rifampin and Hemolysis

A male born in 1935 was diagnosed as having lepromatous leprosy when he was 17 years old. In addition to dapsone (DDS) monotherapy, he had been treated with rifampin (RMP) for 2 terms: first with 450 mg a day for 2 years when he was 39 years old; second with 150 mg a day for 2 months after a 1-year interval from the first regimen. During these entire courses with RMP, no complication was noted. When he was 64 years old in 1999, a diagnosis of relapsed borderline tuberculoid (BT) leprosy was made, and he was started on the multibacillary (MB) regimen of the World Health Organization multidrug therapy (WHO/MDT). After the third dose of monthly RMP, he developed a flu-like syndrome and went into shock. A few hours later, intravascular hemolysis occurred followed by acute renal failure. He was placed on hemodialysis for 7 series and recovered almost completely about 2 months later. The immune complexes with anti-RMP antibody followed by complement binding may have accounted for these symptoms. Twenty-four reported cases of leprosy who had developed side effects of RMP under an intermittent regimen were analyzed; 9 of the cases had had prior treatment with RMP but 15 had not. Adverse effects were more likely to occur in MB cases and were more frequent during the first 6 doses of intermittent regimens. The cases with prior treatment with RMP had had a higher incidence of serious complications such as marked hypotension, hemolysis and acute renal failure. However, many exceptions were also found, and we could not verify any fully dependable factor(s) to predict the side effects of RMP. More field investigation is desirable, and monthly administration of RMP must be conducted under direct observation through the course of WHO/MDT.

Topics: Adrenal Cortex Hormones; Anaphylaxis; Blood Chemical Analysis; Diuretics; Furosemide; Hemolysis; Humans; Leprostatic Agents; Leprosy, Lepromatous; Leprosy, Tuberculoid; Male; Middle Aged; Oliguria; Recurrence; Renal Dialysis; Rifampin

The emergence of multidrug resistance in the clinically significant pathogen

Topics: Adenosine Triphosphate; Animals; Anti-Bacterial Agents; Bacterial Proteins; Erythrocytes; Exotoxins; Gene Expression Regulation, Bacterial; Genes, Essential; Hemolysis; Kinetics; Microbial Sensitivity Tests; Rabbits; Rifampin; Staphylococcus aureus; Time Factors; Transcription, Genetic; Virulence; Virulence Factors

Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The poor response to antitubercular agents necessitates the long-term use of high drug doses, resulting in low patient compliance, which is the main reason for chemotherapy failure and contributes to the development of multidrug-resistant TB. Patient non-compliance has been a major obstacle in the successful management of TB. The aim of this work was to develop and characterise rifapentine (RPT)-loaded PLGA-based nanoparticles (NPs) for reducing dosing frequency.. RPT-loaded PLGA and PLGA-PEG NPs were prepared using premix membrane homogenisation combined with solvent evaporation method. The resulting NPs were characterised in terms of physicochemical characteristics, toxicity, cellular uptake and antitubercular activity. NPs were further evaluated for pharmacokinetic and biodistribution studies in mice.. The application of PLGA-based NPs as sustained-release delivery vehicles for RPT could prolong drug release, modify pharmacokinetics, increase antitubercular activity and diminish toxicity, thereby allowing low dosage and frequency.

Topics: Administration, Oral; Animals; Antitubercular Agents; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hemolysis; Humans; Macrophages; Male; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Prostaglandins A; Rifampin; Tissue Distribution

Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cell Membrane; Clarithromycin; Escherichia coli; Female; Hemolysis; Humans; Hydrophobic and Hydrophilic Interactions; Linezolid; Lipid A; Membrane Fluidity; Mice, Inbred ICR; Microbial Sensitivity Tests; Proline; Protein Binding; Protein Conformation, alpha-Helical; Rifampin

Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2 μg/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.

Topics: Aniline Compounds; Anti-Bacterial Agents; Bacterial Proteins; Benzylamines; Caco-2 Cells; Drug Design; Erythrocytes; Gram-Negative Bacteria; Gram-Positive Bacteria; HeLa Cells; Hemolysis; Humans; Keratinocytes; Microbial Sensitivity Tests; Molecular Structure; Protein Binding; Schiff Bases; Structure-Activity Relationship; Transcription Factors

We present a case of pulmonary tuberculosis treated with a rifampicin (RMP) containing regimen, which led to marked haemolysis and acute kidney injury. The patient was shown to have RMP-induced haemolysis on detailed immunological testing. RMP is described as a rare cause of drug-induced haemolysis in the literature. However, it is a widely used drug and this complication may be severe. RMP-induced haemolysis precludes further treatment with the drug. Clinicians should consider this possibility and seek advice if patients on RMP develop haemolysis.

Topics: Acute Kidney Injury; Adolescent; Antitubercular Agents; Hemolysis; Humans; Male; Rifampin; Tuberculosis, Pulmonary

The inability to discover novel class of antibacterial agents, especially against Gram-negative bacteria (GNB), compel us to consider a broader non-conventional approach to treat infections caused by multidrug-resistant (MDR) bacteria. One such approach is the use of adjuvants capable of revitalizing the activity of current existing antibiotics from resistant pathogens. Recently, our group reported a series of tobramycin (TOB)-based hybrid adjuvants that were able to potentiate multiple classes of legacy antibiotics against various MDR GNB. Herein, we report the modification of TOB-based hybrid adjuvants by replacing TOB domain by the pseudo-disaccharide nebramine (NEB) through selective cleavage of the α-d-glucopyranosyl linkage of TOB. Potent synergism was found for combinations of NEB-based hybrid adjuvants with multiple classes of legacy antibiotics including fluoroquinolones (moxifloxacin and ciprofloxacin), tetracyclines (minocycline), or rifamycin (rifampicin) against both wild-type and MDR P. aeruginosa clinical isolates. We also demonstrated that a combination of the optimized NEB-CIP hybrid 1b and rifampicin protects Galleria mellonella larvae from the lethal effects of extensively drug-resistant (XDR) P. aeruginosa. Mechanistic evaluation of NEB-based hybrid adjuvants revealed that the hybrids affect the outer- and inner membranes of wild-type P. aeruginosa PAO1. This study describes an approach to optimize aminoglycoside-based hybrids to yield lead adjuvant candidates that are able to resuscitate the activity of partner antibiotics against MDR GNB.

Topics: Animals; Anti-Bacterial Agents; Carbon-13 Magnetic Resonance Spectroscopy; Disaccharides; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacteria; HEK293 Cells; Hemolysis; Humans; Larva; Lepidoptera; Microbial Sensitivity Tests; Proton Magnetic Resonance Spectroscopy; Pseudomonas aeruginosa; Pyrans; Rifampin; Spectrometry, Mass, Electrospray Ionization; Swine

Biocompatible polymers and ceramic materials have been identified as vital components to fabricate drug delivery and tissue engineering applications because of their high drug loading capability, sustained release and higher mechanical strength with remarkable in-vivo bioavailability. In the present work, initially we designed κ-carrageenan grafted with maleic anhydride and then reacted it with isoniazid drug (κ-Car-MA-INH). The polymeric system was cross linked with nanohydroxyapatite (NHAP) via electrostatic interaction followed by the addition of rifampicin (RF) and loaded to fabricate κ -Car-MA-INH/NHAP/RF nanocomposites. The chemical modification and interaction of drug with the polymeric-ceramic system were characterised by Fourier Transform Infrared spectroscopy (FT-IR). The zeta potential of the κ -Car-MA-INH/NHAP/RF nanocomposite was observed to be -20.04 mV using Zetasizer. The in vitro drug release studies demonstrated that the nanocomposite releases 76% of RF and 82% of INH in 12 days at pH 5.5. Scanning Electron Microscope analysis revealed the structural deformation of Staphylococcus aureus and Klebsiella pneumoniae upon treatment with this nanocomposite. By using ex-vivo studies combined with physio-chemical characterization methods on the erythrocytes, L929 and MG-63 cell lines, this composite was found to be biocompatible, non-cytotoxic and inducing cell proliferation with less significant hemolysis. Thus, our modified drug delivery nanocomposites afforded higher drug bioavailability with large potential for fabrication as long-acting drug delivery nanocomposites, especially with hydrophobic drugs inducing the growth of osteoblastic bone cells.

Topics: Animals; Antitubercular Agents; Carrageenan; Cell Line; Drug Delivery Systems; Drug Liberation; Durapatite; Erythrocytes; Hemolysis; Humans; Isoniazid; Klebsiella pneumoniae; Macrophages; Maleic Anhydrides; Mice; Nanocomposites; Osteoblasts; Osteomyelitis; Regeneration; Rifampin; Staphylococcus aureus; Tuberculosis

The present investigation was performed to develop a rifampicin (RIF)-loaded solidified self-nanoemulsifying drug delivery system (SNEDDS) (solidified RIF-OF1) for in vitro and in vivo evaluations. Optimized formulations were tested for their powder flow characteristics, loading efficiency, and in vitro dissolution (at pH-1.2, 6.8 and 7.4). Compatibility studies were also performed. The formulations were also tested for hemocompatibility, intestinal permeation, histopathological effects, and in vivo pharmacokinetics. Additionally, an in silico simulation study using GastroPlus was performed. At different varied pH values, we observed immediate release (T

Topics: Administration, Oral; Animals; Antibiotics, Antitubercular; Blood Cells; Computer Simulation; Drug Delivery Systems; Drug Liberation; Emulsions; Enterocytes; Hemolysis; Humans; Intestinal Absorption; Male; Models, Biological; Rats, Sprague-Dawley; Rifampin

Non-natural antimicrobial peptides are ideal as next-generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-α- and α,γ-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 ± 0.03 to 1.35 ± 0.21 μM with the peptide γTatM4) and Gram-negative (MICs 0.71 ± 0.005 to 1.26 ± 0.02 μM with γTatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells.

Topics: Anti-Bacterial Agents; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Erythrocytes; Gram-Negative Bacteria; Gram-Positive Bacteria; Hemolysis; Humans; Microbial Sensitivity Tests; Molecular Structure; Particle Size; Peptidomimetics; Structure-Activity Relationship; Tuberculosis

Photorhabdus luminescens is an enteric bacterium, which lives in mutualistic association with soil nematodes and is highly pathogenic for a broad spectrum of insects. A complete genome sequence for the type strain P. luminescens subsp. laumondii TT01, which was originally isolated in Trinidad and Tobago, has been described earlier. Subsequently, a rifampicin resistant P. luminescens strain has been generated with superior possibilities for experimental characterization. This strain, which is widely used in research, was described as a spontaneous rifampicin resistant mutant of TT01 and is known as TT01-Rif. Unexpectedly, upon phenotypic comparison between the rifampicin resistant strain and its presumed parent TT01, major differences were found with respect to bioluminescence, pigmentation, biofilm formation, haemolysis as well as growth. Therefore, we renamed the strain TT01-Rif. According to the major phenotypic and genotypic differences, the rifampicin resistant P. luminescens strain, now named strain DJC, has to be considered as an independent isolate rather than a derivative of strain TT01. Strains TT01 and DJC both belong to P. luminescens subsp. laumondii.

Topics: Anti-Bacterial Agents; Base Sequence; Biofilms; DNA Transposable Elements; Drug Resistance, Bacterial; Genome, Bacterial; Genomics; Hemolysis; Mutation; Open Reading Frames; Phenotype; Photorhabdus; Prophages; Rifampin; Sequence Analysis, DNA; Symbiosis

Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics. Combination studies indicate the ability of these conjugates to synergize rifampicin and minocycline against MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection model. Mode of action studies indicate that the amphiphilic tobramycin-lysine adjuvants enhance outer membrane cell penetration and affect the proton motive force, which energizes efflux pumps. Overall, this study provides a strategy for generating effective antibiotic adjuvants that overcome resistance of rifampicin and minocycline in MDR and XDR Gram-negative bacteria including P. aeruginosa.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Hemolysis; Lysine; Microbial Sensitivity Tests; Minocycline; Models, Biological; Rifampin; Tobramycin

First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF.. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs.. RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

Topics: Antibiotics, Antitubercular; Delayed-Action Preparations; Drug Liberation; Hemolysis; Humans; Kinetics; Methacrylates; Micelles; Mycobacterium tuberculosis; Polyesters; Rifampin; Tuberculosis

The ineffectiveness of anti-tuberculous therapy against dormant and drug-resistant mycobacteria demands scrutiny of alternative candidates like antimicrobial peptides having different mechanisms of action. The present study was designed to explore the activity of human beta defensin-1 (HBD-1) and its in silico identified short motif Pep-B against active and dormant Mycobacterium tuberculosis (M. tb) H37Rv. Activity of HBD-1 and Pep-B was determined against actively growing M. tb in vitro, inside monocyte-derived macrophages (MDMs) and dormant bacilli in in vitro potassium deficiency and human peripheral blood mononuclear cell (PBMC) granuloma models using colony-forming unit enumeration. The minimum inhibitory concentrations (MIC) of HBD-1 and Pep-B were found to be 2 and 20 μg/ml, respectively. These peptides also inhibited intracellular mycobacterial growth at concentrations lower than in vitro MICs along with increased IFN-γ levels. Although at higher concentration, HBD-1 (× 2 MIC) and Pep-B (× 2 MIC) led to decrease in in vitro dormant mycobacterial load as compared to rifampicin (× 25 MIC) and isoniazid (× 16 MIC). Similarly, both peptides showed higher killing efficacy against dormant mycobacteria inside granuloma as compared to rifampicin. Thus, the present study indicates that HBD-1 and its motif are effective antimicrobial players against both actively growing and dormant mycobacteria.

Topics: Antitubercular Agents; beta-Defensins; Computational Biology; Hemolysis; Humans; Isoniazid; Leukocytes, Mononuclear; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

We report the structure-activity relationship analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12, and 17 were more potent than the lead compound. Analogue 17 was active against carbapenem-resistant and polymyxin-resistant pathogens. This compound at 40 μg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17 showed little hemolysis at 32 μg/mL and lysed 11% of red blood cells at 64 μg/mL. Analogues 9 and 16 were nonhemolytic and retained potent P. aeruginosa-specific antimicrobial activity. These two analogues when used alone lacked activity against Acinetobacter baumannii and Klebsiella pneumoniae; however, analogue 9 and 16 at 4 μg/mL decreased the MIC of rifampicin and clarithromycin against the same pathogens from 16 to 32 μg/mL to nanomolar levels (sensitization factor: 2048-8192). Therefore, paenipeptins, alone or in combination with rifampicin or clarithromycin, are promising candidates for treating bacterial infections.

Topics: Anti-Bacterial Agents; Biofilms; Clarithromycin; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hemolysis; Humans; Lipopeptides; Microbial Sensitivity Tests; Paenibacillus; Rifampin; Structure-Activity Relationship

The spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-β-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Ceftazidime; Ceftriaxone; Cell Line; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Enterobacter; Erythrocytes; Escherichia coli; Fibroblasts; Hemolysis; Humans; Klebsiella pneumoniae; Membrane Potentials; Mice; Microbial Sensitivity Tests; Rifampin; Serratia

Effective global control of tuberculosis (TB) is increasingly threatened by the convergence of multidrug-resistant TB and the human immunodeficiency virus (HIV) infection. TB/HIV coinfections exert a tremendous burden on the host's immune system, and this has prompted the clinical use of immunomodulators to enhance host defences as an alternative therapeutic strategy. In this study, we modified the clinically used synthetic immunomodulatory pentapeptide, thymopentin (TP-5, RKDVY), with six arginine residues (RR-6, RRRRRR) at the N- and C-termini to obtain the cationic peptides, RR-11 (RKDVYRRRRRR-NH2) and RY-11 (RRRRRRRKDVY-NH2), respectively. The arginine residues conferred anti-mycobacterial activity to TP-5 in the peptides as shown by effective minimum inhibitory concentrations of 125 mg/L and killing efficiencies of >99.99% against both rifampicin-susceptible and -resistant Mycobacterium smegmatis. The immunomodulatory action of the peptides remained unaffected as shown by their ability to stimulate TNF-α production in RAW 264.7 mouse macrophage cells. A distinct change in surface morphology after peptide treatment was observed in scanning electron micrographs, while confocal microscopy and dye leakage studies suggested bacterial membrane disruption by the modified peptides. The modified peptides were non-toxic and did not cause hemolysis of rat red blood cells up to a concentration of 2000 mg/L. Moreover, RY-11 showed synergism with rifampicin and reduced the effective concentration of rifampicin, while preventing the induction of rifampicin resistance. The synthetic peptides may have a potential application in both immunocompetent and immunocompromised TB patients.

Topics: Amino Acid Sequence; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Drug Resistance, Bacterial; Hemolysis; Humans; Immunologic Factors; Macrophages; Mice; Microbial Sensitivity Tests; Microscopy, Confocal; Molecular Sequence Data; Mycobacterium smegmatis; Peptides; Rats; Rifampin; Thymopentin; Tumor Necrosis Factor-alpha

Rifampicin is a widely used anti-tuberculosis agent. Apart from hepatotoxicity, rifampicin can rarely lead to adverse reactions of immunologic nature such as acute renal failure (ARF). We report the case of 57-year-old previously healthy man under treatment for pulmonary tuberculosis who presented with hemolysis and severe ARF. Rifampicin was discontinued and the patient was treated with fluid repletion, iv furosemide and dialysis therapy. Kidney biopsy revealed acute tubulointerstitial nephritis with no evidence of granulomas. The patient significantly improved and was discharged after 51 days of hospitalization. Clinicians using rifampicin should be aware of this rather uncommon but severe complication.

Topics: Acute Kidney Injury; Antibiotics, Antitubercular; Hemolysis; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Our previous studies revealed that alpha-melanocyte stimulating hormone (α-MSH) is strongly active against Staphylococcus aureus (S. aureus) including methicillin resistant S. aureus (MRSA). Killing due to α-MSH occurred by perturbation of the bacterial membrane. In the present study, we investigated the in vitro synergistic potential of α-MSH with five selected conventional antibiotics viz., oxacillin (OX), ciprofloxacin (CF), tetracycline (TC), gentamicin (GM) and rifampicin (RF) against a clinical MRSA strain which carried a type III staphylococcal cassette chromosome mec (SCCmec) element and belonged to the sequence type (ST) 239. The strain was found to be highly resistant to OX (minimum inhibitory concentration (MIC) = 1024 µg/ml) as well as to other selected antimicrobial agents including α-MSH. The possibility of the existence of intracellular target sites of α-MSH was evaluated by examining the DNA, RNA and protein synthesis pathways. We observed a synergistic potential of α-MSH with GM, CF and TC. Remarkably, the supplementation of α-MSH with GM, CF and TC resulted in ≥ 64-, 8- and 4-fold reductions in their minimum bactericidal concentrations (MBCs), respectively. Apart from membrane perturbation, in this study we found that α-MSH inhibited ≈ 53% and ≈ 47% DNA and protein synthesis, respectively, but not RNA synthesis. Thus, the mechanistic analogy between α-MSH and CF or GM or TC appears to be the reason for the observed synergy between them. In contrast, α-MSH did not act synergistically with RF which may be due to its inability to inhibit RNA synthesis (<10%). Nevertheless, the combination of α-MSH with RF and OX showed an enhanced killing by ≈ 45% and ≈ 70%, respectively, perhaps due to the membrane disrupting properties of α-MSH. The synergistic activity of α-MSH with antibiotics is encouraging, and promises to restore the lost potency of discarded antibiotics.

Topics: 3T3 Cells; alpha-MSH; Animals; Anti-Bacterial Agents; Bacterial Proteins; Cell Survival; Ciprofloxacin; DNA, Bacterial; Dose-Response Relationship, Drug; Drug Synergism; Fibroblasts; Gentamicins; Hemolysis; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Microbial Viability; Oxacillin; Rifampin; RNA, Bacterial; Tetracycline

Topics: 5-Aminolevulinate Synthetase; alpha-Thalassemia; Anemia, Sideroblastic; Antitubercular Agents; Aza Compounds; Bone Marrow; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Hemolysis; Humans; Isoniazid; Middle Aged; Moxifloxacin; Peritonitis, Tuberculous; Pyrazinamide; Pyridoxine; Quinolines; Rifampin

Polyester vascular prostheses (PVPs) coated with a polymer of hydroxypropyl-β-cyclodextrin (HPβCD) have been designed to provide an in situ reservoir for the sustained delivery of one or more bioactive molecules. The goal of this study was to assess the efficacy, the safety and the healing properties of these prostheses.. Collagen-sealed PVPs were coated with the HPβCD-based-polymer (PVP-CD) using the pad-dry-cure textile finishing method and loaded with one or two antibiotics. Appropriate control and PVP-CD samples were tested in several in vitro and animal model conditions. The study end points included haemolysis, platelet aggregation, antibacterial efficacy, polymer biodegradation, acute toxicity and chronic tolerance.. PVP-CD proved to be compatible with human blood, since it did not induce haemolysis nor influenced ADP-mediated platelet aggregation. Sustained antimicrobial efficacy was achieved up to 7 days against susceptible bacteria when PVP-CDs were loaded with the appropriate drugs. Analysis of harvested PVP-CD from the animal model revealed that the HPβCD-based coating was still present at 1 month but had completely disappeared 6 months after implantation. All grafts were patent, well encapsulated without healing abnormalities. Clinical data, blood-sample analysis and histological examination did not evidence any signs of acute or chronic, local or systemic toxicity in the animal models.. PVP-CD was proved safe and demonstrated excellent biocompatibility, healing and degradation properties. Effective antimicrobial activity was achieved with PVP-CD in conditions consistent with a sustained-release mechanism.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anti-Bacterial Agents; beta-Cyclodextrins; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Ciprofloxacin; Coated Materials, Biocompatible; Dogs; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemolysis; Humans; In Vitro Techniques; Methicillin-Resistant Staphylococcus aureus; Mice; Platelet Aggregation; Prosthesis-Related Infections; Rifampin; Toxicity Tests; Treatment Outcome; Vancomycin; Wound Healing

The antibiotic rifampicin is widely used in the treatment of tuberculosis. Side effects of rifampicin include hemolytic anemia. Loss of circulating erythrocytes resembling hemolytic anemia could result from stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca(2+) activity ([Ca(2+)](i)) and formation of ceramide. The present study explored, whether and, if so, how rifampicin triggers eryptosis. To this end, [Ca(2+)](i) was estimated from Fluo3 fluorescence, cell volume from forward scatter in flow cytometry, PS exposure from annexin binding, ceramide formation from binding of fluorescent antibodies and hemolysis from hemoglobin release. As a result, a 48 h exposure to rifampicin (≥ 24 μg/ml) significantly increased Fluo3 fluorescence, ceramide abundance and annexin binding, and significantly decreased forward scatter. Rifampicin triggered slight, but significant hemolysis. Removal of extracellular Ca(2+) significantly blunted, but did not fully abolish rifampicin induced annexin binding. In conclusion, exposure of human erythrocytes to rifampicin is followed by suicidal erythrocyte death or eryptosis, an effect at least partially due to increase of cytosolic Ca(2+) concentration and stimulation of ceramide formation.

Topics: Aniline Compounds; Antibiotics, Antitubercular; Apoptosis; Calcium; Cell Death; Cell Membrane; Cell Size; Ceramides; Cytosol; Erythrocytes; Flow Cytometry; Hemolysis; Humans; Phosphatidylserines; Rifampin; Xanthenes

Multidrug therapy for leprosy is currently done with dapsone, clofazimine and rifampicin. Dapsone is known to cause hemolytic anemia (HA) and this adverse event during MDT seems to be more frequent than reported. The aim of this report is to discuss and grade HA due to dapsone during MDT treatment for leprosy.. This is a retrospective study of 194 leprosy patients from a Leprosy Control Programme Unit in Vit6ria-ES, Brazil.. HA was observed in 48 (24.7%) patients and occurred within the first 3 months in 51% of these. Mean hematocrit levels fell from 38.5 to 31.5 and hemoglobin from 12.8 to 10.3.. Dapsone used in the MDT regime for leprosy decreases the hematocrit and hemoglobin levels due to a low grade hemolysis, which can result in significant anemia.

Topics: Adolescent; Adult; Aged; Anemia, Hemolytic; Brazil; Clofazimine; Dapsone; Drug Therapy, Combination; Female; Follow-Up Studies; Hematocrit; Hematologic Tests; Hemoglobins; Hemolysis; Humans; Leprostatic Agents; Leprosy; Male; Middle Aged; Retrospective Studies; Rifampin; Treatment Outcome; World Health Organization; Young Adult

Syringomycin E (SRE) is a member of a family of lipodepsipeptides that characterize the secondary metabolism of the plant-associated bacteria Pseudomonas syringae pv. syringae. It displays phytotoxic, antifungal and haemolytic activities, due to the membrane interaction and ion channel formation. To gain an insight into the conformation of SRE in the membrane environment, we studied the conformation of SRE bound to SDS micelle, a suitable model for the membrane-bound SRE. In fact, highly similar circular dichroism (CD) spectra were obtained for SRE bound to sodium dodecylsulphate (SDS) and to a phospholipid bilayer, indicating the conformational equivalence of SRE in these two media, at difference with the CD spectrum of SRE in water solution. The structure of SDS-bound SRE was determined by NMR spectroscopy combined with molecular dynamics calculations in octane environment. The results of this study highlight the influence of the interaction with lipids in determining the three-dimensional structure of SRE and provide the basis for further investigations on structural determinants of syringomycin E-membrane interaction.

Topics: Antifungal Agents; Circular Dichroism; Hemolysis; Hydrogen Bonding; Ion Channels; Lipids; Magnetic Resonance Spectroscopy; Micelles; Molecular Dynamics Simulation; Peptides, Cyclic; Phospholipids; Protein Conformation; Rifampin; Sodium Dodecyl Sulfate; Water

We report two pediatric patients with rifampin-induced hemolysis following treatment with low daily dose rifampin for methicillin-resistant Staphylococcus aureus (MRSA). With the increased use of rifampin to treat MRSA, physicians should be aware that patients receiving rifampin therapy are at risk for hemolysis, even at low daily doses.

Topics: Adolescent; Anemia, Hemolytic; Antibiotics, Antitubercular; Drug Therapy, Combination; Female; Hemolysis; Humans; Infant; Male; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Rifampin; Staphylococcal Infections

A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.

Topics: Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Cell Membrane Permeability; Dose-Response Relationship, Drug; Escherichia coli; Hemolysis; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Microbial Sensitivity Tests; Molecular Conformation; Polyamines; Rifampin; Staphylococcus aureus; Structure-Activity Relationship; Toxicity Tests, Acute

The present study was aimed at developing and exploring the use of mannosylated dendritic architecture for the selective delivery of an anti-tuberculosis drug, rifampicin (RIF) to alveolar macrophages (AM). The mannosylated dendritic architecture was synthesized and characterized by using IR and NMR spectroscopy. RIF was efficiently loaded into mannosylated dendrimer using dissolution method. Various physicochemical and physiological parameters such as UV, SEM, DSC, drug loading, solubilization, pH dependent in-vitro release, hemolytic toxicity, phagocytic AM uptake and cytotoxicity concerning the mannosylated dendrimer were evaluated. RIF loaded mannosylated dendrimer reduced release rate of drug in pH 7.4, hemolytic toxicity and cytotoxicity; whereas enhanced drug release in pH 5.0 and AM uptake was observed. The present novel dendritic system displayed suitability in terms of biocompatibility and site-specific delivery of antitubercular drug RIF.

Topics: Animals; Antibiotics, Antitubercular; Calorimetry, Differential Scanning; Chlorocebus aethiops; Dendrimers; Drug Delivery Systems; Hemolysis; Humans; Hydrogen-Ion Concentration; Macrophages, Alveolar; Magnetic Resonance Spectroscopy; Mannose; Microscopy, Electron, Scanning; Phagocytosis; Rats; Rifampin; Solubility; Spectrophotometry, Infrared

We report a case of borderline tuberculoid leprosy complicated by a median nerve abscess, acute renal failure secondary to rifampicin-induced haemolysis and duodenal ulceration secondary to steroid use. Rifampicin induced hameolysis is a rare and probably under-reported complication of leprosy multi-drug therapy. It should be considered when patients complain of flu-like symptoms after taking their monthly rifampicin.

Topics: Abscess; Acute Kidney Injury; Adult; Female; Hemolysis; Humans; Leprostatic Agents; Leprosy, Borderline; Magnetic Resonance Imaging; Median Nerve; Peptic Ulcer; Rifampin

We report three patients who developed haemolysis following rifampicin treatment. Initially, autoimmune haemolytic anaemia (AIHA) of the warm type and/or an acute haemolytic transfusion reaction (AHTR) was suggested. The direct antiglobulin tests (DAT) were strongly positive for IgG and C3d, and tests for rifampicin-dependent antibodies were positive in all three cases, featuring C-specificity in one case. The outcome was fatal in two out of the three cases, presumably due to belated diagnosis. This shows that rifampicin may stimulate the production of autoantibodies (aab) and/or drug-dependent antibodies (ddab), and that the resulting haemolytic syndrome bears similarities with AIHA and AHTR.

Topics: Adult; Anemia, Hemolytic; Antibiotics, Antitubercular; Antibodies; Autoantibodies; Diagnostic Errors; Fatal Outcome; Female; Hemolysis; Humans; Male; Rifampin; Tuberculosis, Pulmonary

After strict hygienical measures have been exhausted the use of plastic materials with antibacterial activity may reduce catheter related-bacterial colonization. An antimicrobial silicone catheter was investigated by HPLC-measurement, SEM, antimicrobial assays and standard biocompatibility tests. The modified catheter was highly biocompatible and the antimicrobial leaching non-toxic. The initially release rate was governed by the drug solubility in the 'sink' and surface loading ('burst effect'). The second continuous period depended on the drug velocity in the silicone matrix and was extended up to 100 days with a proportionality to square root of t for each drug. Diffusion exponents were in range of 2 x 10(-8) to 1 x 10(-9) (cm2 sec(-1)). The lower diffusion exponent of mupirocin was explained by its higher cohesion energy and lower physico-chemical compatibility with the embedding silicone. The antimicrobial drugs were in a molecular-dispersed state with the silicone-matrix, whereas superficially located crystals of the antibiotics covering the catheter surface could be demonstrated by SEM.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Bacterial Adhesion; Biocompatible Materials; Catheterization; Cerebrospinal Fluid Shunts; Delayed-Action Preparations; Erythrocytes; Fusidic Acid; Hemolysis; Humans; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Mupirocin; Rifampin; Silicones; Staphylococcus aureus; Staphylococcus epidermidis

The ActA protein, the lecithinase PlcB and listeriolysin are the major PrfA-dependent proteins synthesized when brain-heart infusion (BHI)-cultured Listeria monocytogenes is shifted to minimum essential medium (MEM) in the presence of the transcriptional inhibitor rifampicin. Enhanced synthesis of all three proteins under these conditions depends, however, on a short incubation (about 5 min) of the bacteria in MEM without rifampicin, suggesting that induction of these proteins in MEM requires de novo transcription. The enhanced synthesis of these three proteins is observed in the L. monocytogenes wild-type strains EGD and NCTC 7973, both of which belong to the serotype 1/2 a. A significant induction of the bicistronic mRNA for ActA and PlcB is observed in both strains shortly after shifting the bacteria from BHI to MEM. This mRNA as well as the monocistronic listeriolysin (hly)-specific mRNA is highly stable in L. monocytogenes NCTC 7973 shifted to MEM. In contrast to the actA-plcB mRNA, no enhanced transcription in MEM is observed for the regulatory prfA gene or for the PrfA-controlled virulence genes hlyA and plcA in strain NCTC 7973. However, transcription of these genes is induced in strain EGD. Transcriptional induction of the mpl gene is observed in neither strain NCTC 7973 nor in strain EGD. The life-time of the prfA, plcA, and mpl transcripts is short. ActA was also found to be the most abundant newly synthesized surface protein when the two wild-type strains of L. monocytogenes replicated within the phagocytic cell line J774. ActA synthesis seemed to be induced in the cytoplasm since the non-haemolytic mutant M3 did not induce ActA when taken up by J774 cells.

Topics: Animals; Bacterial Proteins; Bacterial Toxins; Base Sequence; Gene Expression Regulation, Bacterial; Genes; Heat-Shock Proteins; Hemolysin Proteins; Hemolysis; Listeria monocytogenes; Macrophages; Membrane Proteins; Metalloendopeptidases; Mice; Molecular Sequence Data; Peptide Termination Factors; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoric Diester Hydrolases; Rifampin; RNA Precursors; Trans-Activators; Transcription, Genetic; Type C Phospholipases; Virulence

Renal failure is a rare complication associated with the use of rifampin. Intravascular hemolysis leading to acute renal failure following rifampin therapy is extremely rare. Two patients with leprosy who developed hemolysis and acute renal failure following rifampin are reported.

Topics: Acute Kidney Injury; Adult; Anemia, Hemolytic; Hemolysis; Humans; Leprosy; Leprosy, Borderline; Leprosy, Tuberculoid; Male; Rifampin

Topics: Acute Kidney Injury; Adult; Hemolysis; Humans; Male; Rifampin

We describe a woman with the 'flu' like syndrome and haemolysis whilst on a supervised daily rifampicin regimen for the treatment of pulmonary tuberculosis. Although these are known complications of rifampicin therapy, they often occur when therapy is intermittent or interrupted. Hence the case we describe is unique and is the first of its kind to be reported in Singapore.

Topics: Adult; Anemia, Hemolytic; Diagnosis, Differential; Female; Hemolysis; Humans; Influenza, Human; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Female; Hemolysis; Humans; Kidney Failure, Chronic; Middle Aged; Rifampin

Acute renal failure following intermittent or discontinuous rifampicin therapy is a relatively infrequent clinical observation. Many pathogenetic mechanisms for the renal failure have been proposed, including intravascular hemolysis with hemoglobinuria and its consequent nephrotoxicity. We report the case of a patient who used rifampicin in a discontinuous fashion and developed hemolysis with nonoliguric acute renal failure. Most reported cases of antirifampicin antibodies are of the IgM class; thus, the development of an IgG antirifampicin antibody is of interest, especially because of its strong in vivo hemolytic properties. In addition, this patient developed a nonoliguric uremic course that did not require dialysis, both of which are distinctly unusual for this clinical setting.

Topics: Acute Kidney Injury; Hemolysis; Humans; Immunoglobulin G; Male; Middle Aged; Rifampin

In a 48-years old woman, intermittent rifampicin treatment induced an immunoallergic reaction with digestive disorders, haemolysis, acute renal failure and prolonged prothrombin time. The reintroduction of rifampicin, 17 days later, resulted in a similar, though more severe, reaction associated with diffuse haemorrhages from disseminated intravascular coagulation, this association being exceptional. The responsibility of rifampicin was demonstrated by the chronological relationship between clinical symptoms and administration of the drug, and by the presence in the patient's serum of anti-rifampicin antibodies. The antigen-antibody reaction with complement activation and haemolysis probably explains the disseminated intravascular coagulation.

Topics: Acute Kidney Injury; Antibodies; Antigen-Antibody Reactions; Complement Activation; Disseminated Intravascular Coagulation; Drug Hypersensitivity; Female; Hemolysis; Humans; Middle Aged; Rifampin

Sixteen patients were given high-dose intermittent rifampicin treatment (900 mg twice weekly) in order to record side-effects of the flu-type. Three patients who experienced a febrile reaction were re-challenged under strict hospital supervision with a single dose (900 mg) of rifampicin. Two patients showed a distinct febrile response together with rapidly subsiding symptoms typical of the rifampicin-induced flu-syndrome, whereas the third patient's reaction was clinically different. During the challenge, the changes in a number of laboratory tests were indicative of a mild haemolytic reaction in the two patients with flu-syndrome. Plasma haemoglobin steeply increased within a few hours following the ingestion of the dose. This was associated with an acute increase in the total bilirubin and with a gradual decrease in the blood haemoglobin and haematocrit values. In further support of a drug-induced haemolysis was the findings that both patients showed a distinct reticulocyte response several days after the challenge. No such changes were seen in the third patient, whose reaction was later demonstrated to be related to isoniazid. The flu-syndrome thus may represent a first warning sign of intravasal haemolysis, which, if massive enough, eventually could lead to haemolytic crises and renal failure.

Topics: Anemia, Hemolytic; Bilirubin; Fever; Hematocrit; Hemoglobins; Hemolysis; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Acute Kidney Injury; Aged; Female; Hemolysis; Humans; Rifampin

Two cases are reported of hemolytic crisis and acute anuria after intermittent rifampicin medication. Immunologic tests demonstrate that the hemolysis was of the drug-induced heteroimmune type whereas the pathogenesis of the anuria was uncertain. For both complications the prognosis is good.

Topics: Acute Kidney Injury; Aged; Antibodies; Anuria; Drug Therapy, Combination; Female; Hemolysis; Humans; Male; Middle Aged; Rifampin; Time Factors; Tuberculosis, Lymph Node; Tuberculosis, Renal

A 53-year-old female patient with ovarian dermatoid cyst and lung tuberculosis had been treated with rifampicin. During repeated rifampicin treatment she developed an acute haemolytic syndrome with haemorrhagic diathesis. Laboratory findings showed that it was caused by disseminated intravascular coagulation. Death ensued despite intensive administration of heparin and Trasylol. It is assumed that the repeated rifampicin application had provoked massive haemolysis by an allergic mechanism leading to thrombofibrinolytic haemorrhagic diathesis.

Topics: Antithrombins; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Hemolysis; Heparin; Humans; Middle Aged; Ovarian Cysts; Rifampin

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Hemolysis; Humans; Liver; Rifampin; Tuberculosis, Pulmonary

Topics: Acute Disease; Acute Kidney Injury; Anticoagulants; Contraceptives, Oral; Digitoxin; Female; Hemolysis; Humans; Nephritis, Interstitial; Rifampin; Thrombocytopenia; Tuberculosis

Topics: Ascorbic Acid; Azo Compounds; Bilirubin; Chemistry, Clinical; Diazonium Compounds; Epinephrine; Hemoglobins; Hemolysis; Histidine; Humans; Hyperlipidemias; Levodopa; Methyldopa; Norepinephrine; Rifampin; Spectrophotometry, Ultraviolet; Statistics as Topic; Tyrosine

Topics: Acute Kidney Injury; Agglutination Tests; Anemia, Hemolytic; Antibodies; Female; Hemolysis; Humans; Middle Aged; Rifampin; Tuberculosis, Renal

Topics: Dose-Response Relationship, Drug; Drug Hypersensitivity; Hemolysis; Humans; Rifampin; Tuberculosis

Topics: Body Temperature; Female; Hematocrit; Hemolysis; Humans; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Animals; Coagulase; Drug Resistance, Microbial; Edetic Acid; Hemolysis; Mice; Mutation; Rifampin; Salmonella typhimurium; Staphylococcus; Virulence

Topics: Adult; Female; Hemolysis; Humans; Rifampin

Topics: Animals; Carbohydrate Metabolism; Clostridium; Erythrocytes; Fermentation; Guinea Pigs; Hemolysis; Horses; Injections, Intramuscular; Injections, Intraperitoneal; Microbial Sensitivity Tests; Penicillin G; Penicillin Resistance; Rifampin; Rolitetracycline; Sheep; Species Specificity; Virulence