Unresolved gustatory, olfactory and auditory adverse drug reactions to antibiotic drugs: a survey of spontaneous reporting to Eudravigilance

Objectives: Sensory adverse drug reactions (ADRs) are generally expected to be transient in nature. However, spontaneous reports describe frequently these events as long-lasting or unresolved. In this study, the authors reviewed the Eudravigilance publicly accessible database to describe the volume and expectedness of potentially unresolved outcomes for gustatory, olfactory and auditory (GOA) suspected ADRs associated with antibiotics for systemic use. Methods: ‘Overall’ and ‘GOA’ suspected ADRs were extracted from Eudravigilance to estimate the distribution of their outcomes among different antibiotic groups. Then, the authors identified the drugs contributing to at least 15% of all suspected GOA ADRs observed for the antibiotic groups, and evaluated the expectedness. Results: The frequency of persistent/permanent outcomes was higher for GOA suspected ADRs, as compared to the overall ones. Unresolved and undetermined outcomes for antibiotic-associated GOA ADRs in Eudravigilance might hide a large number of events with underestimated clinical consequences. Several persistent/permanent antibiotic-associated GOA reactions could be classified as serious and unexpected. Conclusion: Potential long-lasting or irreversible GOA reactions are often reported for all antibiotics drugs. Further studies are warranted to clarify whether this is an actual safety issue or simply it reflects a general difficulty in outcomes assessment for such reactions.</p

Representative photomicrographs of full-thickness normal rat colon showing the distribution pattern of collagen fibers stained with van Gieson (VG, A-D), Sirius Red (SR, E-H) and Sirius Red/Fast Green (SR/FG, I-L).

<p>CM and LM: circular and longitudinal muscle, respectively; MP: myenteric plexus. Scale bars represent 50 μm. Scatter plots show the percentage of positive pixel (PPP) of collagen ± SEM obtained from 6 rats in the whole colonic wall (M) and <i>tunica muscularis</i> (N). *,° P = 0.028 <i>versus</i> VG and SR, respectively.</p

Representative photomicrographs of full-thickness inflamed rat colon showing the distribution pattern of collagen fibers stained with van Gieson (VG, A-D), Sirius Red (SR, E-H) or Sirius Red/Fast Green (SR/FG, I-L).

<p>CM and LM: circular and longitudinal muscle, respectively; MP: myenteric plexus. Scale bars represent 50μm. Scatter plots show the percentage of positive pixel (PPP) of collagen ± SEM obtained from 6 rats in the whole colonic wall (M) and <i>tunica muscularis</i> (N). *,° P = 0.028 <i>versus</i> VG and SR, respectively.</p

Representative photomicrographs of haematoxylin/eosin-stained full-thickness colonic samples from normal rats (A,B), or rats with DNBS-induced colitis at day 6 (C,D).

<p>Normal colon displays a normal morphological architecture of the wall and myenteric ganglia. In the inflamed colon, the following alterations are evident: infiltrated <i>tunica submucosa</i>; thickened and infiltrated <i>tunica muscularis</i> and <i>serosa</i>; vacuolated myenteric ganglia with altered cells and abundant eosinophilic infiltrations along the myenteric ridge (D, arrows and arrowheads, respectively). Scale bars represent 50 μm.</p

Cx43 immunostaining and quantitative analysis in the neuromuscular compartment of normal and diverticular disease human colon.

<p>In normal colon, appreciable amounts of Cx43 are expressed in the circular (CM) and longitudinal muscle (LM) (A), while Cx43 expression is decreased in samples from DD colon (B); scale bar: 100 µm. At higher magnification (C–F), SMCs show a punctuated immunoreactivity, which is localized at the membrane (arrows), cytoplasmic (asterisks), paranuclear and nuclear (arrowheads) level; scale bars: 50 µm. (G) Image analysis of Cx43 expression. Each column represents the PPP mean ± SD (8</p

Positive control tissues for immunohistochemistry.

<p>(A,B) The crypts of normal human colon were selected as control positive structures for Cx26 (A) and Cx43 (B): immunoreactivity is evident in the ephitelial cells of crypts (arrows). (C) Human myocardium was used as positive control for pS368-Cx43: immunoreactivity is localized at level of intercalated disks (arrows); immunoreactivity of myocardium for Cx43 is displayed in the box. (D) A human myenteric neuron, taken as a positive control cell for PKC, displays an intense PKCps immunoreaction. (E) A granulocyte of normal colon, chosen as positive control for RhoA, is markedly immunoreactive. (F) Mast cells (arrows), locked in the <i>tunica muscularis</i> of human normal colon, show a strong immunoreaction for c-Kit. In the same field an intramuscular c-Kit positive ICC is also evident (arrowhead). Scale bar: 50 µm.</p

RhoA immunostaining and quantitative expression in the neuromuscular compartment of normal and diverticular disease human colon.

<p>In normal colon, RhoA is expressed in the circular (CM) and longitudinal muscle (LM) (A), while it is reduced in DD (B); scale bar: 100 µm. At higher magnification, SMCs show a dotted immunoreactivity localized at the membrane (arrows) and cytoplasmic (asterisks) level in normal colon (C,E), while in DD samples the localization is mainly evident in the cytoplasm (asterisks) (D,F); scale bars: 50 µm. (G) Image analysis of RhoA expression. Each column represents the PPP mean ± SD (9</p

Smooth muscle α-actin (α-SMA) immunostaining.

<p>α-SMA is equally expressed in circular (CM) and longitudinal muscle (LM) of normal (A) and diverticular disease (DD) (B) human colon. Scale bar: 100 µm.</p

PKC phosphorylated substrates immunostaining and quantitative analysis in the neuromuscular compartment of normal and diverticular disease human colon.

<p>In normal colon, PKCps immunostaining is expressed in both circular (CM) and longitudinal muscle (LM) (A), while it is reduced in DD (B); scale bars: 100 µm. Myenteric neurons (arrows) are intensely immunostained. (C) Image analysis of PKCps expression. Each column represents the PPP mean ± SD (9</p

Cx43 phosphorylated at serine 368 (pS368-Cx43) immunostaining.

<p>No immunoreactivity is evident in the <i>tunica muscularis</i> of normal (A) and DD (B) human colon; scale bar: 100 µm. (C–D).</p