Antibiotics And The Nervous System—Which Face Of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) Or Mr. Hyde (Neuroprotection)? Part 1

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim oftheir success. Their widespread abuse reduces their anti-infective effectiveness and causes thedevelopment of bacterial resistance. 

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One of the potential options for restoring homeostasis is the use of oral antibioticsthat are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapymay exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactamsand quinolones. 

Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus, or seizures. Their pathomechanism results from thedisturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similaritiesbetween the structure of the -lactam ring and GABA molecule) and impairment of the functioningof benzodiazepine receptors (BZD). 

Antibiotics may, therefore, become promisingelements of multi-targeted therapy for these entities.

1. Introduction. Antibiotics and Antibiotic-Induced Adverse Drug Reactions

Thediscovery of antibiotic agents and their introduction into clinical practice is considered tobe one of the greatest medical breakthroughs of the 20th century [1]. Mankind has usedantibacterial agents of natural origin since the dawn of its history, based on empiricalknowledge and centuries-old tradition in various healing systems (e.g., traditional Chinesemedicine and others). 

Traces of tetracyclines, incorporated into the hydroxyapatite mineralportion of bones, have been found in skeletal remains of ancient people (e.g., of the Romanperiod or even in Sudanese Nubian human remains dated back to 350–550 CE) [2]. 

These researchers became famous in the history of medicine with the introduction of the first modern, arsenic-based antimicrobial agent named Salvarsan, effectivein the treatment of syphilis (Ehrlich; 1909), the discovery of the sulfa drug, sulfonamidochrysoidine (Protonsil), endogenously releasing active sulfanilamide (Domagk; 1935;Nobel Prize laureate in Medicine or Physiology in 1939 for the development of antibacterialeffect of Protonsil) and the discovery of penicillin (Fleming; 1929; Nobel Prize laureate in Medicine or Physiology in 1945 for the discovery of penicillin and its curative effectin various infectious diseases) [2,3]. 

These "milestones" of antibiotic therapywould not have been possible without the prior work of other researchers, such as Antonievan Leeuwenhoek, Robert Hooke, Robert Koch, and Louis Pasteur who laid the basics formodern microbiology [3]. 

Then, "the golden age of antibiotic discovery" began, whichlasted for about 20 years and resulted in the introduction of most of the currently usedantibiotics in clinical practice. 

The twilight of this period, which also includes the presenttimes, is the aftermath and one of the fundamental problems of antibiotic therapy, i.e., thedevelopment of bacterial strains resistant to various antibiotics, which results in the lossof the anti-infective effectiveness of many of the preparations used so far. Uncontrolledinfectious diseases are again becoming an emerging problem in modern medicine. 

Estimates indicate that mortality rates due to multidrug-resistant bacterial infections havebecome increasingly higher-each year, about 25,000 of patients treated in the EU die frommultidrug-resistant bacterial-induced infections and in the USA about 63,000 deaths arecaused by hospital-acquired infections [2]. Currently, bacterial resistance is not limited toprimary inpatients but is especially true for outpatients. 

The ongoing antibiotic resistancecrisis is determined by various factors, the most important of which include excessiveand unreasonable antibiotic consumption (because in many countries antibioticsuse is unregulated and available over the counter without a rational medical recommendation), inappropriate prescribing, and extensive agricultural use (primarily to promote the growth of housed animals and to prevent infections) [4]. Complex genetic mechanisms,including plasmids, bacteriophages, naked DNA, or transposons, are the background forthe development of bacterial resistance to antibiotics. 

Spontaneous mutations are alsoan important cause, allowing the acquisition of bacterial resistance to antibiotics withoutthe exchange of genetic material between various strains [5]. The problem of widespreadbacterial resistance to many, if not most, antibiotics still used in the current therapy is amajor threat and disadvantage. 

To sum up, despite the undisputed benefits ofantibiotics, which have saved millions of lives from the consequences of infectious diseases,the current treatment of these diseases is becoming more and more challenging.Additionally, a significant problem of antibiotic therapy is the occurrence of manypossible antibiotic-related adverse drug reactions (ADR). 

ADRs appear in both outpatients and hospitalized patients and manifest a widespectrum of clinical entities, ranging from mild symptoms to life-threatening disorders.Estimates indicate that ADRs occur in 5–10% of cases of hospital admissions and, in asmany as 0.1–0.3% ADRs, may be serious and cause death [6–8].

Perhapsthe most characteristic of antibiotic-related ADRs are the symptoms caused by hypersensitivity and allergic reactions, which most often take the form of skin reactions (rash, hives,itching), but these can also be severe disorders such as angioedema or anaphylactic shock. 

Other characteristic antibiotic-induced ADRs are complex symptoms originating from thegastrointestinal tract (e.g., nausea, vomiting, bloating, diarrhea/constipation) determinedby the altered secretion, absorption, and motility due to dysbiosis. 

There are also reportedclass-specific (or even compound-specific) antibiotic-related ADRs, for example, the possibility of developing pseudomembranous colitis induced by Clostridium difficile colonizationafter application of antibiotics with broad antibacterial activity, aminoglycoside-associated renal toxicity, fluoroquinolone-related tendonitis and Achilles tendon rupture, myelosuppression after linezolid, cardiac arrhythmias induced by macrolides or diffuse interstitialpneumonitis, and pulmonary fibrosis that might be the consequence of nitrofurantoinadministration [9,10]. 

However, many antibiotics are considered to exert hepato- andnephrotoxicity, peripheral blood disorders (anemia, leukopenia, thrombocytopenia), orelectrolyte abnormalities. Among other potential ADRs induced during antibiotic therapy, uncommon, but possible, neurotoxicity should also be mentioned, mostly associatedwith the use of beta-lactams or quinolones. 

Post-antibiotic neurological disorders aremanifested by hearing loss or labyrinthine dysfunction (characteristic for erythromycinand azithromycin), and by ototoxicity and vestibular dysfunction (pathognomonic foraminoglycosides) or by other forms of neurotoxicity, affecting either peripheral or thecentral nervous system [11]. 

Generally, drug-induced neurological disorders (DIND) aremanifested by a very broad spectrum of disorders, e.g., cerebrovascular disease, delirium,headache, nerve and muscle disorders, movement disturbances, seizure attacks, sleepabnormalities, and others [12,13]. They are listed in Table 1 below. Among the potentialdrugs responsible for the development of DIND, antibiotics should also be mentioned. 

Most commonly, the above-mentioned aminoglycosides and macrolides are characterized by harmful potential toward the nervous system, but this also applies to quinolones,sulfonamides, penicillin, carbapenems, tetracyclines, oxazolidinones, polymyxins' andmetronidazole. These are listed in the next chapter. 

The pathogenesis underlying DIND is complex. To damage nervous system structures, a drug or its metabolites must either cross the blood-brain barrier (BBB) or becomeincorporated into the neuron by peripheral axonal uptake and retrograde axonal transport. 

These disturbances lead to the subsequentintracellular ion entry (Ca2+, Na+) and release of excitatory glutamate which in the "vicious circle" mechanism intensify already existing damage and activity of Ca2+-dependentcellular phenomena. 

Finally, the release of neurotransmitters (serotonin, noradrenaline,dopamine, acetylcholine) is disturbed and the calcium-dependent apoptotic processesof nerve cells occur. 

The triggering factors facilitating the DIND involve drug-relatedfactors (e.g., polydrug abuse, formation of neurotoxic metabolites during endogenous drugmetabolism) and individual-related factors (age, gender, gestational drug exposure, antioxidant status, diet) or influence of environmental conditions (chronic stress, temperature,exposure to environmental toxins and pollutions) [14,15].

2. Antibiotic-Related Neurotoxicity-A General Outline and Pathogenesis

Aswith other ADRs, antibiotic-induced neurological disorders are potentially reversible aslong as they are quickly recognized and corrected.The risk of post-antibiotic peripheral neuropathy occurs with prolonged administration of some antibiotics, e.g., metronidazole. Seizures, twitching, and hallucinations arepossible neurological ADRs caused mostly by penicillin, imipenem-cilastin, cephalosporins, or ciprofloxacin [11]. 

However, central nervous system toxicities were also demonstratedfor sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, metronidazole,isoniazid, rifampin, ethionamide, cyclo-serine, and dapsone. Cranial nerve toxicities, manifested by myopia, optic neuritis, deafness, vertigo, and tinnitus, were associated with theuse of erythromycin, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, vancomycin, isoniazid, and ethambutol. 

Antibiotic-related neurotoxicity depends on the dosing schedule and the functional status of the liver and kidneys.There are reports that penicillin G intravenous administration may lead to harmful effectson the central nervous system when given more than 50 million units per day in adults [16].The maximum recommended dose of imipenem-cilastin in adults with preserved renalfunction that does not cause neurological disorders is 4 g per day and estimates indicatethat seizures occurring in patients using this antibiotic occur in 2% of cases [17]. 

Similarly,fluoroquinolone use was found to be associated with seizures and headaches in 1–2% ofrecipients. The other, unusual effects observed in patients treated with fluoroquinolones(ofloxacin, sparfloxacin) included orofacial dyskinesia and a Tourette-like syndrome [18]. 

Neuromuscular blockade and the possibility of intensification of the action of intraoperative muscle relaxants is the most commonly known neurological ADR of aminoglycosides, but the symptoms were also demonstrated for tetracyclines, polymyxins, lincomycin, clindamycin, although to a much lesser extent. Thus, aminoglycosides should be avoided inpatients with inherited neuromuscular disturbances, e.g., myasthenia gravis [16]. 

Ototoxicity or vestibular dysfunction are also well-known neurological ADRs of aminoglycosides.These disturbances are usually dose- and frequency-dependent and correlated with otherrisk factors for cranial nerve VIII damage, such as advanced age, fever, anemia, baselinecreatinine level, and concomitant use of other ototoxic agents (e.g., furosemide, salicylate) [19–21]. 

Macrolides-erythromycin and azithromycin administration may cause bilateral hearing loss or labyrinthine dysfunction and vertigo, and patients with hepaticinsufficiency are especially predestined to develop these disturbances. 

In most cases, thesecomplications were described as dose-dependent and usually reversible within 2 weeksafter discontinuation of the treatment, although there have also been reports of irreversiblehearing loss [22–25].

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