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Inicio Acta Otorrinolaringológica Española On ciprofloxacin concentration in chronic rhinosinusitis
Información de la revista
Vol. 69. Núm. 1.
Páginas 35-41 (Enero - Febrero 2018)
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Vol. 69. Núm. 1.
Páginas 35-41 (Enero - Febrero 2018)
Original article
DOI: 10.1016/j.otorri.2017.06.008
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On ciprofloxacin concentration in chronic rhinosinusitis
Acerca de la concentración de ciprofloxacino en la rinosinusitis crónica
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José Gameiro dos Santosa,
Autor para correspondencia
jgameirosantos@gmail.com

Corresponding author.
, Rosário Figueirinhasa, José P. Liberalb, João C. Almeidaa, Joana Sousac, Amílcar Falcãoc, Corália Vicented, João Paçoe, Cecília A. Sousaa
a Department of Otolaryngology – Head and Neck Surgery, CHP-Hospital Santo António, Porto, Portugal
b Department of Pharmacology, CHP-Hospital Santo António, Porto, Portugal
c Faculdade de Farmácia, Universidade de Coimbra, Coimbra, Portugal
d Instituto de Ciência Biomédicas Abel Salazar, Porto, Portugal
e Hospital CUF Infante Santo, Lisboa, Portugal
Información del artículo
Resumen
Texto completo
Bibliografía
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Estadísticas
Tablas (5)
Table 1. Diagnosis of chronic rhinosinusitis (CRS) – EPOS criteria.
Table 2. Distribution regarding the pharmaceutical formulation.
Table 3. Pharmaceutical formulations description.
Table 4. Mucosal concentration results (μg/g).
Table 5. Statistical significant results (Kruskall–Wallis) comparing all the formulations with or without nasal polyps.
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Abstract
Objective

Considering that all the evidence indicates that chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are distinct entities, the aim of this study was to compare the concentrations obtained in plasma and in sinonasal mucosa with oral and nasal topical ciprofloxacin, in patients with and without nasal polyps, without evaluating the effectiveness of the use of an antibiotic.

Methods

Prospective clinical study with single-blind randomization. The population consisted of patients with chronic rhinosinusitis with eligible for endonasal surgery, over 18 years old. It took place between January 2010 and December 2014. A single preoperative dose of ciprofloxacin (oral or nasal topic- spray, gel or drops) was given and samples of plasma and nasal mucosa (inferior turbinate, middle turbinate, ethmoid and maxillary sinus) were collected prior to surgery. The plasma and mucosal ciprofloxacin concentrations were assayed with high performance liquid chromatography (HPLC) with fluorescence detection (FD).

Results

The oral ciprofloxacin achieved better mucosal concentrations but had a significant plasmatic expression in all patients. None of the topical formulations achieved measurable ciprofloxacin plasmatic levels. Among the topical formulations, the gel had the best mucosal results, despite the existence of polyposis.

Keywords:
Chronic rhinosinusitis
Nasal polyps
Topical antibiotic
Nasal gel
Nasal drops
Resumen
Objetivo

Considerando todas las evidencias de que la rinosinusitis crónica sin poliposis nasal (RSCsPN) y la rinosinusitis crónica con poliposis nasal (RSCcPN) son entidades distintas, el objetivo de este estudio fue comparar las concentraciones obtenidas en el plasma y en la mucosa nasal con ciprofloxacino oral y tópico nasal en pacientes con y sin pólipos nasales, sin evaluar la efectividad del uso del antibiótico.

Métodos

Estudio clínico prospectivo con asignación aleatoria. La población se componía de pacientes con rinosinusitis crónica propuestos para cirugía endonasal, mayores de 18 años. Se desarrolló entre enero de 2010 y diciembre de 2014. Se administró una dosis única preoperatoria de ciprofloxacino (oral o tópico nasal, en aerosol, gel o gotas) y se recogieron muestras de plasma y mucosa nasal (cornetes, etmoides y seno maxilar) antes de la cirugía. La concentración de ciprofloxacino en el plasma y en la mucosa se ensayó mediante cromatografía líquida de alto rendimiento con detección de fluorescencia.

Resultados

El ciprofloxacino oral logró las concentraciones mucosas más altas pero tuvo una expresión plasmática significativa en todos los pacientes. Ninguna de las formulaciones tópicas ha generado niveles plasmáticos de ciprofloxacino medibles. Entre las formulaciones tópicas, el gel fue el que presentó mejores resultados mucosos, a pesar de la existencia de poliposis.

Palabras clave:
Rinosinusitis crónica
Pólipos nasales
Antibiótico tópico
Gel nasal
Gotas nasales
Texto completo
Introduction

Chronic rhinosinusitis is a symptomatic inflammation of the paranasal sinuses and nasal cavity that lasts more than 12 weeks, with or without acute exacerbations.1 US National ambulatory care data from 2006 to 2010 revealed that rhinosinusitis accounted for more outpatient antibiotic prescriptions than any other diagnosis.2

CRS is primarily an inflammatory disease, with occasional exacerbations associated with infection. Treating only the acute exacerbations leaves the underlying condition untreated, likely contributing to an increased frequency of exacerbations. CRS is associated with sinus edema and impaired mucociliary clearance. With edema-related obstruction and retained mucus, bacterial infection can more easily set up within the sinuses.3

Current consensus classifies chronic rhinosinusitis (CRS) into two subgroups: chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP).1 In the past few years, there are a growing number of investigators showing the differences between the sub-types of CRS, stating them as two distinct entities. These differences are becoming proved in many characteristics of the diseases, beyond their phenotype.4 For instance, its already demonstrated that CRSwNP and CRSsNP have distinct disease markers (cytokines, mediators, and cellular profiles).4,5 These findings are already affecting the treatment approaches for CRS.

It remains unknown why do polyps develop in some patients but not in others.

Based on the phenotype and on the different expression of the inflammatory cytokines and remodeling patterns, we can distinguish CRSwNP from CRSsNP.4,5

The nasal polyps are poorly vascularized structures. Several authors claim that polyps have a normal basal membrane vascularization, but they seem to have an increased expression of vascular permeability factor and have a lack of vasoconstrictor innervation. These factors may play a significant role either in their formation and in its edema or in reducing venous drainage.6–8 Does this interfere with local antibiotic concentration?

The current treatments for rhinosinusitis are aimed to reduce the inflammation, controlled the infection and restore the mucociliary clearance within the sinuses.

The more commonly responsible microbiological agents for rhinosinusal infection are sensitive to first line antibiotics, but there are some patients infected with resistant bacteria (Pseudomonas or MRSA). Furthermore, one of the more consensual etiologic factors is the presence of biofilms in the nasal mucosa. It is known that biofilms perpetuate the inflammation and the mucociliar disfunction, and therefore, to treat CRS, it is necessary to eradicate the biofilms. Desrosiers demonstrated, in vitro, that a much higher concentration of antibiotic is required to achieve a bactericidal effect on bacteria of biofilms, than the necessary to have bactericidal effect on planktonic bacteria.9 It questions the effectiveness of oral/systemic antibiotics, leading to the hypothesis that topical nasal antibiotic therapy may be more effective, since it may allow that a higher amount of the active substance reaches the desired location with insignificant systemic absorption and, therefore, without any side effect for patients. There are already some studies concluding that nasal topical antibiotics, used in acute rhinosinusitis (ARS) and in CRS, provoke no side effects to patients.10 However, there are only a few studies comparing the several available topical presentations and there are still no studies comparing the topical use of antibiotics between patients with CRS with and without nasal poliposis.

Regarding all the evidences that CRSsNP and CRSwNP are distinct entities,3 the aim of this study was to compare the plasma and in sinonasal mucosa concentrations obtained with oral and nasal topical ciprofloxacin, in CRS patients, with and without nasal polyps, not evaluating the effectiveness of the antibiotic.

The process of approving drugs for clinical use is based on seeking evidence of the efficacy and safety of the drug through clinical trials, usually comparing it to a placebo or another active ingredient for the same purpose and for a specific indication. This way, the off-label use of drugs consists of using drugs for one indication, population subset or in a dosage/route of administration not approved by the national regulatory authority, since this, while regulating the drug market, it has no jurisdiction to regulate the uses/prescriptions. This practice is an unavoidable reality in modern health systems.11 Furthermore, if one medication from a class of drugs has Food and Drug Administration (FDA) approval to treat a specific pathology, physicians commonly use other medications from the same class, without specific FDA approval to that specific pathology, for the same purpose. In addition, if the pathology or physiology of two conditions are similar, a physician may use a medication approved for one of these conditions for both.11,12

MethodsStudy population

The population size was of 109 patients, 74 males and 35 females, with ages between 20 and 77 years old (mean 44.79).

The study included adult patients, with diagnosed chronic rhinosinusitis, following the consensual criteria of EPOS 2012 (Table 1), confirmed and documented by nasal endoscopy and sinusal CT scan, and proposed for endoscopic sinus surgery. It included primary and revision surgical cases. The patients were divided into two sub-groups: CRS patients with nasal polyps and CRS patients without nasal polyps.

Table 1.

Diagnosis of chronic rhinosinusitis (CRS) – EPOS criteria.

2 or more symptoms ≥12 weeks
• Nasal blockage/obstruction/congestiona
• Nasal discharge (anterior/posterior nasal drip)a
• Facial pain/pressure
• Reduction or loss of smell
Demonstrated by (and/or)Nasal endoscopy• Nasal polyps, and/or 
• Mucopurulent discharge primarily from middle meatus 
and/or 
• Edema/mucosal obstruction primarily in middle meatus 
  CT scan  Mucosal changes within the ostiomeatal complex and/or sinuses 
a

At least one of them.

All patients under 18 years old, with cystic fibrosis or other known cilia dysfunction, fungal pathology, immunodeficiency, vasculitis or granulomatous disease, were excluded.

The existence of asthma or allergies was not registered. No patient was taking antibiotics or systemic steroids.

The study took place between January 2010 and March 2014.

Study design

The study was validated by the hospital ethic committee. All patients gave their written informed consent (reference 036/08 (NA-DEFI/028-CES)).

All the CT scans were classified by the Lund-Mackay score.

All patients took, in the 24h prior to the surgery, a single dose of ciprofloxacin, and the intake hour was registered.

Both subgroups (CRSwNP and CRSsNP) were randomly divided into four groups (Table 2).

Table 2.

Distribution regarding the pharmaceutical formulation.

  Patients (n=109) 
Ciprofloxacin 500mg oral  24 
Ciprofloxacin drops 50mg  29 
Ciprofloxacin spray 50mg  17 
Ciprofloxacin gel 50mg  39 

As the topical formulations are successfully used for many years in the treatment of otitis, and assuming that the pathogenic agents are similar, its use in rhinosinusitis patients theoretically may allow us to treat the infection, achieving higher local antibiotic concentrations, in order to be effective in the biofilms. The topical ciprofloxacin dosage used in this study was of 50mg per nostril in each application, and the formulations were made in a way that assure the same dosage (Table 3). This dosage is the most frequently used off label. There is no information regarding the ciprofloxacin biodisponibility in a transmucosal application. In this study, we are more concerned about the mucosal ciprofloxacin absorption, given that our target organ is the nasosinusal mucosa. Ciprofloxacin was chosen because of its spectrum of activity and ease of handling in the topical presentations. It is consensual that the most common agents of chronic rhinosinusitis are usually sensitive to quinolones.

Table 3.

Pharmaceutical formulations description.

Formulation  Application per nostril  Ciprofloxacin dosage 
Spray
Ciprofloxacin IV 200mg/100mL  0.25mL (2 puffs)  50mg 
Gel
Ciprofloxacin IV 2mg/mL – 6.6667mL  0.75mL50mg
Metilcelulose – 0.150
Parahidroxibenzoato de metilo – 0.018
Parahidroxibenzoato de propilo – 0.002
Distilled water qbp 10mL 
Drops
Ciprofloxacin IV 200mg/mL  0.25mL (5 drops)  50mg 
Oral
Ciprofloxacin 500mg  –  500mg 
Tissue sampling

A blood sample was taken from each patient before the anesthetic induction. Samples of the inferior turbinate mucosa, middle turbinate mucosa, maxillary sinus mucosa and of the anterior ethmoid mucosa were collected from the side with higher Lund-Mackay score, prior to the surgical procedure. The exact sampling time (blood and mucosa) was registered.

The blood and nasal samples were frozen (without fixation) and sent to analysis. The HPLC-UV method was used to evaluate the mucosal ciprofloxacin concentration, and chromatography was used to determine the antibiotic plasmatic concentration.

Quantification of ciprofloxacin13–15

The plasma and sinonasal mucosa samples were assayed for ciprofloxacin concentration with high performance liquid chromatography (HPLC) with fluorescence detection (FD).

For ciprofloxacin analysis, two different HPLC-FD methods were developed and employed, one for each biological matrix. The chromatographic analysis of the pre-treated plasma and sinonasal tissue samples was performed on a LiChroCART Purospher® Star column.

In the case of plasma samples, the chromatographic method used was fully validated,13 while for sinonasal samples only a partial validation of the bioanalytical method using nasal mucosa (20mg) of mice was performed in this rare matrix, due to the limited supply of blank human nasal samples and the invasive nature of the collection procedures. Both described HPLC-FD methods fulfilled the requirements established by FDA guidelines. The lower limit of quantification was 0.02μg/mL for ciprofloxacin in plasma, and 0.8ng/mL in nasal mucosa.

Data analysis

Data analysis was performed using IBM-SPSS Statistics version 23.

The Kruskal–Wallis test was used to compare concentrations in the several sites studied. It is a nonparametric (distribution free) test. This test assesses for significant differences on a dependent variable by a grouping independent variable (with three or more groups) when one cannot assume that there is an equal variance on the scores for each group.

Table 4.

Mucosal concentration results (μg/g).

Formulation  CRS    Ethmoid sinus  Maxilary sinus  Inferior turbinate  Middle turbinate 
OralwNPN  14  14  14  14 
Mean  3.799  6.079  5.592  5.302 
St deviation  3.252  7.796  6.452  5.425 
sNPN  10  10  10  10 
Mean  1.426  1.157  1.852  1.835 
St deviation  1.494  1.102  2.573  2.423 
GelwNPN  25  25  25  25 
Mean  0.115  0.180  3.309  0.400 
St deviation  0.201  0.351  6.189  0.861 
sNPN  14a  15  15  15 
Mean  0.163  0.431  1.385  0.547 
St deviation  0.298  1.024  2.665  0.887 
DropswNPN  21  21  20a  19a 
Mean  0.098  0.151  1.769  0.160 
St deviation  0.201  0.273  5.447  0.294 
sNPN 
Mean  0.028  0.029  0.766  0.062 
St deviation  0.054  0.082  1.420  0.158 
SpraywNPN  10  10  9a  10 
Mean  0.067  0.031  0.227  0.070 
St deviation  0.105  0.061  0.417  0.159 
sNPN  6a 
Mean  0.023  0.079  0.545  0.008 
St deviation  0.056  0.158  1.079  0.021 
TotalN  109  109  108  108 
Mean  0.695  1.026  2.293  1.065 
St deviation  1.752  3.389  4.816  2.670 

CRS, chronic rhinosinusitis; sNP, without nasal polyps; wNP, with nasal polyps.

a

Unavailable sample.

Table 5.

Statistical significant results (Kruskall–Wallis) comparing all the formulations with or without nasal polyps.

  PP/NP (IPP/NP (JMean difference (IJStd. error  P-value 
NES  oral wNP  oral sNP  2.373*  0.522  0.007 
    gel wNP  3.684*  0.421  <0.001 
    gel sNP  3.636*  0.476611  <0.001 
    drops wNP  3.701*  0.435  <0.001 
    drops sNP  3.771*  0.559  <0.001 
    spray wNP  3.732*  0.522  <0.001 
    spray sNP  3.776*  0.584  <0.001 
NMS  oral wNP  oral sNP  4.921*  1.180  0.021 
    gel wNP  5.899*  0.951  <0.001 
    gel sNP  5.647*  1.059  0.001 
    drops wNP  5.927*  0.983  <0.001 
    drops sNP  6.050*  1.26  0.004 
    spray wNP  6.047*  1.180  0.001 
    spray sNP  6.000*  1.391  0.014 
NMT  oral wNP  oral sNP  3.468*  0.894  0.045 
    gel wNP  4.903*  0.720  <0.001 
    gel sNP  4.755*  0.802  <0.001 
    drops wNP  5.143*  0.760  <0.001 
    drops sNP  5.240*  0.957  <0.001 
    spray wNP  5.232*  0.894  <0.001 
    spray sNP  5.294*  1.000  0.001 

PP, pharmaceutical formula; CRS, chronic rhinosinusitis; sNP, without nasal polyps; wNP, with nasal polyps; NP, classification into CRSwNP or CRSsNP; NES, ethmoidal sinus; NMS, maxillary sinus; NMT, middle turbinate.

*

The mean difference is significant at the 0.05 level.

Results

  • The sample analysis showed that systemic antibiotic delivery reached much higher concentrations in all studied sites when compared with the topical formulations, for example in CRSsNP 1.426±1.494μg/g and respectively, for gel, drops and spray, 0.163±0.298μg/g, 0.028±0.054μg/g and 0.023±0.058μg/g. This was especially true in patients with polyposis, where the achieved concentrations with oral antibiotic were significantly higher in all sites, for example, in CRSwNP and with the same order, 3.799±3.852μg/g, 0.115±0.201μg/g, 0.098±0.201μg/g and 0.067±0.105μg/g (Tables 4 and 5).

  • Among the topical formulations, although without statistical significance, the gel formulation seemed to reach higher mucosal concentrations than the other formulas. Even comparing with the oral antibiotic in patients with CRSwNP, it reached higher concentrations in the inferior turbinate (Tables 4 and 5).

  • In patients with CRSsNP, the gel formulation had higher measurable concentrations in all loci, except in the inferior turbinate, compared to all other topical formulations.

  • The drops formulation achieved higher concentrations in all sites in patients with CRSwNP, compared with patients with CRSsNP.

  • The spray formulation results were inconsistent.

  • The plasmatic concentration was only detectable in patients that took oral ciprofloxacin (0.390±0.504μg/g).

  • None of the topical formulations generated measurable results in plasma, that is higher than 0.02μg/g.

Discussion

With the oral formulation, a ten times higher antibiotic concentration is achieved, either in plasma as in the sinonasal mucosa. This is easily explained by the fact that the given dosage was also ten times higher. It is interesting to notice that the mucosal concentrations measured in patients with CRSwNP were higher, with statistical significance, in the ethmoidal sinus (p=0.007), maxillary sinus (p=0.021) and in the middle turbinate (p=0.043), compared with the same locations in CRSsNP patients. In the inferior turbinate, the difference was notorious but not statistically significant. We assume that this may be due to the known increased vascular permeability and maybe to the reduced venous drainage present in the polyps.4,6

Most of the published studies do not compare neither the results between patients with CRSwNP and with CRSsNP, neither, in the same patient group, the different antibiotical delivery regarding the used devices.17

A systematic review published by Lim in 200818 concluded that topical antibiotics appear effective in the management of CRS. Most of the published studies do not compare neither the results between patients with CRSwNP and with CRSsNP, neither, in the same patient group, the different antibiotic delivery regarding the used devices.17

With its density and viscosity, the gel formulation may have some difficulty surpassing the polyps, explaining the lower concentrations in the CRSwNP patients, in comparison with CRSsNP patients.16 On the other hand, in the inferior turbinate, the concentration is higher in CRSwNP, maybe because the polyps restrict the gel progression, leading to deposition in the inferior turbinate. Despite these considerations, the gel was the topical formulation with better mucosal concentrations.

The drops formulation achieved higher concentrations in all loci in CRSwNP patients than in CRSsNP patients. The increased vascular permeability and reduced venous drainage, characteristic of CRSwNP, may again explain the difference.4,6 Compared to the gel results, with the drops there was no difference between the inferior turbinate and the other loci in the patients with polyps. We can conclude that the drops can easily surpass the polyps, achieving the sinus mucosa, without deposition in the inferior turbinate.

The spray formulation results were inconsistent. We believe that this is due to the difficulty in reproducing the administration technique and the widespread of the spray.

There are several published studies that concluded, however, that the anatomical particularities of the nose change the absorption and distribution of the topical drugs.17 In all topical formulations, despite the existence of polyps, the inferior turbinate was the site with higher ciprofloxacin concentrations. When we give nasal topical drugs to the patient, are we treating the sinusitis or only the rhinitis?

These results show the need to other studies that assure the medical community that we are choosing the right topical formulation for each problem. Currently, there are much more nasal topical medications in spray than in drops or gel.

More studies are needed, with bigger statistical samples, to confirm these data, to achieve more robust conclusions and eventually to extrapolate to other organs with polyps.

Conclusion

Higher ciprofloxacin mucosal concentrations were achieved in CRSwNP patients, either with oral or topical ciprofloxacin. This can be another difference between CRSwNP and CRSsNP, with clinical and therapeutical meaningfulness.

The oral ciprofloxacin achieved better mucosal concentrations than the topical formulations. However, the used dosage was significantly higher. The inexistence of measurable plasma ciprofloxacin with the topical formulations leads us to extrapolate that it is possible to “exponentially” increase the ciprofloxacin concentration in order to try to have higher mucosal concentration, trying to affect the biofilms.

The type of topical administration lead to different results, appearing the gel formulation to be the more effective one, among the tested, despite the existence of nasal polyps.

Conflict of interests

The authors declare that they have no conflicts of interest.

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Copyright © 2017. Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello
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