Fuentes de ingresos

anti-inflammatory as well as antimicrobial properties and

may therefore have a role in the treatment of CRS. The treatment of CRS with macrolide antibiotics stems from early studies of lower airway disease, where erythromycin was used in panbronchiolitis to improve clinical symptoms

and 5-year survival rates.742_{Current understanding of the}

macrolides’ mechanism of action suggests both antibacte- rial and immunomodulatory roles and the proposed effects

of macrolides are diverse.743, 744 _{They are known to de-}

crease proinflammatory cytokine production while altering leukocyte reaction by decreasing IL-8 and also inhibit a key proinflammatory transcription factor, nuclear factor kB

(NF-kB).745–748_{Significant literature also suggests a role for}

macrolide disruption of neutrophilic action, particularly in

limiting migration, adhesion, and oxidative response.749, 750

In 2004, Ragab et al.751_{published an RCT that compared}

CRS patients randomized to surgery or medical therapy. Both CRSwNP and CRSsNP were included and analyzed separately. The medical therapy arm for CRSsNP patients was comprised of INCS, alkaline nasal irrigations, and long-term low-dose oral macrolide therapy. Erythromycin 500 mg BID was administered for 2 weeks, followed by 250 mg BID for 10 weeks. At the conclusion of the 12-week trial, patients treated with medical therapy and those treated with surgery had similar subjective and objective outcomes.

In 2013, Soler et al.752_{published a review of macrolides}

in CRS as part of a larger work on antimicrobials in CRS. They identified 17 studies that evaluated the use of macrolide antibiotics in CRS for their anti-inflammatory properties. The aggregate quality of the evidence was found to be B, with 2 placebo-controlled RCTs, 1 retrospective case-control study, and 14 observational cohort studies

with no controls. The 2 RCTs753, 754 _{used robust CRS}

definitions and the duration of therapy was 3 months in

both studies. Wallwork et al.754 _{treated CRSsNP patients}

with roxithromycin 150 mg daily and found improved SNOT-20 and endoscopy scores compared to placebo, but no difference in other metrics, including olfactory function, peak nasal inspiratory flow (PNIF), saccharine transit time, and nasal lavage markers. These results were not sustained after cessation of treatment. Interestingly, patients without elevated IgE appeared to have better results.

Videler et al.753 _{examined CRSsNP patients and CR-}

SwNP patients with low-grade polyps using a similar combination of patient-reported outcome and objective measures and found that azithromycin 500 mg/week after an initial loading dose showed no benefit over placebo. Notably, CRSwNP patients comprised 52% of the 60 subjects. Limitations of this study beyond the mixing of CRSwNP with CRSsNP is the possible higher severity of disease, inasmuch as all patients had failed prior antibiotic or INCS treatments, and patients with prior ESS were eligible, averaging 2.5 prior ESS procedures.

Of the remaining 15 studies examined by Soler et al.,752

three specifically examined CRSwNP, 1 was a nonclinical study examining rheologic properties of mucus, and 10 did not delineate polyp status. Interestingly, 1 study combined

both CRSwNP and CRSsNP patients and found that those

without NPs responded better to macrolides.755

Soler et al.752 _{provided a summary of the evidence}

and recommendations for macrolide use in CRS, finding a balance between benefit and harm and considering macrolides an option in the treatment of CRS. Unfortu- nately, like much of the literature on which their review

and recommendations were based, Soler et al.752 _did

not differentiate CRSwNP from CRSsNP. Others have more recently examined this same published data and have similarly found a general lack of high-level evidence, a propensity to combine CRSwNP and CRSsNP, and

significant harms to balance benefits.756–758

Since these systematic reviews and meta-analyses were published, 2 additional studies have been published exam- ining macrolide treatment in CRSsNP and 1 in CRSsNP

combined with low-grade CRSwNP. Zeng et al.715 _com-

pared oral clarithromycin to mometasone topical nasal spray in 43 patients with CRSsNP. They found compa- rable improvement in total symptoms, nasal obstruction, headache, and rhinorrhea, as well as endoscopic findings of mucosal swelling and nasal discharge at 4 weeks of therapy.

As has been seen previously,754 _{patients with AR did not}

have as robust a response to macrolide therapy. Luo et al.759

treated CRSsNP patients with clarithromycin and found improved nasal symptom scores, as well as reductions in IL-8 and myeloperoxidase in nasal secretions. Macrolide therapy was found to be more effective in patients with high

IL-8 levels prior to treatment. Majima et al.760 _examined

the effect of clarithromycin in CRSsNP patients and CR- SwNP patients with limited polyps. Subjects were treated with clarithromycin or clarithromycin and carboxymethyl- cysteine. Clarithromycin-treated patients showed statisti- cally significant improvement in SNOT-20 and CT after 12 weeks of treatment.

One additional study of CRSsNP and CRSwNP patients examined the use of erythromycin following ESS, with evaluation of patient-reported outcomes and physiologic

measurements.761 _{Both CRSsNP and CRSwNP patients}

treated with erythromycin had better endoscopy scores than control patients, but CRSsNP patients demonstrated a greater improvement with erythromycin compared to similarly treated CRSwNP patients. CRSsNP patients also showed trends toward greater improvement than CRSwNP patients in SNOT-20 scores, olfaction, and saccharin transit times.

Maniakis et al.762 _{performed a retrospective audit on a}

cohort of 21 patients who did not respond to topical budes- onide irrigations. Twelve of the 21 received azithromycin 250 mg three times weekly, with 8 of the 12 showing a favorable response. The authors postulated topical corticosteroid-unresponsive CRS patients may represent a distinct clinical entity that may respond to macrolide therapy. Polyp status was not reported for these 12 patients. Although most macrolide studies have utilized treatment duration of approximately 12 weeks, no specifications

exist for ideal treatment length. Nakamura et al.763 _eval-

uated treatment duration using daily clarithromycin for 12-week or 24-week treatment courses in post-ESS CRS patients. CRSwNP and CRSsNP patients were included. Although both 12-week and 24-week treatment groups showed reduction in symptoms at early time points, only the 24-week treatment group demonstrated durable suppression of rhinorrhea and PND 12 months after ESS.

Few adverse events were noted in any published trials. Gastrointestinal disorders including mild diarrhea, vague abdominal discomfort, or nausea and vomiting were most

common, reported in less than 5% of all patients.753, 754, 761

In non-sinus studies, macrolides have been implicated in

causing ototoxicity764 _{and liver dysfunction.}765 _Concerns

about overuse resulting in host antibiotic resistance have

been raised.766 _{Perhaps most importantly, a growing}

body of literature has associated macrolide antibiotic use with ventricular arrhythmias and cardiac arrest, including azithromycin, which has a perceived lower risk

of cardiotoxicity.767, 768 _{These findings have resulted in}

an FDA advisory cautioning against the use of macrolides

in patients with high baseline cardiovascular risk.769

Finally, macrolides are metabolized by the liver and have known interactions with other medications, predominantly due to their inhibition of CYP 3A4–mediated activity

of cytochrome P-450.765 _{Warfarin, cisapride, benzodi-}

azepines, cyclosporine, antihistamines, and statins all have

previously reported minor interactions with macrolides.757

In summary, a few RCTs concerning macrolides in CRSsNP have been published and 2 have rather compelling findings about the short-term efficacy, whereas 1 shows no benefit. Careful review of the evidence demonstrates that most systematic reviews are based on these RCTs with conflicting results and a large number of noncontrolled cohort studies. The subgroup of CRSsNP patients that best benefit from macrolides is not currently known. Various drugs and dosages have been studied so that the optimal drug and dosages are also not currently known. Macrolides have significant side effects and contraindications. More- over, the long-term outcomes of macrolide-treated patients are not entirely known, with some evidence showing a lack of permanent effect. The efficacy of macrolides appear to differ by CRS phenotype, so that additional work will need to be performed in order to better clarify the balance between benefit and harm of macrolide therapy in CRSsNP (Table VII-16).

r

Aggregate Grade of Evidence: B (Level 1a: 2 studies;

Level 1b: 2 studies; Level 1a-2a: 2 studies; Level 2b: 3 studies).

r

_{Benefit: Reduction in endoscopy scores and some symp-}

toms in patients with CRSsNP, particularly in patients without elevated IgE. Effects appear to be comparable to INCS. Benefit may not last long following cessation of therapy.

r

Harm: Significant potential for medication interactions.

Rare mild adverse events. Potential for severe cardiovas- cular complications.

TABLE VII-16. Evidence for CRSsNP management with macrolide antibiotics

Study Year LOE Study design Study groups Clinical endpoint Conclusions

Cervin757 _{2014 1a Systematic review CRSsNP and CRSwNP: 2 RCTs;}

22 open/cohort studies

Support for macrolide use in refractory CRS in absence of high IgE levels Pynnonen756 _{2013 1a Meta-analysis of 3} RCTs CRSsNP and CRSwNP: 183 (3 studies) Insufficient evidence demonstrating a clinically significant impact of long-term macrolide therapy

Soler752 _{2013 1a Systematic review of}

RCTs and cohort studies

CRSsNP and CRSwNP: 2 RCTs; 15 open/cohort studies

Recommendation level: option (especially patients with low IgE)

Piromchai758 _{2011 1a Meta-analysis of 1}

study, involving macrolides

CRSsNP: 64 (1 study) 1. Clinical cure rate; 2. Improvement scale; 3. Bacteriological cure rate; 4. Radiographic response rate; 5. Relapse rate; 6. Adverse effects

Insufficient response to recommend the use of any kind of antibiotic in CRS

Haxel761 _{2015 1b RCT 1. Erythromycin 250 mg daily}

(n=29); 2. Placebo (n= 29)

1. ECP and MPO in nasal secretions; 2. Multiple other patient reported and clinical measures

Improved nasal endoscopy score. Duration or low-dose of this trial not efficacious. High chance of Type II error Ragab751 _{2004 1b RCT 1. Surgical treatment (n=}

45); 2. Erythromycin 500 mg BID, fluticasone 400μg BID (n=45)

1. SNOT-20; 2. VAS for symptoms; 3. Multiple other patient-reported and clinical measures

No difference in VAS or SNOT-20 between groups. CRSwNP better at 12 months in medical therapy group

Majima760 _{2012 2b Cohort study 1. Clarithromycin 200 mg}

daily (n=158); 2. Clarithromycin 200 mg daily+ S-carboxymethylcysteine daily (n=159) 1. SNOT-20; 2. CT score; 3. Subjective symptom score; 4. Nasal endoscopy findings

Combination group was more improved at 12 weeks. Improvement grew in both groups with longer treatment

Luo759 _{2011 2b Cohort study 1. Clarithromycin 250 mg}

daily (n=33)

1. Symptoms scores (VAS); 1. Nasal resistance; 2. IL-8, MPO levels; 3. SNOT-20; 4. SF-36

Improved symptoms and QoL CRSsNP patients. Reduction in IL-8 and MPO

Zeng715 _{2011 2b Cohort study 1. Mometasone furoate 200}

μg daily (n=21); 2. Clarithromycin 250 mg daily (n=22)

1. VAS; 2. Endoscopic score INCS and clarithromycin had comparable effect for CRSsNP

MPO=myeloperoxidase.

r

Cost: Low.

r

Benefits-Harm Assessment: Benefits appear to outweigh

harms. Benefit of treatment over placebo is seen in most but not all studies. Harm, though rare is significant.

r

Value Judgments: Macrolides appear to confer a benefit

in the short term. The benefit may not last following cessation of therapy. Optimal drug, dosage, and length of therapy are not known.

r

Policy Level: Option.

r

Intervention: Macrolides are an option for patients with

CRSsNP.

VII.E.4.d.

CRS Management with Antibiotics:

In document Modelo de negocios para la empresa Home Deko en la ciudad de Cuenca para el periodo 2017 2020 (página 108-126)