Adverse Effects of Antimicrobials via Predictable or Idiosyncratic Inhibition of Host Mitochondrial Components

Abstract

This minireview explores mitochondria as a site for antibiotic-host interactions that lead to pathophysiologic responses manifested as nonantibacterial side effects. Mitochondrion-based side effects are possibly related to the notion that these organelles are archaic bacterial ancestors or commandeered remnants that have co-evolved in eukaryotic cells; thus, this minireview focuses on mitochondrial damage that may be analogous to the antibacterial effects of the drugs. Special attention is devoted to aminoglycosides, chloramphenicol, and fluoroquinolones and their respective single side effects related to mitochondrial disturbances. Linezolid/oxazolidinone multisystemic toxicity is also discussed. Aminoglycosides and oxazolidinones are inhibitors of bacterial ribosomes, and some of their side effects appear to be based on direct inhibition of mitochondrial ribosomes. Chloramphenicol and fluoroquinolones target bacterial ribosomes and gyrases/topoisomerases, respectively, both of which are present in mitochondria. However, the side effects of chloramphenicol and the fluoroquinolones appear to be based on idiosyncratic damage to host mitochondria. Nonetheless, it appears that mitochondrion-associated side effects are a potential aspect of antibiotics whose targets are shared by prokaryotes and mitochondria-an important consideration for future drug design. SIDE EFFECTS OF ANTIBACTERIAL DRUGST he desired activity of an antibiotic is to kill or prevent the growth of offending pathogenic bacteria, and yet these drugs may impact the host in an injurious manner. Generalized adverse events are common to most antibiotics (e.g., gastrointestinal distress with any oral antibacterial drug), but certain antibiotics are associated with specific effects (Table 1). Some adverse events are mild, e.g., yellowing of the teeth for tetracyclines (77, 79), increased intestinal peristalsis related to erythromycin therapy (7, 67), and reversible orange discoloration of skin and body fluids as observed with rifampin treatment (23, 31). Altered drug metabolism (106) is a common side effect that, in the absence of co-drug therapy, could also be considered mild. More serious side effects include photosensitivity (44) and anaphylactoid reactions (34) observed with many agents, ototoxicity (27, 83) following aminoglycoside therapy, chondrotoxicity (85, 88) and retinopathy (95) with fluoroquinolones, neuropathies associated with metronidazole (30, 107) and linezolid (15), and lactic acidosis and serotonin syndrome attributed to linezolid (21, 61). Other consequences can be severe or even devastating such as: the dermonecrolytic Stevens-Johnson syndrome associated with sulfonamide antimicrobial agents (74, 81); nephrotoxicity related to aminoglycosides (63, 73); aplastic anemia due to chloramphenicol (9, 91); hepatitis caused by many drugs, including isoniazid (72, 89); neuromuscular blockade related to aminoglycoside (64, 65) or lincosamide (4, 70) therapy; myopathies due to ionophores (5, 28, 75); and neoplasia related to metronidazole (19)....

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