Florfenicol Enhances Colonization of a Salmonella enterica Serovar Enteritidis floR Mutant with Major Alterations to the Intestinal Microbiota and Metabolome in Neonatal Chickens.

Florfenicol is an important antibiotic commonly used in poultry production to prevent and treat Salmonella infection. However, oral administration of florfenicol may alter the animals' natural microbiota and metabolome, thereby reducing intestinal colonization resistance and increasing susceptibility to Salmonella infection. In this study, we determined the effect of florfenicol (30 mg/kg of body weight) on gut colonization of neonatal chickens challenged with Salmonella enterica subsp. enterica serovar Enteritidis. We then analyzed the microbial community structure and metabolic profiles of cecal contents using microbial 16S amplicon sequencing and liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics, respectively. We also screened the marker metabolites using a multi-omics technique and assessed the effect of these markers on intestinal colonization by S. Enteritidis. Florfenicol administration significantly increased the loads of S. Enteritidis in cecal contents, spleen, and liver and prolonged the residence of S. Enteritidis. Moreover, florfenicol significantly affected cecal colony structures, with reduced abundances of Lactobacillus and Bacteroidetes and increased levels of Clostridia, Clostridium, and Dorea. The metabolome was greatly influenced by florfenicol administration, and perturbation in metabolic pathways related to linoleic acid metabolism (linoleic acid, conjugated linoleic acid [CLA], 12,13-EpOME, and 12,13-diHOME) was most prominently detected. We screened CLA and 12,13-diHOME as marker metabolites, which were highly associated with Lactobacillus, Clostridium, and Dorea. Supplementation with CLA maintained intestinal integrity, reduced intestinal inflammation, and accelerated Salmonella clearance from the gut and remission of enteropathy, whereas treatment with 12,13-diHOME promoted intestinal inflammation and disrupted intestinal barrier function to sustain Salmonella infection. Thus, these results highlight that florfenicol alters the intestinal microbiota and metabolism of neonatal chickens and promotes Salmonella infection mainly by affecting linoleic acid metabolism. IMPORTANCE Florfenicol is a broad-spectrum fluorine derivative of chloramphenicol frequently used in poultry to prevent/treat Salmonella. However, oral administration of florfenicol may lead to alterations in the microbiota and metabolome in the chicken intestine, thereby reducing colonization resistance to Salmonella infection, and the possible mechanisms linking antibiotics and Salmonella colonization in poultry have not yet been fully elucidated. In the current study, we show that increased colonization by S. Enteritidis in chickens administered florfenicol is associated with large shifts in the gut microbiota and metabolic profiles. The most influential linoleic acid metabolism is highly associated with the abundances of Lactobacillus, Clostridium, and Dorea in the intestine. The screened target metabolites in linoleic acid metabolism affect S. Enteritidis colonization, intestinal inflammation, and intestinal barrier function. Our findings provide a better understanding of the susceptibility of animal species to Salmonella after antibiotic intervention, which may help to elucidate infection mechanisms that are important for both animal and human health.

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.

Effects of oral florfenicol on intestinal structure, function and microbiota in mice.

Many kinds of antibiotics have effects on intestinal structure and function. In the current experimental study, we evaluate the effect of oral florfenicol on intestinal barrier in mice. Thirty adult male mice were randomly divided into two groups, the group none (N) and the group florfenicol (F), the mice in group F were orally administered florfenicol 100 mg/kg body weight (BW) for 7 days. At day 8, mice were euthanized and sampled for the analysis of alterations in genes and proteins from jejunum, jejunum morphology and microbiota analysis. Administration of florfenicol caused higher liver index (P < 0.05). In the jejunum, mucosa injury and villus rupture, compared with the group N, the villus length and V/C (villus length/crypt depth) in group F were marked decrease (P < 0.01). The transcription level of Muc2 and occludin in group F were significantly lower than those in group N (P < 0.01 or P < 0.05). The expression of APRIL, IL-17, IL-22, BAFF and sIgA on protein level were significantly down-regulated (P < 0.01 or P < 0.05), while the expression of IL-10, TGF-ß, IL-6, IL-4 were significantly up-regulated (P < 0.01) in group F. The abundances of bacteria in Firmicutes and Lactobacillus decreased significantly (P < 0.01) in group F. Our results indicated that oral administration of florfenicol might have a negative impact on functions of intestinal mucosal barrier, immune system and the intestinal microbiota.

Oral administration of antibiotics increased the potential mobility of bacterial resistance genes in the gut of the fish Piaractus mesopotamicus.

BACKGROUND: Aquaculture is on the rise worldwide, and the use of antibiotics is fostering higher production intensity. However, recent findings suggest that the use of antibiotics comes at the price of increased antibiotic resistance. Yet, the effect of the oral administration of antibiotics on the mobility of microbial resistance genes in the fish gut is not well understood. In the present study, Piaractus mesopotamicus was used as a model to evaluate the effect of the antimicrobial florfenicol on the diversity of the gut microbiome as well as antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) using a metagenomic approach. RESULTS: The total relative abundance of ARGs and MGEs significantly increased during the antibiotic exposure. Additionally, phage integrases, transposases, and transposons flanking ARGs accumulated in the gut microbiome of P. mesopotamicus because of the antibiotic exposure. MGEs co-occurring with ARGs showed a significant positive correlation with the total ARGs found. Furthermore, shifts in the gut microbiome towards well-known putative pathogens such as Salmonella, Plesiomonas, and Citrobacter were observed following florfenicol treatment. Mainly Plesiomonas and Citrobacter harbored genes that code for multidrug and phenicol efflux pumps. Moreover, several genes related to RNA processing and modification, cell motility, SOS response, and extracellular structure were enriched due to the antibiotic application. The observed effects were visible during the complete application phase and disappeared at the post-exposure phase. CONCLUSIONS: Our findings suggest that the oral administration of antibiotics increases the potential for MGE-mediated exchange of ARGs in the gut of fish and could contribute to the enrichment and dispersion of ARGs in aquaculture systems. Importantly, this increase in the potential for ARGs exchange could be an effect of changes in community structure and/or ARG mobilization.

Molecular ecological network analysis reveals the effects of probiotics and florfenicol on intestinal microbiota homeostasis: An example of sea cucumber.

Animal gut harbors diverse microbes that play crucial roles in the nutrition uptake, metabolism, and the regulation of host immune responses. The intestinal microbiota homeostasis is critical for health but poorly understood. Probiotics Paracoccus marcusii DB11 and Bacillus cereus G19, and antibiotics florfenicol did not significantly impact species richness and the diversity of intestinal microbiota of sea cucumber, in comparison with those in the control group by high-throughput sequencing. Molecular ecological network analysis indicated that P. marcusii DB11 supplementation may lead to sub-module integration and the formation of a large, new sub-module, and enhance species-species interactions and connecter and module hub numbers. B. cereus G19 supplementation decreased sub-module numbers, and increased the number of species-species interactions and module hubs. Sea cucumber treated with florfenicol were shown to have only one connecter and the lowest number of operational taxonomic units (OTUs) and species-species interactions within the ecological network. These results suggested that P. marcusii DB11 or B. cereus G19 may promote intestinal microbiota homeostasis by improving modularity, enhancing species-species interactions and increasing the number of connecters and/or module hubs within the network. In contrast, the use of florfenicol can lead to homeostatic collapse through the deterioration of the ecological network.

Investigating the potential role of vitamin E in modulating the immunosuppressive effects of tylvalosin and florfenicol in broiler chickens.

Tylvalosin (TVS) is a third-generation macrolide drug used for prophylaxis and treatment of mycoplasma, however; it is supposed to possess an immunosuppressive effect. In the current study, the immunosuppressive effect of TVS and florfenicol (FFC) and the potential immunomodulatory role of Vit E were investigated. The experiment included one day old chick groups treated with either TVS, FFC, Vit E, TVS/Vit E, FFC/Vit E and control non-treated group. Chicks were vaccinated with inactivated H9N2 avian influenza (AI) vaccine and humoral antibody titers to viral antigen as well as innate immunity (serum lysozyme activity and nitric oxide levels) were evaluated. Total and differential leucocytic counts, serum liver enzymes level, blood leucocytic DNA damage and cellular area percentages within the lymphoid organs were also screened. Treatment with TVS and FFC significantly decreased immune response of chickens while treatment with Vit E improved the humoral immune response at 4 and 5weeks post-vaccination. Vit E also significantly increased the cellular immune response. The combination of Vit E with either TVS or FFC modulated their immunosuppressive effect and resulted in mild immunostimulatory effects. TVS alone induced a genotoxic effect on chickens' blood leucocytes and the genotoxicity was inhibited by combination of TVS with Vit E. Histopathology revealed that chickens treated with either TVS or FFC exhibited toxic effect on the lymphatic tissues.

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.

Determination of florfenicol residues in broiler meat and liver samples using RP-HPLC with UV-visible detection.

BACKGROUND: Broilers are vulnerable to various types of microorganisms, including Salmonella, Escherichia coli and Staphylococcus aureus, resulting in multiple infections. Broad-spectrum antibacterial drugs such as florfenicol (FF) are widely used in the treatment of such infections. Suspected residues of these drugs in body tissues of treated birds can be passed to humans through meat consumption and thus lead to serious ill effects on human health. The present study was designed to estimate the presence of FF residues in broiler meat and liver samples. RESULTS: The mean residual concentrations of FF in broiler meat and liver samples were 311.42 ± 186.56 and 2585.44 ± 1759.71 µg kg(-1) respectively, which are higher than their respective maximum residual limits (MRLs). The results showed that 126 and 24 samples were FF-positive and FF-negative respectively. Of the positive samples, 84 and 42 samples were above and below the MRL respectively. CONCLUSION: The results indicate the presence of FF residues in broiler meat and liver samples. Usage of this contaminated meat causes resistance in consumers and poses a public health threat. Thus there is a need to educate farmers about the ill effects of residual drugs on human health and their withdrawal times in poultry. © 2015 Society of Chemical Industry.

Florfenicol induces early embryonic death in eggs collected from treated hens.

BACKGROUND: Florfenicol, a commonly used veterinary antibiotic, was reported to have caused a severe drop in egg hatchability following its off-label use on a broiler breeder farm in South Africa. According to the pharmacovigilance report, hatchability dropped by 80 % for up to a week following a five day course at 10 mg/kg (both males and females treated metaphylactically) to manage an Escherichia coli infection. While mammalian toxicity studies indicate the potential for early embryonic death in utero or testicular damage, no literature is available on the avian toxicity of florfenicol. For this study we investigated the effects of florfenicol at various doses from 10 to 90 mg/kg on the egg hatchability in a breeder flock we kept and established under controlled conditions, with the same cockerels and hens being exposed in a phased manner. RESULTS: Following five days of oral exposure, no toxic signs were evident in any of the cockerels or hens treated at doses up to 90 mg/kg. Treatment of only the cockerels had no effect on egg hatchability, while treatment of only the hens at doses of 60 and 90 mg/kg resulted in decreased hatchability of 0 % in comparison to 70 % of the control as early 24 h after treatment. In all cases, decreased hatchability was associated with embryonic death at 5 days of development. The toxic effects of florfenicol were completely reversible with comparable hatchability being present by day 4 post-treatment withdrawal. Toxicity correlated with total egg florfenicol concentrations with an LC50 of 1.07 µg/g. CONCLUSION: Florfenicol appears to be toxic to the developing chick embryo at around day 5 of incubation, in the absence of related toxicity in the hen or cockerel.

Toxicity to the hematopoietic and lymphoid organs of piglets treated with a therapeutic dose of florfenicol.

Florfenicol (FLO) is a broad-spectrum antibacterial agent for treatment of bacteriosis of piglets in veterinary practice. To study the toxicity to the hematopoietic and lymphoid organs of piglets treated with a therapeutic dose of FLO, 20 healthy weaned piglets were selected and randomly divided into two groups. Piglets in the FLO group were fed with fodder supplemented with 30mg/kg BW of FLO twice a day for 10 days. Blood samples were drawn at four time points: 1 day before FLO administration and 1, 7, and 14 days post-withdrawal. Three or four piglets were euthanized at each time point post-withdrawal and tissue samples (bone marrow, thymus and spleen) were collected for fixation and cryostorage. The levels of classical swine fever virus (CSFV) antibody against the vaccine, the concentrations of Hsp70 and IL-6 in serum and Hsp70 in tissues, and the mRNA expression levels of B-cell lymphoma 2 (bcl-2) and tumor suppressor p53 were detected, the hematology of the piglets were analyzed, and the histopathology and the status of apoptosis of the hematopoietic and lymphoid organs was examined. The results showed changes in several indicators in the FLO group 1 day post-withdrawal: the concentration of red blood cells (RBCs) was decreased, and that of platelets (PLTs) was significantly lower (p<0.05); the volumes of RBC and PLT were increased; the sum of blood lymphocytes was statistically decreased (p<0.05); the concentration of IL-6 was significantly increased (p<0.05); the concentrations of Hsp70 in serum and tissues were increased; obvious atrophy of the hematopoietic cell lines and partial replacement by fat cells were observed in bone marrow; thymus and spleen tissues showed lower concentrations and sparser arrangement of lymphocytes in the thymic medulla and white pulp of the spleen respectively; and the mRNA expression levels of bcl-2 in the three tissues were up-regulated, while that of p53 was down-regulated. With time after cessation of FLO administration, the indicators of the FLO group gradually returned to close to that of the control group and the histological lesions of the tissues gradually recovered, and the differences in the densities of lymphocytes and cell arrangements in the tissues between two groups gradually decreased. In conclusion, a therapeutic dose of FLO induces temporary toxicity in the hematopoietic and lymphoid organs of piglets to some extent, and influences hemopoiesis and immune function. These effects gradually decrease after cessation of FLO administration.

Treatment of naturally occurring bovine respiratory disease in juvenile calves with a single administration of a florfenicol plus flunixin meglumine formulation.

The efficacy and safety of a florfenicol plus flunixin meglumine formulation in the treatment of respiratory disease was evaluated in calves less than six weeks of age, compared with a positive control group treated with a well-established florfenicol formulation. A total of 210 calves, selected from nine sites in Belgium, France and Spain, showing severe signs of respiratory disease, were randomly assigned to treatment with either florfenicol plus flunixin meglumine (Resflor; MSD Animal Health) or florfenicol (Nuflor; MSD Animal Health), both administered subcutaneously once. Animals were clinically observed daily for 10 days following treatment initiation. The predominant respiratory pathogens were Pasteurella multocida, Mycoplasma bovis, Mannheimia haemolytica and Histophilus somni. All isolates were subject to in vitro sensitivity testing and found susceptible to florfenicol. In both groups, rectal temperature dropped and clinical index (depression and respiratory signs) significantly improved after treatment. Specifically, for the change in rectal temperature from pretreatment to six hours post-treatment, the florfenicol-flunixin formulation was found significantly superior to florfenicol. Moreover, the florfenicol-flunixin formulation alleviated the clinical signs of disease more rapidly, and was demonstrated to be non-inferior to florfenicol on days 4 and 10. The use of the product combining florfenicol and flunixin in calves is safe and efficacious in the treatment of outbreaks of bovine respiratory disease.

Safety of florfenicol administered in feed to tilapia (Oreochromis sp.).

The safety of Aquaflor(®) (50% w/w florfenicol [FFC]) incorporated in feed then administered to tilapia for 20 days (2× the recommended duration) at 0, 15, 45, or 75 mg/kg body weight/day (0, 1, 3, or 5× the recommended dose of 15 mg FFC/kg BW/d) was investigated. Mortality, behavioral change, feed consumption, body size, and gross and microscopic lesions were determined. Estimated delivered doses were >96.9% of target. Three unscheduled mortalities occurred but were considered incidental since FFC-related findings were not identified. Feed consumption was only affected during the last 10 dosing days when the 45 and 75 mg/kg groups consumed only 62.5% and 55.3% of the feed offered, respectively. There were significant, dose-dependent reductions in body size in the FFC-dose groups relative to the controls. Treatment-related histopathological findings included increased severity of lamellar epithelial hyperplasia, increased incidence of lamellar adhesions, decreased incidence of lamellar telangiectasis in the gills, increased glycogen-type and lipid-type hepatocellular vacuolation in the liver, decreased lymphocytes, increased blast cells, and increased individual cell necrosis in the anterior kidney, and tubular epithelial degeneration and mineralization in the posterior kidney. These changes are likely to be of minimal clinical relevance, given the lack of mortality or morbidity observed. This study has shown that FFC, when administered in feed to tilapia at the recommended dose (15 mg FFC/kg BW/day) for 10 days would be well tolerated.

Efficacy and safety of a new 450 mg/ml florfenicol formulation administered intramuscularly in the treatment of bacterial bovine respiratory disease.

The objective of the study was the safety and efficacy evaluation of a new 450 mg/ml florfenicol formulation in the treatment of naturally occurring respiratory disease when administered intramuscularly, compared with a positive control group treated with the well-established 300 mg/ml formulation. A total of 174 calves, selected from five sites in France and Spain, aged from 1 to 17 months, showing severe signs of respiratory disease, were randomly assigned to treatment with either the 300 mg/ml (3 ml/45 kg; Nuflor; MSD Animal Health) or 450 mg/ml (2 ml/45 kg; Nuflor Minidose; MSD Animal Health) florfenicol formulation, both administered intramuscularly twice, two days apart. Animals were clinically observed daily for 14 days following treatment initiation. The predominant pathogens present in pretreatment respiratory tract samples were Mannheimia haemolytica and Pasteurella multocida. Mycoplasma bovis and Histophilus somni were also present. All isolates were subjected to in vitro sensitivity testing and found susceptible to florfenicol. In both treatment groups, rectal temperature dropped and clinical index (depression and respiratory signs) significantly improved (P<0.05) after treatment. As a result, 97.7 per cent of the 450 mg/ml florfenicol formulation-treated animals were considered treatment successes on day 5. On day 14, 67.82 per cent of the animals were classified as treatment successes and among them 63.22 per cent were cured. The intramuscular injection of the new 450 mg/ml florfenicol formulation was found equally efficacious as the original 300 mg/ml formulation.

Aerosol therapy with thiamphenicol glycinate: a retrospective study on efficacy and safety in a group of sixty-six oncological patients.

The purpose of this paper is to present the effectiveness of aerosol administration of TG in a group of oncological patients. Thiamphenicol is an antimicrobial agent active in the treatment of infection of different etiology and localisation due to its broad spectrum of antimicrobial activity as well as its pharmacokinetic properties. The data of the retrospective study analysis of the activity of TG, administered to oncological patients affected by infections of the respiratory tract, showed that TG administered alone or in association with other antibiotics was globally effective in more than 95% of patients. These positive results were obtained in immunologically compromised patients. The therapeutic advantages of using TG are: ease of use - aerosol therapy permits good local action; tolerability - no adverse reaction or intolerance; the possibility of using it in an ideal association with other antibiotics to combat the infectious pathology.

Safety of florfenicol in the adult lobster (Homarus americanus).

Aerococcus viridans, the causative agent of the disease gaffkemia, was a major cause of mortality in lobsters (Homarus americanus) held in tidal impoundments during the 1970s and 1980s. Despite reports of an increase in the mortality of lobsters during impoundment, and the widespread prophylactic use of oxytetracycline against A. viridans, this bacterium has not been detected in active disease surveillance of the Maine postcapture lobster population. However, Photobacterium indicum may be an emerging opportunistic pathogen of stressed lobsters. An acute toxicity trial was conducted as a rapid screening procedure for the potential future use of the antibiotic florfenicol. Based on the results of this experiment, florfenicol appears to be well tolerated in adult H. americanus by intrapericardial injection at the 10-100 mg/kg dose. Oxytetracycline dihydrate is contraindicated by intrapericardial injection at the 10-100 mg/kg dose.

Aerosol antibiotic therapy in children with chronic upper airway infections: a potential alternative to surgery.

Tonsillectomy and adenoidectomy remain the first choice treatment of chronic or recurrent acute infections of the upper respiratory tract in children. The aim of this study is to investigate the efficacy of the combination of thiamphenicol glycinate acetylcysteinate plus beclomethasone, administered as aerosol, in children awaiting tonsillectomy and/or adenoidectomy. The study comprised 204 children, aged 1 to 12 years, with chronic adenotonsillitis who had been listed for surgery due to obstructive symptoms and recurrent acute infections. Patients were randomized to treatment with thiamphenicol glycinate acetylcysteinate, dosage 250 mg/day in 2 administrations plus beclomethasone with a dosage of 400 microg/day in 2 administrations, or no treatment, control group, unless required. The drugs were administered by aerosol for 10 days/month over a period of 6 months. Clinical visits were at 4, 7 and 12 months after the start of treatment. The primary efficacy outcome was the reduction in the number of patients requiring surgery. Secondary efficacy measures were the reduction of nasal obstruction, the decrease in the number of infectious episodes and the tolerability of the treatment. Aerosol treatment with thiamphenicol glycinate acetylcysteinate plus beclomethasone resulted in a significantly lower proportion of patients requiring surgery (29 of 101; 29 percent) compared to patients in the control group (100 of 103; 97 percent) (p < 0.0001). Treatment was also associated with a reduction of nasal obstruction and a decrease in the number of infectious episodes. No treatment-related adverse events were reported and the aerosol therapy proved easy to administer to children. The aerosol therapy with the combination of thiamphenicol glycinate acetylcysteinate plus beclomethasone was able to prevent or postpone surgery in a substantial percentage of patients, without adverse events. These preliminary results suggest that this novel approach could play a role in the antibiotic prophylaxis of chronic infectious diseases of the upper airways.

A therapeutic approach in the treatment of infections of the upper airways: thiamphenicol glycinate acetylcysteinate in sequential treatment (systemic-inhalatory route).

Eight hundred and seventeen patients with upper respiratory tract infections were treated with thiamphenicol glycinate acetylcisteinate (TGA) or other standard antibiotics for 6-10 days in a randomised trial. In 419 out of 817 patients, the symptomatology was severe and they were treated with TGA in sequential therapy (TGA 500 mg- as thiamphenicol- b.i.d. intramuscularly on the first day and TGA 500 mg b.i.d by aerosol during the following days) (n=151), or with antibiotics of comparison (n=268) given intramuscularly. In this group the disappearance of the symptomatology with TGA ranged from 90 percent of the patients with otitis media to 94 percent in pharyngotonsillitis and rhinosinusitis; in this latter group TGA was significantly better than cefazolin. In 398 patients with mild symptomatology TGA (250 mg as thiamphenicol- b.i.d.) was given by aerosol (n=149) and the antibiotics of comparison by oral route (n=249). In TGA patients, the disappearance of symptoms was achieved in 87 percent of those with rhinosinusitis, in 88 percent of those with pharyngotonsillitis and in 91 percent of those with otitis media. S. pyogenes, S. pneumoniae and H. influenzae were the most frequently isolated pathogens, and none of the isolated bacteria proved to be resistant to TGA. Microbiological eradication was obtained in TGA groups in a percentage of patients ranging from 90.2 to 96.0 percent in those with severe forms, and from 86.2 to 91.6 percent in those with a mild clinical picture. Investigators rated the TGA efficacy as excellent in 96-100 percent of the patients with severe forms and in 85.5-100 percent of the patients with mild forms, whereas in the group of patients with rhinosinusitis the comparison of TGA versus other treatment was significantly in favour of TGA. The Investigator rating of treatment tolerability significantly favoured TGA in sequential treatments in comparison to the other antibiotics. No patient dropped out from the trial because of adverse events.

Efficacy of N-acetyl-cysteine in combination with thiamphenicol in sequential (intramuscular/aerosol) therapy of upper respiratory tract infections even when sustained by bacterial biofilms.

A total of 102 patients with recurrent upper respiratory tract infections underwent microbiological exploration with appropriate sampling and direct biopsies of the infected sites. Therapy was then started and on day 1 each patient received two intramuscular injections of thiamphenicol glycinate acetylcysteinate (TGA). From day 2 to 10 sequential therapy with the same drug was continued employing TGA administered by aerosol. All putative etiologic agents recovered were susceptible to thiamphenicol and only 24 demonstrated the ability to produce in vitro biofilms. The organisms comprised 10 Staphylococcus aureus, 6 Streptococcus pyogenes, 4 Streptococcus pneumoniae and 3 Haemophilus influenzae. Of the 24 subjects in whom biofilms were demonstrated to be present in vivo by Scanning Electron Microscopy, clinical and bacteriological cure was obtained in 21 cases (87.5%) following sequential therapy with TGA. Failures were considered to be persistent signs and symptoms at day 15 after initiation of treatment and lack of eradication of 3 S. aureus strains, despite their in vitro susceptibility to thiamphenicol. Very few adverse events attributable to TGA were reported in this cohort of patients. In no case was discontinuation of treatment deemed necessary by the attending physician.