Ex Vivo Toxicity of Commonly Used Topical Antiseptics and Antibiotics on Human Chondrocytes.

Topical povidone-iodine, chlorhexidine, bacitracin, and vancomycin are commonly used antiseptic and antimicrobial agents to reduce risk and treat surgical site infections in numerous orthopedic procedures. Chondrocytes potentially may be exposed to these agents during operative procedures. The impact of these topical agents on chondrocyte viability is unclear. The goal of this study is to determine human chondrocyte viability ex vivo after exposure to commonly used concentrations of these topical antiseptic and antimicrobial agents. Human osteochondral plugs were harvested from the knee joint of a human decedent within 36 hours of death. Individual human osteochondral plugs were exposed to normal saline as a control; a range of concentrations of povidone-iodine (0.25%, 0.5%, and 1%), chlorhexidine (0.01% and 0.5%), and bacitracin (10,000 units/L, 50,000 units/L, and 100,000 units/L) for 1-minute lavage; or a 48-hour soak in vancomycin (0.16 mg/mL, 0.4 mg/mL, and 1.0 mg/mL) with nutrient media. Chondrocyte viability was evaluated with a live/dead viability assay at 0, 2, 4, and 6 days after exposure to bacitracin at 0, 3, and 6 days). Control subjects showed greater than 70% viability at all time points. Povidone-iodine, 0.5% chlorhexidine, and vancomycin showed significant cytotoxicity, with viability dropping to less than 40% by day 6. Chondrocytes exposed to 0.01% chlorhexidine maintained viability. Chondrocytes exposed to bacitracin showed viability until day 3, when there was a large drop in viability. Commonly used topical concentrations of povidone-iodine, vancomycin, and bacitracin are toxic to human chondrocytes ex vivo. A low concentration of chlorhexidine appears safe. Caution should be used when articular cartilage may be exposed to these agents during surgery. [Orthopedics. 2022;45(5):e263-e268.].

Validation of putative genomic biomarkers of nephrotoxicity in rats.

Drug-induced renal injury is a common finding in the early preclinical phase of drug development. But the specific genes responding to renal injury remain poorly defined. Identification of drug-induced gene changes is critical to provide insights into molecular mechanisms and detection of renal damage. To identify genes associated with the development of drug-induced nephrotoxicity, a literature survey was conducted and a panel of 48 genes was selected based on gene expression changes in multiple published studies. Male Sprague-Dawley rats were dosed daily for 1, 3 or 5 days to the known nephrotoxicants gentamicin, bacitracin, vancomycin and cisplatin, or the known hepatotoxicants ketoconazole, 1-naphthyl isothiocyanate and 4,4-diaminodiphenylmethane. Histopathological evaluation and clinical chemistry revealed renal proximal tubular necrosis in rats treated with the nephrotoxicants, but not from those treated with the hepatotoxicants. RNA was extracted from the kidney, and RT-PCR was performed to evaluate expression profiles of the selected genes. Among the genes examined, 24 genes are confirmed to be highly induced or repressed in rats treated with nephrotoxicants; further investigation identified that 5 of the 24 genes were also altered by hepatotoxicants. These data led to the identification of a set of genomic biomarker candidates whose expression in kidney is selectively regulated only by nephrotoxicants. Among those genes displaying the highest expression changes specifically in nephrotoxicant-treated rats were kidney injury molecule 1 (Kim1), lipocalin 2 (Lcn2), and osteopontin (Spp1). The establishment of such a genomic marker set offers a new tool in our ongoing quest to monitor nephrotoxicity.

Toxic effects of wound irrigation solutions on cultured tibiae and osteoblasts.

Irrigating wounds with solutions of antiseptic or antibiotic agents is routinely performed in orthopaedic surgery to reduce the incidence of microbial infection. The effects of these agents on healthy bone tissue is unknown. Three commonly employed antiseptic agents (hydrogen peroxide, Betadine solution, Betadine scrub) and one antibiotic solution (bacitracin) were tested on tibiae and osteoblasts isolated from embryonic chicks. Osteoblast function was evaluated by glycolytic energy metabolism (lactate production), cell number (DNA content), and collagen synthesis ([3H]proline hydroxylation). Two series of experiments were performed. To study concentration-related effects, tibiae or cells were exposed to a range of concentrations of the agents (diluted in saline, 0.9% NaCl) for 2 min, rinsed with saline, and incubated for 24 h in medium containing [3H]proline. For the recovery study, the cells were exposed to an effective, but nonlethal, concentration of the antiseptic agents for 2 min, rinsed with saline, and the incubation was continued in complete culture medium for 6, 12, 24, 48, or 72 h with [3H]proline added for the final 6 h. Solutions containing the antiseptic agents were cytotoxic to both bones and cells at concentrations well below those used clinically in irrigation solutions. In contrast, bacitracin at the concentrations tested was safe for osteoblasts and tibiae. These results suggest that the use of irrigation solutions containing H2O2, Betadine solution, or Betadine scrub on exposed bone tissue should be considered with caution.

Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction.

The cell surface of mammalian cells is capable of reductively cleaving disulfide bonds of exogenous membrane-bound macromolecules (for instance, the interchain disulfide of diphtheria toxin), and inhibiting this process with membrane-impermeant sulfhydryl reagents prevents diphtheria toxin cytotoxicity. More recently it was found that the same membrane function can be inhibited by bacitracin, an inhibitor of protein disulfide-isomerase (PDI), and by monoclonal antibodies against PDI, suggesting that PDI catalyzes a thiol-disulfide interchange between its thiols and the disulfides of membrane-bound macromolecules. We provide evidence that the same reductive process plays a role in the penetration of membrane-bound human immunodeficiency virus (HIV) and show that HIV infection of human lymphoid cells is markedly inhibited by the membrane-impermeant sulfhydryl blocker 5,5'-dithiobis(2-nitrobenzoic acid), by bacitracin, and by anti-PDI antibodies. The results imply that HIV and its target cell engage in a thiol-disulfide interchange mediated by PDI and that the reduction of critical disulfides in viral envelope glycoproteins may be the initial event that triggers conformational changes required for HIV entry and cell infection. These findings suggest additional approaches to impede cell infection by HIV.

Topical antimicrobial toxicity.

Three topical antibiotics and four antiseptics (1% povidone-iodine, 0.25% acetic acid, 3% hydrogen peroxide, and 0.5% sodium hypochlorite) were directly applied to cultured human fibroblasts to quantitatively assess their cytotoxicity. The four antiseptics were found to be cytotoxic; all of the cytotoxic agents except hydrogen peroxide were subsequently found to adversely affect wound healing in an animal model. Comparison of bactericidal and cytotoxic effects of serial dilutions of these four topical agents indicated the cellular toxicity of hydrogen peroxide and acetic acid exceeded their bactericidal potency. Bactericidal noncytotoxic dilutions of povidone-iodine and sodium hypochlorite were identified. These experiments provide evidence that 1% povidone-iodine, 3% hydrogen peroxide, 0.5% sodium hypochlorite, and 0.25% acetic acid are unsuitable for use in wound care. This sequence of experiments could be used to identify bactericidal, noncytotoxic agents prior to their clinical use.

[Chemotherapeutic intolerance]. / Chemotherapeutische Unverträglichkeiten

Incombatibility reactions can be observed in almost all antibiotics and chemotherapeutics. Kind and severity oftthe side effects depend on the terrain component and on the particular antibiotics. Clinical distinctions were made between allergic, toxic and dysmicrobial reactions. Special attention was given to nephrotoxicity and to the side effects of the combination of trimethoprim and sulfomethoxazol.