Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Among Patients With Acute Otitis Externa: A Randomized Clinical Trial.

Importance: Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution seems to be efficacious and safe in treating acute otitis externa (AOE) compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone. Objective: To evaluate the superiority of ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone in treating AOE. Design, Setting, and Participants: A phase 3 randomized, double-blind, active-controlled clinical trial was conducted between August 1, 2017, and September 14, 2018, at 36 centers in the US. The study population comprised 493 patients aged 6 months or older with AOE of less than 21 days' duration with otorrhea, moderate or severe otalgia, and edema, as well as a Brighton grading of II or III (tympanic membrane obscure but without systemic illness). Statistical analysis was performed from November 14, 2018, to February 14, 2019. Interventions: Participants were randomly assigned to receive ciprofloxacin plus fluocinolone, ciprofloxacin, or fluocinolone twice daily for 7 days and were evaluated on day 1 (visit 1; baseline), days 3 to 4 (visit 2; conducted via telephone), days 8 to 10 (visit 3; end of treatment), and days 15 to 17 (visit 4; test of cure). Main Outcomes and Measures: The primary outcome was therapeutic cure (clinical and microbiological) at the end of the treatment period. The principal secondary end point was the time to end of ear pain. Efficacy analyses were conducted in the microbiological intent-to-treat population, clinical intent-to-treat population, and microbiological intent-to-treat population with Pseudomonas aeruginosa and Staphylococcus aureus. Results: A total of 493 patients (254 female patients [51.5%]; mean [SD] age, 38.2 [23.1] years) were randomized (197 to receive ciprofloxacin plus fluocinolone, 196 to receive ciprofloxacin, and 100 to receive fluocinolone). Therapeutic cure in the modified intent-to-treat population with ciprofloxacin plus fluocinolone (63 of 103 [61.2%]) was statistically comparable to that of ciprofloxacin (49 of 91 [53.8%]; difference in response rate, 7.3%; 95% CI, -6.6% to 21.2%; P = .30) and fluocinolone (20 of 45 [44.4%]; difference in response rate, 16.7%; 95% CI, -0.6% to 34.0%; P = .06) at visit 3 and significantly superior to ciprofloxacin at visit 4 (90 of 103 [87.4%] vs 69 of 91 [75.8%]; difference in response rate, 11.6%; 95% CI, 0.7%-22.4%; P = .04). A statistically faster resolution of otalgia was achieved among patients treated with ciprofloxacin plus fluocinolone (median, 5.0 days [range, 4.2-6.3 days]) vs ciprofloxacin (median, 5.9 days [range, 4.3-7.3 days]; 95% CI, 4.3-7.3 days; P = .002) or fluocinolone (median, 7.7 days [range, 6.7-9.0 days]; 95% CI, 6.7-9.0 days; P < .001). Ciprofloxacin plus fluocinolone demonstrated statistical superiority in sustained microbiological response vs ciprofloxacin (94 of 103 [91.3%] vs 74 of 91 [81.3%]; difference in response rate, 9.9%; 95% CI, 0.3%-19.6%; P = .04) and fluocinolone (34 of 45 [75.6%]; difference in response rate, 15.7%; 95% CI, 2.0%-29.4%; P = .01) and in the microbiological outcome vs fluocinolone by visit 3 (99 of 103 [96.1%] vs 37 of 45 [82.2%]; difference in response rate, 13.9%; 95% CI, 2.1%-25.7%; P = .01) and ciprofloxacin by visit 4 (97 of 103 [94.2%] vs 77 of 91 [84.6%]; difference in response rate, 9.6%; 95% CI, 0.9%-18.2%; P = .02). Fifteen adverse events related to study medications were registered, all of which were mild or moderate. Conclusions and Relevance: Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution was efficacious and safe in treating AOE but did not demonstrate superiority vs ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solutions alone in the main study end point of therapeutic cure. Trial Registration: ClinicalTrials.gov Identifier: NCT03196973.

Retrospective analysis of outcomes of outpatient parenteral antimicrobial therapy (OPAT) for necrotising otitis externa.

Necrotising otitis externa (NOE) is an uncommon but life-threatening infection that requires prolonged systemic antimicrobial therapy. This study aims to identify factors associated with treatment response and outcome in patients with NOE treated through outpatient parenteral antimicrobial therapy (OPAT). We performed a retrospective analysis of patients with NOE treated over a 4-year period (January 2018-January 2022) at a tertiary referral hospital in Derbyshire, UK. We defined OPAT failure as unplanned readmission within 30 days of discontinuation of OPAT. Prolonged duration of therapy was defined as length of parenteral antimicrobial treatment of more than 8 weeks. A total of 46 cases of NOE were reviewed. OPAT failure and prolonged therapy were recorded in 9 (19.6%) and 23 (50.0%) episodes respectively. Facial nerve involvement (odds ratio [OR], 14.54; 95% confidence interval [CI], 2.76-76.60; p = 0.002), dementia (OR, 7.65; 95% CI, 1.23-47.46; p = 0.029), Charlson comorbidity score (OR, 1.41 per unit increase; 95% CI, 1.00-2.00; p = 0.049) and peak CRP level (OR, 1.03 per unit increase; 95% CI, 1.00-1.06; p = 0.027) were associated with increased risk of treatment failure. Facial nerve involvement (OR, 16.30; 95% CI, 2.60-102.31; p = 0.003) and peak CRP level (OR, 1.04; 95% CI, 1.01-1.07; p = 0.016) were also associated with an increased need for prolonged antimicrobial therapy. In addition, extent of disease (based on imaging findings) was linked to prolonged therapy (OR, 22.89; 95% CI, 3.62-144.76; p = 0.001). NOE could be effectively managed as outpatient via OPAT. However, vigorous antimicrobial treatment and close monitoring of patients with pre-existing comorbidities, facial nerve paralysis, extensive disease and markedly elevated inflammatory markers are essential to optimise clinical outcomes.

IL-36 signaling in keratinocytes controls early IL-23 production in psoriasis-like dermatitis.

IL-36R signaling plays an important role in the pathogenesis of psoriasis. We ought to assess the specific function of IL-36R in keratinocytes for the pathology of Aldara-induced psoriasis-like dermatitis. Il36r ΔK mice presenting deletion of IL-36R in keratinocytes were similarly resistant to Aldara-induced ear inflammation as Il36r -/- mice, but acanthosis was only prevented in Il36r -/- mice. FACS analysis revealed that IL-36R signaling in keratinocytes is mandatory for early neutrophil infiltration in Aldara-treated ears. RNASeq and qRT-PCR experiments demonstrated the crucial role of IL-36R signaling in keratinocytes for induction of IL-23, IL-17, and IL-22 at early time points. Taken together, our results demonstrate that IL-36R signaling in keratinocytes plays a major role in the induction of Aldara-induced psoriasis-like dermatitis by triggering early production of IL-23/IL-17/IL-22 cytokines and neutrophil infiltration.

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation.

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

External auditory canal stenosis due to the use of powdered boric acid.

Acquired stenosis of the external auditory canal (EAC) may occur because of chronic external otitis, recurrent chronic catarrhal otitis media associated with tympanic membrane perforation, chronic dermatitis, tumors, and trauma. Stenosis occurs generally at the one-third bone part of the external auditory canal. In this article, we present 3 cases of acquired EAC stenosis due to the previous powdered boric acid application. Besides the presentation of surgical intervetions in these cases, we want to notify the physicians not to use or carefully use powdered boric acid because of the complication of EAC stenosis.

Cantharidin-induced inflammation in mouse ear model for translational research of novel anti-inflammatories.

The murine model of cantharidin-induced ear inflammation was profiled in detail for its alignment with the human model and to explore the mechanism of anti-inflammatory activity of the macrolide antibiotics, clarithromycin and azithromycin. Ear swelling in CD1 mice persisted for 7 days, with peak intensity at 16 h after inflammation induction. As in humans, cantharidin (12.5 µg/ear) generated macrophage-inflammatory protein (MIP)-2, monocyte chemoattractant protein (MCP)-1, keratinocyte-derived chemokine (KC), interleukin (IL)-6, IL-1ß, and myeloperoxidase (MPO) production, as well as neutrophil accumulation in mouse ear tissue. The tested macrolides, clarithromycin and azithromycin, administered orally (2 × 150 mg/kg) 0.5 h before and 5 h after cantharidin challenge, reduced MIP-2, MCP-1, KC, and MPO concentrations and thereby decreased ear swelling. Our results suggest that cantharidin-induced acute inflammation represents an excellent model for translational research of novel anti-inflammatories.

Anti-inflammatory activity of seed essential oil from Zizyphus jujuba.

This study was undertaken to evaluate the effect of essential oil from seeds of Zizyphus jujuba on TPA-induced skin inflammation in experimental mice. Exposure of TPA on the ear of the BALB/c mice caused a marked increase in both ear thickness and skin water content. The ear thickness was measured for TPA-induced ear was 0.54 mm, as compared to control (0.23 mm). Treatment with 1% and 10% of essential oil caused significant decrease in ear thicknesses which were measured to be 0.30 and 0.35 mm, as well as reduce the water content about 51% and 53% in the TPA-induced skin inflammation model, respectively. Furthermore, histological analysis clearly confirmed that Z. jujuba essential oil inhibited the inflammatory responses of skin inflammation in animal model. Therefore, our findings demonstrate that the essential oil of Z. jujuba seeds might accelerate the development of new drugs for various inflammatory diseases.

In vivo efficacy study of the anti-inflammatory properties of Surolan.

This study evaluated the anti-inflammatory properties of Surolan with the use of a pinna model of inflammation in 80 mice and a randomized complete block design. Within each of 8 blocks, 10 treatments, consisting of different combinations of the constituents of Surolan with and without the prednisolone acetate component, were randomly assigned to the 9-wk-old CD-1 mice. The treatments were administered as a single dose 30 min after pinna inflammation was induced with tetradecanoylphorbol acetate. Ear-skin edema and erythema were assessed and measured 4 and 6 h thereafter. Treatment effects were evaluated with repeated-measures analysis of variance. Inclusion of prednisolone acetate with the Surolan vehicle, either alone or in combination with the nonsteroidal constituents of the suspension, resulted in a significant reduction in mean ear-skin thickness and erythema. The inflammation-reducing properties of prednisolone were not significantly affected by the other components of Surolan.

Topical anti-inflammatory activity of 2alpha-hydroxy pentacyclic triterpene acids from the leaves of Ugni molinae.

Leaf extracts of Ugni molinae Turcz. are used in the Chilean cosmetic industry on the assumption that they have decongestant, regenerative, and anti-aging properties. A bioassay-guided fractionation of this plant material showed that some extracts have potent anti-inflammatory activities. Further fractionation led to the isolation and identification of betulinic acid, a mixture of ursolic and oleanolic acids, and the 2alpha-hydroxy derivatives alphitolic, asiatic, and corosolic acids. The latter three were evaluated in vivo in the mouse ear assay for their topical anti-inflammatory activity, inducing inflammation with either arachidonic acid (AA) or 12-O-tetradecanoylphorbol-13 acetate (TPA). Only corosolic acid was active in the AA assay, with similar potency to nimesulide, but all three triterpene acids inhibited TPA-induced inflammation with potencies comparable to that of indomethacin.

Potential of atelocollagen-mediated systemic antisense therapeutics for inflammatory disease.

To study the possibility of using atelocollagen as an oligonucleotide (ODN) delivery carrier in vivo, the activity of formulated antisense ODN targeted against the intercellular adhesion molecule-1 (ICAM-1) mRNA was investigated in an allergic dermatitis model in mice. The allergic dermatitis was elicited in one ear of animals sensitized by treatment with 2,4-dinitrofluorobenzene. Antisense ODN was given to the animals as a single intravenous injection of formulation containing atelocollagen. Antisense activity was determined by measurement of ear thickness, histopathology, and immunohistochemistry 24 hr after the initiation of the dermatitis. Antisense activity was found to increase according to the concentration of atelocollagen in the formulation. The effect mediated by the ODN formulated with 0.05% atelocollagen was more than 50 times greater than that provided by ODN infusion, although the levels of ODN formulated with atelocollagen dropped below that of the 24-hr infusion group within 30 min. The formulated ODN could suppress inflammatory progression by treatment at 8 hr after the ear challenge when inflammation had already commenced at the challenged site. Moreover, antisense activity was noted even when the formulated ODN was injected 3 days before the initiation of inflammation. These data demonstrate that atelocollagen can enhance antisense activity remarkably and that the sustainable antisense activity mediated by the formulation of ODN with atelocollagen could completely change the strategy of antisense therapeutics.

[Sarcoidal allergic contact dermatitis due to palladium following ear piercing]. / Sarkoidale allergische Kontaktdermatitis auf Palladium nach Ohrpiercing.

Granulomatous tissue reactions due to jewelry made of gold, silver, nickel and palladium are rare but nevertheless have been known for a long time. A female patient developed nodular infiltrates after having been pierced with ear stickers containing palladium. A contact allergic reaction could be demonstrated as the underlying cause by inducing similar histological changes following patch testing with palladium.

Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse.

The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (Ptgs2). Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid. However, they develop severe nephropathy and are susceptible to peritonitis.

Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration.

Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2.

Suppressive effects of central opioids on delayed type hypersensitivity to trinitrochlorobenzene: comparative study with morphine and electroacupuncture.

We reported previously that electroacupuncture (Acu) applied to the acu-point equivalent to GV4 in the mouse just before the 2,4,6-trinitrochlorobenzene (TNCB) challenge suppressed the delayed type hypersensitivity (DTH) through endogenous opioidergic systems in the brain, and the pituitary was pivotal in this immunosuppression. The purpose of the present study was to compare the suppressive effects of Acu with those of single, acute doses of morphine on TNCB-DTH in intact and hypophysectomized (HPX) mice. Subcutaneous morphine 10 mg/kg in ddY mice, 30 mg/kg in BALB/c mice or intracisternal morphine 40 micrograms/mouse in BALB/c mice given just before TNCB challenge suppressed (40-53%) the maximal extent of ear swelling at 24 hrs after challenge in intact mice. In HPX mice, the suppressive effects of intracisternal morphine 10 and 100 micrograms/mouse were less pronounced than those observed in intact mice and there was no significant difference between intact and HPX groups. In addition, suppressive effects observed with Acu or subcutaneous morphine (30 mg/kg) were effectively antagonized by pretreatment with intracisternal naloxone at a dose of as low as 2 micrograms/mouse. Naloxone alone had no effect of its own. These results suggest that 1) the activation of opioid receptor-mediated pathways in the brain, which occurs when opioids are endogenously released (Acu) or exogenously given (morphine), is important in the suppression of TNCB-induced DTH, a cell-mediated immune response, and 2) the pituitary is less pivotal in the suppressive effects of acute morphine than in those of Acu.

A new assay for antiphlogistic activity: zymosan-induced mouse ear inflammation.

A new model of local inflammation has been developed: intradermal zymosan-induced mouse ear edema. The symptoms of inflammation induced by injecting zymosan into one of the ears were followed up for 72 h. The ear edema and the local accumulation of polymorphonuclear leukocytes' (PMN) marker enzyme, myeloperoxidase (MPO), were determined. Edema peaked at 4-6 h, while MPO activity peaked at 24 h after zymosan application. The correlation between inflammatory response and concentration of zymosan was also tested. Of the various concentrations tested, 1% suspension has been found optimal. Anti-inflammatory drugs and mediator antagonists were examined in order to establish the selectivity and sensitivity of the assay. A glucocorticoid (dexamethasone), two cyclooxygenase inhibitors (indomethacin, piroxicam) and an interleukin-1 (IL-1) release inhibitor (IX 207-887, Sandoz) all reduced edema and MPO activity as well. However, a lipoxygenase inhibitor (phenidone), a serotonin receptor antagonist (methysergide) and H1 and H2 receptor antagonists (clemastine and cimetidine, respectively) all failed to inhibit the reaction.

Study on the suppressive effect of iodine-enriched egg on LT-C4 production in arachidonic acid-induced ear inflammation.

The anti-inflammatory mechanism of iodine-enriched egg was investigated in mice by means of arachidonic acid-induced ear inflammation. The lipid fraction of iodine-enriched egg was capable of suppressing the increase in ear weight induced by arachidonic acid in a dose-dependent manner. The lipid fraction was further separated into neutral and polar lipid fractions. Of these two fractions, only the neutral lipid fraction was capable of suppressing LT-C4 production in arachidonic acid inflammation. Neither the neutral nor polar lipid fractions of ordinary egg, however, showed any anti-inflammatory effect. These results suggest that the anti-inflammatory activity of iodine-enriched egg is present in the neutral lipid fraction, and its mechanism is assumed to be inhibition of LT-C4 production.