445

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broad clinical application. PT interventions such astherapeutic US have been advocated as treatment forrhinosinusitis. Until recently, however, the benefitsof US on rhinosinusitis had not been reported. Thefirst report on the effectiveness of US was by Nakhos-tin Ansari, Naghdi, and Farhadi in 2004, who treateda patient with CSR successfully with pulsed US. Sincethen, a number of studies have been published(Table 1), which have demonstrated the therapeuticbenefits of US on both acute rhinosinusitis andCRS. Reported improvement in symptom scoresrange from 34% to 87% (Table 1).

Although US alone has been shown effective inthe treatment of CRS, one could assume that the

combined effect of US and antibiotic therapy couldincrease the success rate of US in CRS (Bartley andYoung, 2009). Delivering a drug locally to thesinuses may be an alternative method to enhancedrug distribution to the paranasal sinuses. Thera-peutic US is also used in PT as a physical enhancerfor transdermal drug delivery – a technique calledphonophoresis (Polat, Hart, Langer, and Blanksch-tein, 2011). Delivering drugs using phonophoresis isa non-invasive, well-tolerated technique that avoidssystemic side effects (Polat, Hart, Langer, andBlankschtein, 2011). This case report describes awoman with a history of CRS refractory to conven-tional medical treatment who has had sustained

TABLE 1 Trials testing the effect of therapeutic US on rhinosinusitis symptoms.

Study author(s), numbers Type of study Frequency Type and intensity Duration of treatment Results

Høsøien,Lund, andVasseljen(2010),n = 48

RCT withconcealedallocation

1 MHz Continuous, 1.0 W/cm2 10 minutes, daily, 4 days US as effective as oralantibiotics for acutesinusitis

Ansari,Naghdi,and Farhadi(2007),n = 20

Single-blind RCT 1 MHz Continuous, 1.0 and0.5 W/cm2 for themaxillary and frontalsinuses, respectively

5 minutes for eachmaxillary sinus and 4minutes for eachfrontal sinus, 3 days aweek for 10 treatmentsessions

The symptomimprovement in the USgroup (87%) wassignificantly better thanthe control group (37%)(p= 0.007)

Ansari,Naghdi,Farhadi,and Jalaie(2007),n = 57

Case series 1 MHz Pulsed (1:9), 1.0 and0.5 W/cm2 for themaxillary and frontalsinuses, respectively


Most symptoms improved( p< 0.05). Symptomimprovement = 81.3%

Naghdi,Ansari, andFarhadi(2008),n = 30

Case series 1 MHz Continuous, 1.0 and0.5 W/cm2 for themaxillary and frontalsinuses, respectively


74% improvement insymptoms ( p< 0.05)largely maintained at 1month

Young,Morton,and Bartley(2010),n = 22

Case series 1 MHz Pulsed (1:9), 1.0 and0.5 W/cm2 for themaxillary and frontalsinuses, respectively

5 minutes for eachmaxillary sinus and 4minutes for eachfrontal sinus, 2–3 daysper week for sixsessions

SNOT-20 score improvedby 34% ( p< 0.0001)

Rocha et al(2011),n = 26

Cohort placebo-controlled study

1 MHz Continuous, 1.0 W/cm2 4 minutes for themaxillary sinuses andnasal septum

64% improvement of nasalobstruction comparedwith the placebo group

Ansari et al(2012),n = 40

Prospective,randomized,double-blind,parallel groupstudy

1 MHz Continuous or pulsed(1:9), 1.0 and 0.5 W/cm2 for the maxillaryand frontal sinuses,respectively

5 minutes for eachmaxillary sinus and 4minutes for eachfrontal sinus, 3 daysper week, every otherday, for 10 sessions

65 % and 44%improvement in thepulsed and continuousgroup, respectively

RCT, randomized controlled trial; US, ultrasound; MHz, megahertz.

160 Nakhostin Ansari et al.

Copyright © Informa Healthcare USA, Inc.

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improvement after treatment with erythromycinphonophoresis.

CASE DESCRIPTION

A 31-year-old woman with the diagnosis of CRS wasreferred by her physician to the physiotherapy clinicfor treatment with therapeutic US. Her CRS was per-sistent for 7 months. The drug therapies she hadreceived had not been effective in treating her symp-toms. The referring physician had prescribed no othertreatments to the patient. The patient did not take anyover-the-counter medications for her CRS during thecourse of treatment.

Examination

A thorough history, physical examination, and com-puted tomographic (CT) scan to verify the diagnosisof CRS had been performed by the referring physicianwho was blinded to the type of treatment. The refer-ring physician who examined the patient scored theCTs pretreatment and posttreatment, and therefore,he was not blinded to the CT scan reviews. On endo-scopic nasal examination, no material could be seen inmiddle meatus for appropriate gram stain and micro-biological culture.

Severity of sinus symptoms (facial pain/pressure,headache, nasal obstruction, nasal discharge, post-nasal drip (PND), smell disturbance, fatigue, cough,overall discomfort, and CRS severity) were ratedwith an ordinal scale from 0 to 3 (0 = absent, 1 =mild, 2 =moderate, 3 = severe). The scores obtainedfor 10 items were summed to calculate a “total sinu-sitis symptom score”. The “total sinusitis symptomscore” was recorded pretreatment and posttreatmentand at 5-month follow-up (Table 2).

The pretreatment CT scan showed a septum devi-ation to the right side, a large left concha bullosa, anda large left accessory ostium. The right and leftmaxillary and ethmoidal sinuses were opacified(Figure 1a). The ostiomeatal complexes (OMCs)on both sides were occluded. CT scans performedpretreatment and posttreatment were graded from 0(clear) to 3 (total opacification) (Ansari, Fathali,Naghdi, and Hasson, 2010; Ansari et al, 2012).The findings of the CT scan are presented inTable 3.

Evaluation and diagnosis

The results of clinical examination and the CT scanfindings were consistent with the diagnosis of CRS.

At the impairment level, the main symptoms wereheadache, smell disturbance, and fatigue.

At the disability level, she had, on average, 30% dis-comfort (sometimes 100%) for performing her activi-ties of daily living (ADL). At the handicap level, shereported that her symptoms especially headache hadsufficient impact that forced her to stop her ADLs aswell as social activities.

Prognosis

The treatment goals for the patient were relief of hersymptoms including headache, smell disturbance,fatigue, and PND. Another important goal was thenormal reappearance of the paranasal sinuses on theCT scan.

Drug therapy using antibiotics is commonly pre-scribed by physicians for the treatment of CRS.Authors suggested that the US particularly when com-bined with antibiotic therapy could be more effectivethan the US or antibiotic therapy alone in the treat-ment of refractory CRS (Ansari, Naghdi, andFarhadi, 2007; Bartley and Young, 2009; Young,Morton, and Bartley, 2010). Phonophoresis with ery-thromycin 5% was used for this patient.

INTERVENTION

An US machine (model US-750; ITO Co, Japan) wasused. The applicator surface area was 1 cm2 with aneffective radiating area of 0.9 cm2. The beam non-uniformity ratio 3.6 was very low. Initially, the

TABLE 2 The symptomscore at pretreatment andposttreatment.

Symptoms Pretreatment PosttreatmentFollow-

up

Facial pain/pressure

0 0 0

Headache 3 0 0Nasal obstruction 0 0 0Nasal discharge 0 0 0PND 1 0 0Smell disturbance 3 0 0Fatigue 2 0 0Cough 0 0 0Overall discomfort 2 0 0CRS severity 1 0 0Total score 12 0 0Percent

improvement– 100 –

Symptoms were rated with an ordinal scale from 0 to 3(0= absent, 1= mild, 2= moderate, 3= severe).

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physiotherapist applied erythromycin ointment 5%,produced by a licensed pharmacist, with a thicknessof 1–2 mm to the treatment area over the right orleft cheek. Then, US coupled with Sonogel(Germany) was applied using small circular move-ments. The phonophoresis of erythromycin wasdone at 1 MHz, spatial average/temporal peak inten-sity of 1 W/cm2 programmed in pulsed mode (20%duty cycle), 5 minutes for each maxillary sinus, 3times a week, every other day for 10 treatmentsessions.

OUTCOMES

Total scores for symptoms and CT scan findings wereobtained for the patient before and after treatment.The “percent improvement” was calculated as pre-treatment total score minus posttreatment total scoredivided by pretreatment total score × 100 and

classified as: no change (0): 0–15%; poor (1): 16–35%; fair (2): 36–60%; good (3): 61–85%; excellent(4): 86–100% (Ansari, Naghdi, and Farhadi, 2007;Ansari, Fathali, Naghdi, and Hasson, 2010; Ansariet al, 2012; Naghdi, Ansari, and Farhadi, 2008).The outcome measure used in this report has beenshown to be valid as reported by Naghdi, Ansari,and Farhadi (2008). In this case report, the disease-specific validated instruments (e.g., 20-Item Sino-Nasal Outcome Test [SNOT-20]) were not usedbecause they are not validated in the Persian language.There are several non-uniform radiological stagingsystems. Among these systems, the Lund andMackay (1993) system is the most widely acceptedCT scan classification system because it has the leastinter-observer variation of all the systems and can bedone more easily than the other systems. The validityof the CT grading system was assessed against Lund–Mackay staging system which depends on whether thesinus is clear (0); partially opacified (1); or totally

FIGURE 1 (a) Pretreatment and (b) posttreatment computed tomography scans of a woman with chronic rhinosinusitis. After pho-nophoresis therapy with erythromycin, there has been significant improvement in the maxillary and anterior ethmoid sinus disease(gray = opacification [soft tissue density], and black = clear [air]). The left maxillary sinus and left anterior ethmoid sinuses arelabeled M and A, respectively, on the posttreatment scan.

TABLE 3 CT scan scores: CT scans performed pretreatment and posttreatment were graded from 0 (clear) to 3 (total opacification) forthe respective sinuses.

Sinus

Right Left

Pretreatment Posttreatment Pretreatment Posttreatment

Maxillary 1 0 3 0Anterior ethmoid 1 0 1 0Posterior ethmoid 1 0 1 0Sphenoid 0 0 0 0Frontal 0 0 0 0OMC 3 0 3 0Total score 6 0 8 0Percent improvement – 100 100



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opacified (2) with OMC obstruction being scoredeither 0, for not obstructed, or 2, for obstructed. In30 patients with CRS (mean age 42 ± 14 years,mean disease duration 78 ± 96.34 months), the CTtotal score (mean 17 ± 8.07) was significantly corre-lated with Lund–Mackay total score (mean 11.8 ±5.08) (Pearson r = 0.98, p < 0.001).

After treatment, the patient reported complete res-olution of all her sinus symptoms (Table 1). Sustainedimprovement was reported at 5-month follow-up fromthe last treatment session. A posttreatment CT scanshowed resolution of the right and left maxillary andethmoidal sinus opacification as well as opening ofthe OMC (Figure 1b) indicating that the CRS hadresolved.

DISCUSSION

To the authors’ knowledge, there are no reports in theliterature describing a case of a patient with CRS re-ferred to PT for treatment with phonophoresis.

The case reported here is a woman with CRS whowas treated successfully with erythromycin phono-phoresis applied to the soft tissues over the maxillarysinuses. Following a total of 10 treatments of erythro-mycin phonophoresis, the CRS completely resolved asobserved with complete resolution of symptoms andwith CT scan findings of normal sinuses.

Bacteria within biofilms are resistant to most anti-biotics. This resistance has been attributed to a trans-port barrier created by the biofilm, binding ofantibiotics to the exopolysaccharide in the biofilm,and the bacteria in mature biofilms being metaboli-cally dormant and thus not taking up and/or metabo-lizing antibiotics (Bartley and Young, 2009). Asantibiotics are not effective in the treatment of bac-terial biofilms, alternative treatments such as blockingmolecular communication between bacteria (quorumsensing); inhibiting biofilm matrix production; andinterventions that damage bacterial membranes arebeing explored as treatment options (Al-Mutairi andKilty, 2011).

US treatment at sufficiently high energy levels iscapable of killing bacteria (Hedges, Lewis, Lunec,and Cramp, 1980; Scherba, Weigel, and O’Brien,1991). In this situation, bacterial killing is usually at-tributed to cavitation in or on the bacteria or to thegeneration of free radicals, which subsequently killthe bacteria (Hedges, Lewis, Lunec, and Cramp,1980; Scherba, Weigel, and O’Brien, 1991). Atlower levels of ultrasonic power, sufficiently low thatUS does not kill the bacteria, US has a synergisticeffect with antibiotics. This has been defined as thebioacoustical effect (Qian, Sagers, and Pitt, 1999).

US’s hypothesized actions against biofilms at lowerenergy levels include

. increasing the effectiveness of antibiotics by increas-ing the rate of antibiotic transport to bacteria(Carmen et al, 2004);

. increasing the metabolic activity and growth of thebacteria perhaps by increasing oxygen and other nu-trient transport (Pitt and Ross, 2003). US has alsobeen shown to damage the bacterial cell wall. Thisin turn leads to increased energy requirementsneeded for repair (Broekman, Pohlmann, Beard-wood, and de Meulenaer, 2010). Theoretically,the increased metabolic activity and growth of thebacteria makes them more susceptible to the anti-biotics and/or the body’s natural defenses;

. damaging the biofilm matrix. One confocal scan-ning laser microscopy study has shown that thestructure does not change (Qian, Stoodley, andPitt, 1996). However, another study has shownthat calcium can be lost from the biofilm matrix,which leads to decreased biofilm stability (Broek-man, Pohlmann, Beardwood, and de Meulenaer,2010).

The mechanisms by which phonophoresis en-hances the absorption of topically applied drugs areunclear (Polat, Hart, Langer, and Blankschtein,2011). At frequencies between 1 and 3 MHz, Mitra-gotri, Edwards, Blankschtein, and Langer (1995)showed that cavitation within cavities near the corneo-cytes of the stratum corneum enhanced skin per-meability; 1 MHz increases transdermal flux by 13-fold, whereas 3 MHz increases transdermal flux byonly 50% (Mitragotri, Edwards, Blankschtein, andLanger, 1995). The direct interaction of the oscillatingcavitation bubbles causing disordering of the stratumcorneum lipid bilayers is hypothesized to cause the ob-served increase in skin permeability (Mitragotri,Edwards, Blankschtein, and Langer, 1995). Althoughstudies have used topically applied drugs without US,research indicates that the topical drug administrationleads to enhanced local delivery to tissues subjacent tothe skin (McNeill, Potts, and Francoeur, 1992). Theskin and 5% erythromycin ointment have similaracoustic impedance so there is no significant reflectionof the US wave at the interface between the skin andthe coupling medium. This facilitates drug delivery(Polat, Hart, Langer, and Blankschtein, 2011). Thearterial supply of the lateral wall of the maxillarysinus and overlying soft tissue is from the posteriorsuperior alveolar and infraorbital arteries (Traxleret al, 1999). The mucus membrane of the lateralmaxillary sinus also receives its arterial blood supplyfrom these vessels (Traxler et al, 1999). High



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antibiotic concentrations in the overlying soft tissuescould then easily be transmitted through to themucus membranes lining the maxillary sinuses.

A number of antibiotics including penicillin, strep-tomycin, and tetracycline have been delivered usinghigh-frequency US (Polat, Hart, Langer, andBlankschtein, 2011). Erythromycin as part of themacrolide group was chosen because in addition tohaving antibiotic actions it also offers potential as aquorum blocker inhibiting the formation of bacterialbiofilms (Giamarellos-Bourboulis, 2008). Further-more, erythromycin is readily available and inexpen-sive and has well-documented effects in CRS.Clarithromycin is effective in CRS, but is expensive.Few other antibiotics have quorum blocking activity.Azithromycin, another macrolide, also offers con-siderable potential as a quorum blocker (Skindersoeet al, 2008).

Azithromycin, however, has not been used in CRS.Macrolides also appear to have a considerable anti-inflammatory effect (Giamarellos-Bourboulis, 2008).As most other conventional antibiotics are ineffectiveagainst bacteria in a biofilm state even when laboratorysensitivities indicate that they should be, antibioticchoice for phonophoresis may be important.

CRS is an inflammatory condition that begins withmucosal congestion and obstruction of the OMCs(Osur, 2002). US has an anti-inflammatory effect(Chung et al, 2012) which could reduce inflammationaround the OMC facilitating sinus drainage. The posi-tive effects of phonophoresis with erythromycin onCRS could also be from mechanical vibrationsinduced by US (Mason, 2011; O’Brien, 2007). USalso has analgesic effects which may have also led topain improvement (Baker, Robertson, and Duck2001). Both erythromycin delivered through phono-phoresis and pulsed US have antibacterial and anti-inflammatory effects which might be responsible forbeneficial effects.

Whether the positive outcomes were due primarilyto the phonophoresis or to the US therapy needs to beexplored. A study comparing the erythromycin phono-phoresis with pulsedUS in patients with CRS is under-way to determinewhether erythromycin phonophoresisis superior in improving CRS symptoms.

CONCLUSION

This case report provides a new and novel concept fora modality clinically utilized by PTs. A case of CRS isreported where erythromycin phonophoresis lead tocomplete resolution of CRS symptoms. Erythromycinphonophoresis offers promise as an effective treatmentfor CRS. Further studies are needed to determine the

effectiveness of phonophoresis with erythromycin andother antibiotics especially compared with either anti-biotic therapy or US therapy alone.

Acknowledgment

The authors alone are responsible for the content andwriting of the article.

Declaration of interest: The authors report noconflicts of interest.

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treatment of chronic rhinosinusitis using erythromycin phonophoresis

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