[Role of chloramphenicol in current clinical practice].

INTRODUCTION: Chloramphenicol is an antibiotic with a broad spectrum of action and excellent tissue penetration. It had been widely used in clinical practice until the 1970s, but due to its potential myelotoxicity, it was gradually replaced by newly introduced antibiotics in the following years. The aim of the study was to find out to what extent and with what experience it is currently used in the Czech Republic. METHODS: A questionnaire survey was conducted in July and August 2022. The heads of all inpatient infectious diseases departments, hospital infectious diseases specialists and consulting microbiologists from antibiotic centers in large teaching hospitals without an infectious diseases department were asked to fill out the questionnaire. RESULTS: Thirty-five out of 39 hospitals contacted took part in the study, a response rate of 90 %. Chloramphenicol is used in 37 % of participating hospitals, with a frequency of up to 10 patients treated per year. The most common indications are brain abscesses, purulent meningitis, intra-abdominal, pelvic and lung abscesses, and polymicrobial infections with anaerobes. Chloramphenicol is almost always administered as an alternative antibiotic because of polyvalent allergy, bacterial resistance, and failure of previous treatment. Sixty-six percent of respondents described the effect as reliable or partially reliable, 34 % did not rate the effect. Fifty-two percent of respondents considered a dose of 8-9 g to be the maximum dose for an adult patient. In practice, 60 % of respondents did not encounter or could not assess the myelotoxic effects of chloramphenicol, 37 % observed reversible bone marrow suppression at least once, and only one respondent encountered aplastic anemia once. CONCLUSION: Unfortunately, chloramphenicol is currently used in less than half of hospitals in the Czech Republic. Because of its unique properties, it still has a place in today's anti-infective treatment. When properly indicated and after weighing the benefits and risks, it can be a suitable and sometimes life-saving alternative.

Characterization of antimicrobial resistance markers & their stability in Salmonella enterica serovar Typhi.

BACKGROUND & OBJECTIVES: Typhoid fever is a major cause of morbidity and mortality in the developing countries including India. Resistance to multiple antimicrobial agents is an emerging global problem that has serious impact on the treatment of disease. There are many factors associated with the emergence of resistance. Most important of them is the acquisition and further transmission and spread of resistance markers among various bacterial species. Therefore, we conducted this study to characterize the resistance plasmids in terms of their transferability and stability among Salmonella enterica serovar Typhi. METHODS: Six multidrug-resistant S. Typhi isolates were evaluated for the stability and transfer of resistance markers. The resistance plasmids were also checked for the presence of RepHI1A replicon. RESULTS: All resistance markers were found to be transferred to the recipient through conjugation and transformation, except for nalidixic acid. None of the resistance plasmid was found to harbour RepHI1A replicon and therefore, did not belong to incompatibility group IncHI1. Resistance markers were found to be highly stable in all the isolates during serial passages and storage as stab cultures at different temperatures for different time periods. INTERPRETATION & CONCLUSIONS: Resistance markers for chloramphenicol, ampicillin, streptomycin and trimethoprim were transferred through conjugation as well as transformation whereas that for nalidixic acid was not transferred in any of the isolates. Markers for chloramphenicol and streptomycin resistance were found to be most stable during various storage conditions. Presence of small-sized non-IncHI1 resistance plasmids is a matter of concern due to their capability to exist inside the host, thereby increasing the possibility of their transmission and spread among S. Typhi and other bacterial species.

Novel Hybrid Peptide Cecropin A (1-8)-LL37 (17-30) with Potential Antibacterial Activity.

Hybridizing different antimicrobial peptides (AMPs) is a particularly successful approach to obtain novel AMPs with increased antimicrobial activity but minimized cytotoxicity. The hybrid peptide cecropin A (1-8)-LL37 (17-30) (C-L) combining the hydrophobic N-terminal fragment of cecropin A (C) with the core antimicrobial fragment of LL37 (L) was designed and synthesized. C-L showed higher antibacterial activity against all indicator strains than C and L, and no hemolytic activity to sheep erythrocytes was observed. C-L kills bacterial cells and causes disruption of surface structure, as determined by scanning electron microscopy. Synergistic effects were observed in the combination of C-L with several antibiotics (chloramphenicol, thiamphenicol, or neomycin sulfate) against Escherichia coli and Staphylococcus aureus.

Efficacy and safety of chloramphenicol: joining the revival of old antibiotics? Systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Chloramphenicol is an old broad-spectrum antibiotic. We assessed its efficacy and safety. METHODS: This was a systematic review and meta-analysis. Electronic databases were searched to identify randomized controlled trials (RCTs) that assessed patients, of any age, with systemic bacterial infections that can cause sepsis and compared chloramphenicol alone versus other antibiotics. No restrictions on the date of publication, language or publication status were applied. The primary outcome assessed was overall mortality. RESULTS: Sixty-six RCTs fulfilled the inclusion criteria, and these included 9711 patients. We found a higher mortality with chloramphenicol for respiratory tract infections [risk ratio (RR) 1.40, 95% CI 1.00-1.97] and meningitis (RR 1.27, 95% CI 1.00-1.60), both without heterogeneity. The point estimate was similar for enteric fever, without statistical significance. No statistically significant difference was found between chloramphenicol and other antibiotics regarding treatment failure, except for enteric fever (RR 1.46, 95% CI 1.07-2.00, without heterogeneity). This difference derived mainly from studies comparing chloramphenicol with fluoroquinolones (RR 1.85, 95% CI 1.07-3.2). There were no statistically significant differences between chloramphenicol and other antibiotics in terms of adverse events, including haematological events, except for anaemia, which occurred more frequently with chloramphenicol (RR 2.80, 95% CI 1.65-4.75, I(2) =0%), and gastrointestinal side effects, which were less frequent with chloramphenicol (RR 0.67, 95% CI 0.46-0.99, I(2) =0%). Many of the studies included were sponsored by pharmaceutical companies marketing the comparator drug to chloramphenicol, and this might have influenced the results. CONCLUSIONS: Chloramphenicol cannot be recommended as a first-line treatment for respiratory tract infections, meningitis or enteric fever as alternatives are probably more effective. Chloramphenicol is as safe as treatment alternatives for short antibiotic courses. RCTs are needed to test this treatment against MDR organisms when better alternatives do not exist.

Chloramphenicol use and susceptibility patterns in Israel: a national survey.

BACKGROUND: Due to increasing antimicrobial resistance, there has been renewed interest in old drugs that have fallen into disuse because of toxic side effects. One such drug is chloramphenicol. Data on the use and susceptibility patterns to chloramphenicol in developed countries in recent years are limited. OBJECTIVES: To assess the susceptibility of bacteria to chloramphenicol, and evaluate the use of chloramphenicol in Israeli hospitals as influenced by infectious disease specialists' attitudes with regard to its potential harms. METHODS: A national survey was conducted in all Israeli hospitals. Questionnaires were sent to the directors of infectious disease units and included items on chloramphenicol susceptibility in clinical isolates, use of chloramphenicol for the treatment of inpatients, local recommendations for use of chloramphenicol, and concerns regarding side effects. RESULTS: Chloramphenicol is used in 83.3% of hospitals, mostly for the treatment of aspiration pneumonia. While 22.2% of infectious disease unit directors believe that chloramphenicol should be avoided because of dangerous side effects, 88.9% believe there is a place for chloramphenicol in the treatment of patients in this era of increasing antibiotic resistance. Chloramphenicol susceptibility is routinely assessed in 44.4% of hospitals, with high susceptibility rates found among gram-positive, gram-negative and anaerobic bacteria. CONCLUSIONS: In an era of increasing antibiotic resistance, many Israeli infectious disease unit directors believe that chloramphenicol has a role in the treatment of respiratory tract and other infections in hospitalized patients.

Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs.

OBJECTIVE: To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. STUDY DESIGN: Non-randomized, sequential design. ANIMALS: Six healthy Greyhound dogs (three male, three female). METHODS: Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. RESULTS: Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment.

Neurological manifestation of phenytoin toxicity, resulting from drug interaction with chloramphenicol: a case report.

Phenytoin toxicity masquerading as deterioration of neurological symptoms caused by interaction with chloramphenicol is a very rare but real risk. To the authors' knowledge only one such case occurring in humans has been reported in the English literature. No case of clinical phenytoin toxicity occurring at less than double the serum phenytoin therapeutic levels, occurring as a result of chlorampenicol interaction has been documented, hence our report. A 17 year old man, whose frontal subdural empyema had been drained, had his seizures well controlled on phenytoin. Shortly after, he had a parasagital subdural empyema which was also drained. He was put on chloramphenicol. He improved tremendously until he then developed cerebellar symptoms. Phenytoin levels were noted to be almost twice the maximum therapeutic value. On stopping chloramphenicol, phenytoin levels normalized and symptoms resolved. Possibility of phenytoin toxicity should always be entertained in patients who are also taking chlorampenicol, presenting with new or worsening neurological symptoms.

Randomized Controlled Trial of Azithromycin versus Doxycycline or Chloramphenicol for Treatment of Uncomplicated Pediatric Scrub Typhus.

OBJECTIVE: To evaluate the efficacy and safety of azithromycinfor treatment of uncomplicated pediatric scrub typhus. MATERIAL AND METHOD: A randomized controlled trial was performed. We compared azithromycin with doxycycline or chloramphenicol in uncomplicated pediatric scrub typhus from inpatient pediatric department of Chiangrai Prachanukroh Hospital. The primary outcome was cure rate at day 3. The secondary outcomes were timing to defervescence within 72 hours, side effects, and relapsed rate. We compared data between both groups with Fisher's exact test or Mann-Whitney U test, and failure rate was demonstrated by Kaplan-Meier survival curve and Log-rank test. RESULTS: We included 57 patients, ofwhom, 28 were assigned to doxycycline or chloramphenicol (control group) and 29 to azithromycin (study group). The baseline characteristics of both groups were similar The cure rate was 85.7% in the doxycycline or chloramphenicol group, as compared to 79.3% in the azithromycin group (p = 0.73), and a median time to defervescence was 30 hours (IQR 21, 48) vs. 36 hours (IQR 20, 68) respectively (p = 0.166). There was a little minor side effect in azithromycin group. No relapsed was found in either groups. CONCLUSION: Azithromycin was as effective as doxycycline or chloramphenicol in treatment of uncomplicated pediatric scrub typhus.

High error rates in selenocysteine insertion in mammalian cells treated with the antibiotic doxycycline, chloramphenicol, or geneticin.

Antibiotics target bacteria by interfering with essential processes such as translation, but their effects on translation in mammalian cells are less well characterized. We found that doxycycline, chloramphenicol, and Geneticin (G418) interfered with insertion of selenocysteine (Sec), which is encoded by the stop codon, UGA, into selenoproteins in murine EMT6 cells. Treatment of EMT6 cells with these antibiotics reduced enzymatic activities and Sec insertion into thioredoxin reductase 1 (TR1) and glutathione peroxidase 1 (GPx1). However, these proteins were differentially affected due to varying errors in Sec insertion at UGA. In the presence of doxycycline, chloramphenicol, or G418, the Sec-containing form of TR1 decreased, whereas the arginine-containing and truncated forms of this protein increased. We also detected antibiotic-specific misinsertion of cysteine and tryptophan. Furthermore, misinsertion of arginine in place of Sec was commonly observed in GPx1 and glutathione peroxidase 4. TR1 was the most affected and GPx1 was the least affected by these translation errors. These observations were consistent with the differential use of two Sec tRNA isoforms and their distinct roles in supporting accuracy of Sec insertion into selenoproteins. The data reveal widespread errors in inserting Sec into proteins and in dysregulation of selenoprotein expression and function upon antibiotic treatment.

Changes in behavior and hematological parameters of freshwater African catfish Clarias gariepinus (Burchell 1822) following sublethal exposure to chloramphenicol.

The present study was aimed at evaluating the effects of different concentrations of the most commonly used fish antimicrobial drug, chloramphenicol (CAP), on the behavior and hematological parameters of Clarias gariepinus. Fish specimens were exposed to three (2.5, 5.0 and 10.0 mg L(-1)) sublethal concentrations of CAP and a control. Abnormal behavioral changes were observed in fish exposed to higher concentration of CAP. Blood erythrocytes were sampled on days 1, 5, 10 and 15 postexposure to evaluate hematological parameters. Results showed concentration- and time-dependent significant increase in packed cell volume after day 5 of exposure (p < 0.05). Hemoglobin values also significantly decreased from day 5, whereas values of mean cellular volume significantly decreased throughout the experimental period (p < 0.05). A mixed trend was observed in the mean values of red blood cells, white blood cells, mean cellular hemoglobin and mean cellular hemoglobin concentration as well as neutrophils. Activities of lymphocytes were significantly increased in all CAP-treated fish during the exposure period, whereas no significant differences were observed in values of monocytes, eosinophils and basophils among the treatment groups and control. Consequently, precautions must be taken, especially when high concentrations of CAP are used in long-term treatments of C. gariepinus in aquaculture.

Mitochondrial translational inhibitors in the pharmacopeia.

The vast majority of energy necessary for cellular function is produced in the mitochondria by the phosphorylation of ADP to ATP. Other critical mitochondrial functions include apoptosis and free-radical production. Chemical agents, including those found in the modern pharmacopeia, may impair mitochondrial function by a number of mechanisms. The mitochondria are vulnerable to environmental injury because of their complex physical structure, electrochemical properties of the inner mitochondrial membrane (IMM), dual genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) and inherent properties of the translational and transcriptional machinery. Mitochondria have evolved from alpha-proteobacteria and the residual structural similarity to bacterial translational machinery has left the mtDNA genes vulnerable to inhibition by commonly used translation-targeted antibiotics. Many of these medications cause adverse effects in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of the spectrum of disease caused by inhibition of mitochondrial translation and improve the safe and effective use of antibiotics that inhibit bacterial and human mitochondrial translation. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.

Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components.

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.

A meta-analysis comparing the safety and efficacy of azithromycin over the alternate drugs used for treatment of uncomplicated enteric fever.

BACKGROUND: Drug-resistant typhoid fever is a major clinical problem globally. Emergence of multidrug-resistant (MDR) S. Typhi has complicated therapy by limiting treatment options. OBJECTIVES: A meta-analysis was planned to determine the strength of evidence supporting use of azithromycin over the alternate drugs available for treatment of uncomplicated typhoid fever. MATERIALS AND METHODS: Studies were identified using electronic database such as MEDLINE and other data at the National Library of Medicine assessed using PUBMED search engine as well as Cochrane Clinical Trial Register. Randomized control trials (RCTs) comparing azithromycin with chloramphenicol, fluoroquinolones and cephalosporins in culture-proven enteric fever were included. Data was extracted and methodological quality was assessed. Risk ratio (RR) with 95% confidence intervals was estimated for the dichotomous outcomes and mean difference (MD) with 95% confidence was estimated for continuous data. Primary outcomes studied were clinical failure (CF), microbiological failure, and relapse. RESULTS: A total of seven RCTs involving 773 patients met with our inclusion criteria. In comparison to older fluoroquinolones, azithromycin is marginally better in reducing the chance of CF with RR 0.46 (95% CI 0.25-0.82), while in comparison to ceftriaxone, it significantly reduced the chance of relapse with RR 0.1 (95% CI 0.01- 0.76). There were no serious adverse events reported in any of the trials. CONCLUSION: Azithromycin can be recommended as a second-line drug in MDR typhoid fever, however, large trials involving pediatric age group patients are recommended to arrive at a definite conclusion.

The efficacy and tolerability of antibiotics in scrub typhus: an updated network meta-analysis of randomized controlled trials.

OBJECTIVES: Inadequate treatment of scrub typhus results in severe complications such as septic shock and is also associated with a high median mortality rate of 6%. However, there has been no conclusive evidence about the superiority of different antibiotics in managing scrub typhus in terms of efficacy and tolerability. METHODS: We conducted a network meta-analysis (NMA) using the frequentist method. The included participants were pediatric and adult patients infected with scrub typhus. The primary outcome was the cure rate in the patients included. The subgroup analysis was done according to pediatric or adult patients. RESULTS: Overall, 14 randomized controlled trials (RCTs) with 1264 participants were included in this study. The NMA revealed that all the investigated antibiotics were associated with cure rates similar to those of doxycycline. The chloramphenicol and minocycline were ranked to be associated with the highest cure rate in the pediatric subgroup and adult subgroup, respectively. Second-generation quinolones, including ofloxacin, ciprofloxacin, and chloramphenicol, were associated with significantly lower adverse event rates than doxycycline. CONCLUSION: The current updated NMA provides evidence for the efficacy of chloramphenicol and minocycline in scrub typhus management. However, future large-scale RCTs with longer follow-up times are warranted.

Unsafe "crossover-use" of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action.

Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies. Therefore, a One Health approach is required to understand the wider impact of community antibiotic use and improve overall effectiveness of intervention policy and regulatory action.

Evaluation of the Acute Effects and Oxidative Stress Responses of Phenicol Antibiotics and Suspended Particles in Daphnia magna.

Suspended particles (SP) exist widely in various water systems and are able to adsorb other pollutants in water, producing ecotoxic effects on aquatic nontarget species. Until now, however, few studies have focused on the effects of SP on antibiotics. Therefore, the present study investigated the effects of the mixtures of SP and phenicol antibiotics (chloramphenicol [CAP], thiamphenicol [TAP]) on acute toxicity and oxidative stress responses in Daphnia magna. The results indicated that the acute toxicity of phenicol antibiotics in D. magna was increased when combined with SP. Besides, the immobilization of daphnids caused by phenicol drugs in the presence of 10 mg/L of SP was more intense than that with 200 mg/L of SP. Furthermore, the impact of SP with diverse concentrations on the activity of catalase and the level of reduced glutathione in D. magna was different. Notably, almost all CAP + TAP + SP treatments markedly increased malondialdehyde content in D. magna, causing potential cellular oxidative damage in D. magna. In summary, the present study provides insights into the toxic effects of phenicol antibiotic and SP mixtures on aquatic organisms. Environ Toxicol Chem 2021;40:2463-2473. © 2021 SETAC.

A worldwide systematic review and meta-analysis of bacteria related to antibiotic-associated diarrhea in hospitalized patients.

INTRODUCTION: Antibiotic-associated diarrhea (AAD) is a major hospital problem and a common adverse effect of antibiotic treatment. The aim of this study was to investigate the prevalence of the most important bacteria that cause AAD in hospitalized patients. MATERIALS AND METHODS: PubMed, Web of Science and Scopus databases were searched using multiple relevant keywords and screening carried out based on inclusion/exclusion criteria from March 2001 to October 2021. The random-effects model was used to conduct the meta-analysis. RESULTS: Of the 7,377 identified articles, 56 met the inclusion criteria. Pooling all studies, the prevalence of Clostridioides (Clostridium) difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus as AAD-related bacteria among hospitalized patients were 19.6%, 14.9%, 27%, and 5.2%, respectively. The prevalence of all four bacteria was higher in Europe compared to other continents. The highest resistance of C. difficile was estimated to ciprofloxacin and the lowest resistances were reported to chloramphenicol, vancomycin, and metronidazole. There was no or little data on antibiotic resistance of other bacteria. CONCLUSIONS: The results of this study emphasize the need for a surveillance program, as well as timely public and hospital health measures in order to control and treat AAD infections.