ABSTRACT
Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multi-drug-resistant bacteria or 'superbugs'. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. The authors derivatized a clinically used fluoroquinolone antibiotic ciprofloxacin (Cip), and complexed it to a copper phenanthrene framework. This resulted in the development of two novel metallo-antibiotics of general formula [Cu(N,N)(CipHA)]NO3 where N,N represents a phenanthrene ligand and CipHA represents a hydroxamic acid of Cip derivative. Comprehensive studies, including a detailed proteomic study in which Staphylococcus aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent antibacterial activity against S. aureus and methicillin-resistant S. aureus. In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to the innate immune system of mammals. These findings suggest that proteins involved in virulence, pathogenesis, and the synthesis of nucleotides and DNA repair mechanisms are most affected. In addition, both complexes affected similar cell pathways when compared with clinically used Cip, including cationic antimicrobial peptide resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2',3'-c]phenazine) analogue also induces cell leakage, which leads to an altered proteome indicative of reduced virulence and increased stress.
Subject(s)
Anti-Bacterial Agents/pharmacology , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Copper/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Animals , Copper/chemistry , Drug Design , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial/genetics , Humans , Hydroxamic Acids/chemistry , Methicillin-Resistant Staphylococcus aureus/genetics , Moths/drug effects , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Staphylococcal Infections/drug therapyABSTRACT
OBJECTIVE: Of study is improving the results of treatment of patients with pyo-necrotic complications of diabetic foot syndrome by including the method of negative pressure wound treatment in the complex treatment program in combination with using of the combined antibacterial drug Cifran ST and immunocorrective therapy. MATERIAL AND METHODS: The results of examination and treatment of 184 patients with pyo-necrotic complications of the neuropathic form of diabetic foot syndrome were analyzed. According to choice of treatment methods in the postoperative period all patients were divided into two groups. In 95 patients (group I), iodine-containing ointments based on polyethylene glycol were used for local treatment of purulent foot wounds and standard systemic antibacterial therapy was performed. In 89 patients (group II), negative pressure wound treatment (NPWT) was used to treat wounds in the postoperative period. In addition to standard parenteral antimicrobial therapy, these patients also received an oral combined antibacterial drug Cifran ST and immunocorrective cytokine therapy (Leukinferon). The analysis of the dynamics of the wound process was carried out based on the clinical picture and the results of cytological, bacteriological and immunological studies of the wound exudate. RESULTS: The presented strategy of complex treatment of pyo-necrotic complications of the neuropathic form of diabetic foot syndrome allowed group II patients to significantly reduce the degree of microbial contamination of wounds, to achieve a faster regression of the content of proinflammatory and inflammatory cytokines in the wound exudate, as well as to reduce the time of wound cleansing and the transition of the pyo-necrotic process to the reparative stage in comparison with group I patients. This allowed group II patients to reduce the time of plastic closure of the wound from 24.3±0.5 to 15.6±1.7 days, to avoid generalization of infection, death and high level amputation of the limb. At the same time, 11.6% of patients in group I had high level limb amputation due to generalization of infection. The mortality rate in group I was 5.3%. CONCLUSIONS: Adding of vacuum therapy of wounds, systemic antimicrobial therapy using the combined antibacterial drug Cifran ST and immunocorrective cytokine therapy in the complex treatment program for patients with neuropathic form of diabetic foot syndrome after radical surgical treatment of the pyo-necrotic lesion allows reducing the time of wound cleansing and the transition of the pyo-necrotic process to the reparative stage. On the other hand, this makes it possible for this category of patients to perform plastic closure of the wound at an earlier date, avoid generalization of infection and high level amputation of the limb.
Subject(s)
Diabetic Foot/therapy , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , Amputation, Surgical , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/administration & dosage , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/therapeutic use , Combined Modality Therapy , Diabetic Foot/complications , Diabetic Foot/pathology , Drug Combinations , Humans , Interferon Type I/administration & dosage , Interferon Type I/therapeutic use , Necrosis/etiology , Necrosis/therapy , Negative-Pressure Wound Therapy , Suppuration/drug therapy , Suppuration/etiology , SyndromeABSTRACT
Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Tier-1 Select Agents that cause melioidosis and glanders, respectively. These are highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis, and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened â¼220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis, a closely related BSL-2 surrogate. We identified 268 hits, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm Among these were a fluoroquinolone analog, which we named burkfloxacin (BFX), which potently inhibits growth of intracellular Burkholderia, and flucytosine (5-FC), an FDA-approved antifungal drug. We found that 5-FC blocks the intracellular life cycle at the point of type VI secretion system 5 (T6SS-5)-mediated cell-cell spread. Bacterial conversion of 5-FC to 5-fluorouracil and subsequently to fluorouridine monophosphate is required for potent and selective activity against intracellular Burkholderia In a murine model of fulminant respiratory melioidosis, treatment with BFX or 5-FC was significantly more effective than ceftazidime, the current antibiotic of choice, for improving survival and decreasing bacterial counts in major organs. Our results demonstrate the utility of cell-based phenotypic screening for Select Agent drug discovery and warrant the advancement of BFX and 5-FC as candidate therapeutics for melioidosis in humans.
Subject(s)
Burkholderia pseudomallei/drug effects , Ciprofloxacin/pharmacology , Drug Repositioning , Flucytosine/pharmacology , Melioidosis/drug therapy , Animals , Burkholderia pseudomallei/pathogenicity , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/therapeutic use , Cytoplasm/drug effects , Cytoplasm/microbiology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Flucytosine/therapeutic use , HEK293 Cells , High-Throughput Screening Assays , Humans , Melioidosis/microbiology , Mice , Microbial Sensitivity Tests , Treatment Outcome , VirulenceABSTRACT
BACKGROUND: Antimicrobial resistance in staphylococci, often associated with treatment failure, is increasingly reported in veterinary medicine. The aim of this study was to investigate patterns and predictors of antimicrobial resistance among Staphylococcus spp. isolates from canine samples submitted to the bacteriology laboratory at the University of Pretoria academic veterinary hospital between 2007 and 2012. Retrospective data of 334 Staphylococcus isolates were used to calculate the proportion of samples resistant to 15 antimicrobial agents. The Cochran-Armitage trend test was used to investigate temporal trends and logistic regression models were used to investigate predictors of antimicrobial resistance in Staphylococcus aureus and Staphylococcus pseudintermedius. RESULTS: Results show that 98.2% (55/56) of the S. aureus isolates were resistant to at least one drug while 42.9% were multidrug resistant. Seventy-seven percent (214/278) of the S. pseudintermedius isolates were resistant to at least one drug and 25.9% (72/278) were multidrug resistant. Resistance to lincospectin was more common among S. aureus (64.3%) than S. pseudintermedius (38.9%). Similarly, resistance to clindamycin was higher in S. aureus (51.8%) than S. pseudintermedius (31.7%) isolates. There was a significant (p = 0.005) increase in S. aureus resistance to enrofloxacin over the study period. Similarly, S. pseudintermedius exhibited significant increasing temporal trend in resistance to trimethoprim-sulphamethoxazole (p = 0.004), clindamycin (p = 0.022) and orbifloxacin (p = 0.042). However, there was a significant decreasing temporal trend in the proportion of isolates resistant to doxycycline (p = 0.041), tylosin (p = 0.008), kanamycin (p = 0.017) and amoxicillin/clavulanic acid (p = 0.032). CONCLUSIONS: High levels of multidrug resistance and the increasing levels of resistance to sulphonamides, lincosamides and fluoroquinolones among Staphylococcus spp. isolates in this study are concerning. Future studies will need to investigate local drivers of antimicrobial resistance to better guide control efforts to address the problem.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Dog Diseases/microbiology , Staphylococcal Infections/veterinary , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Animals , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/therapeutic use , Clindamycin/therapeutic use , Dog Diseases/drug therapy , Dog Diseases/epidemiology , Dogs , Doxycycline/therapeutic use , Drug Resistance, Bacterial , Drug Resistance, Multiple, Bacterial , Enrofloxacin , Female , Fluoroquinolones/therapeutic use , Hospitals, Animal/statistics & numerical data , Kanamycin/therapeutic use , Lincomycin/therapeutic use , Male , Retrospective Studies , South Africa/epidemiology , Spectinomycin/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Staphylococcus/drug effects , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Tylosin/therapeutic useABSTRACT
Biofilm formation can cause refractory urinary tract infections (UTIs) in dogs; however, minimum biofilm eradication concentrations (MBECs) of veterinary drugs against canine uropathogens remain to be investigated. In this study, the MBECs of orbifloxacin (OBFX), trimethoprim-sulfamethoxazole (TMS) and amoxicillin/clavulanate (ACV) over different time periods for treatment of canine uropathogenic Escherichia coli (n = 10) were determined. The MBECs of OBFX for other bacterial uropathogens, including Staphylococcus pseudintermedius (n = 5), Pseudomonas aeruginosa (n = 5), Klebsiella pneumoniae (n = 5) and Proteus mirabilis (n = 5) were also determined. Minimum inhibitory concentrations (MICs) were identified for all strains by broth microdilution, and MBECs were determined at 24, 72, and 168 hr using the Calgary biofilm method. The 24 hr MBECs of OBFX, TMS and ACV for the E. coli strains were significantly higher than the MICs (P < 0.05), and the 72 and 168 hr MBECs were significantly lower than those at 24 hr (P < 0.05). In addition, the 24 hr OBFX MBECs for the four other uropathogens were significantly higher than the corresponding MICs (P < 0.05). The 72 and/or 168 hr OBFX MBECs for S. pseudintermedius, K. pneumoniae and P. mirabilis were significantly lower than the 24 hr concentrations (P < 0.05), whereas for P. aeruginosa, no significant difference was found between any of the MBECs (P > 0.05). These data indicate that the administration period and uropathogenic bacterial species are important factors affecting the efficacy of OBFX treatment of biofilm-related UTIs in dogs.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Ciprofloxacin/analogs & derivatives , Dog Diseases/drug therapy , Dog Diseases/microbiology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Urinary Tract Infections/veterinary , Amoxicillin-Potassium Clavulanate Combination/pharmacology , Animals , Biofilms/growth & development , Ciprofloxacin/pharmacology , Disease Eradication , Dogs , Microbial Sensitivity Tests , Trimethoprim, Sulfamethoxazole Drug Combination/pharmacology , Urinary Tract Infections/microbiologyABSTRACT
Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a "target and release" chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 µmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 µmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/therapeutic use , Diphosphonates/chemistry , Diphosphonates/therapeutic use , Osteomyelitis/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Biofilms/drug effects , Bone and Bones/drug effects , Bone and Bones/microbiology , Ciprofloxacin/pharmacology , Diphosphonates/pharmacology , Drug Design , Female , Osteomyelitis/microbiology , Rats, Sprague-Dawley , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiologyABSTRACT
Ciprofloxacin (CP) is a fluoroquinolone that is highly active against diverse microorganisms. At concentrations less than 1 µg/ml it is active against a diverse types of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Bacillius subtilius, Escherichia coli and Mycobacterium tuberculosis. In addition, it has shown to be effective against other diseases such as malaria, cancer and AIDS. The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous. In the pursuit of increasing their effectiveness against these diseases and prevent unwanted resistance, researchers have begun to synthesize a class of organic, inorganic and organometallic derivatives, which have displayed interesting activities. This review describes the development and recent advances on the evaluation of CP and its derivatives as a new class of drugs with potential for clinical development.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/therapeutic use , Acquired Immunodeficiency Syndrome/drug therapy , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Humans , Malaria, Falciparum/drug therapy , Microbial Sensitivity Tests , Neoplasms/drug therapyABSTRACT
The paper presents the results of clinical examination of 114 patients aged 60-88 years with acute odontogenous periostitis receiving treatment in in-patient maxillofacial surgery unit. The dynamic of clinical symptoms is used to carry out the comparative effectiveness study of several peroral antibiotics in elderly patients.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Jaw Diseases/drug therapy , Jaw Diseases/microbiology , Periostitis/drug therapy , Periostitis/microbiology , Acute Disease , Aged , Aged, 80 and over , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Ciprofloxacin/analogs & derivatives , Female , Fluoroquinolones/therapeutic use , Humans , Jaw Diseases/diagnosis , Male , Middle Aged , Ofloxacin/therapeutic use , Periostitis/diagnosis , Suppuration/diagnosis , Suppuration/drug therapy , Suppuration/microbiology , Treatment OutcomeABSTRACT
The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable.
Subject(s)
Ciprofloxacin/analogs & derivatives , Drug Evaluation, Preclinical/methods , Models, Theoretical , Software , Administration, Oral , Animals , Area Under Curve , Ciprofloxacin/administration & dosage , Ciprofloxacin/pharmacokinetics , Models, Statistical , Rats , Rats, Wistar , Research DesignABSTRACT
OBJECTIVE: Our objective was to monitor the evolution of bone and/or joint infections with the aid of successive radiolabelled ciprofloxacin (Infecton) scans during antimicrobial treatment and to compare the results of an Infecton scan at the end of therapy with the respective results of clinical evaluation, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in predicting resolution or recurrence of infection after a long period of posttreatment follow-up. METHODS: Thirty-three patients with documented bone and/or joint infection were subjected to successive Infecton scans on two or three visits. Infecton scans were evaluated visually and scored accordingly. Clinical evaluation was scored by the referring clinicians. ESR and CRP values were evaluated independently. A minimum of 2-year free-of-infection follow-up after discontinuation of the antibiotic treatment served as a measure of successful antimicrobial therapy and nonrecurrence of infection. Statistics included survival analysis (Cox regression). RESULTS: During follow-up, five patients in the study presented with recurrence, and three died as a result of an irrelevant cause. The remaining patients were followed up for a median of 108 months (range 97-132 months) without any signs of recurrence of infection. Recurrence of infection was 4.2 times more likely to occur in patients with positive Infecton scans [hazard ratio (HR): 4.2, confidence intervals 95%: 1.39-12.67, P=0.011]. Infecton had the highest sensitivity (83.3%), accuracy (69.69%) and negative predictive value (94.74%), whereas CRP had the highest specificity (76.92%). CONCLUSION: Infecton scintigraphy proved to be more sensitive and accurate and had a higher negative predictive value compared with clinical evaluation, ESR and CRP in predicting infection resolution or recurrence in patients with chronic bone and joint infections.
Subject(s)
Arthrography/methods , Bone Diseases, Infectious/diagnosis , Joint Diseases/diagnosis , Tomography, Emission-Computed/methods , Adult , Aged , Blood Sedimentation , Bone Diseases, Infectious/mortality , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , C-Reactive Protein/metabolism , Chronic Disease , Ciprofloxacin/analogs & derivatives , Disease Progression , Female , Follow-Up Studies , Humans , Joint Diseases/mortality , Joints/diagnostic imaging , Joints/pathology , Male , Middle Aged , Organotechnetium Compounds , Osteomyelitis/diagnostic imaging , Osteomyelitis/mortality , Predictive Value of Tests , Prospective Studies , Radiopharmaceuticals , Recurrence , Survival Analysis , Tomography, X-Ray Computed/methods , Treatment OutcomeABSTRACT
The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB-8902) were evaluated. In vitro time-kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP-resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the toxicity of UB-8902, its 50% protective dose (PD(50)) (peritoneal sepsis model), its pharmacokinetic/pharmacodynamic (PK/PD) parameters and its efficacy in a pneumonia model were studied. The maximum tolerated dose of UB-8902 was 512 mg/kg. PD(50) values were 16, 128 and 32 mg/kg for Ab58, Ab661 and Ab33, respectively. Pharmacokinetic parameters of UB-8902 were similar to MXF and were lower than those for CIP, whilst pharmacodynamic parameters were better than CIP. In the pneumonia model, UB-8902 decreased the bacterial lung concentration [4.62 colony-forming units (CFU)/g and 4.15log(10)CFU/g] and positive blood cultures (60% and 62.5%) for Ab58 and Ab33, respectively, compared with the control. In conclusion, UB-8902 presents bactericidal activity against A. baumannii strains resistant to CIP. Moreover, it is effective at reducing mortality in a model of peritoneal sepsis with a dose lower than the toxic one, and it is efficacious in a murine pneumonia model.
Subject(s)
Acinetobacter Infections/drug therapy , Acinetobacter baumannii/drug effects , Anti-Infective Agents/pharmacology , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Pneumonia/drug therapy , Acinetobacter Infections/microbiology , Acinetobacter baumannii/isolation & purification , Animals , Anti-Infective Agents/pharmacokinetics , Anti-Infective Agents/therapeutic use , Blood Bactericidal Activity , Ciprofloxacin/pharmacokinetics , Ciprofloxacin/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial , Female , Fluoroquinolones/pharmacology , Lethal Dose 50 , Maximum Tolerated Dose , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Molecular Conformation , Pneumonia/microbiology , Quinolones/pharmacokinetics , Quinolones/pharmacology , Quinolones/therapeutic useABSTRACT
Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Subject(s)
Epilepsy, Absence/metabolism , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Electroencephalography/drug effects , Epilepsy, Absence/drug therapy , Epilepsy, Absence/genetics , Excitatory Amino Acid Antagonists/pharmacology , Male , Motor Activity/drug effects , Motor Activity/physiology , Nucleic Acid Synthesis Inhibitors/pharmacology , Quinolines/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Inbred ACI , Rats, Inbred Strains , Receptors, Metabotropic Glutamate/genetics , Signal Transduction/drug effects , Thalamic Nuclei/metabolism , Thalamic Nuclei/physiopathology , Thalamus/metabolism , Thalamus/physiopathologyABSTRACT
In the evidence-based medicine era, objective treatment guidelines have been laid down for pulmonary tuberculosis, but the same is not true for osteoarticular tuberculosis. This has led to demands for standardising the treatment protocol and to a lack of consensus between doctors regarding the composition and duration of treatment. Twenty-five patients with extraspinal osteoarticular tuberculosis were evaluated prospectively. Following the diagnosis, patients were given standard directly observed treatment short course (DOTS) regimen and were monitored for disease activity at zero, three and six months with the help of technetium-99m-labelled ciprofloxacin ((99m)Tc) scan. Tracer activity at the site was recorded and compared on sequential scans. Clinical and radiological profile of all the patients were also recorded at regular intervals and compared. All 25 cases had a positive (99m)Tc bone scan initially. Four patients (16%) converted to negative scans at three months, whereas the remaining 21 patients (84%) showed negative scans at six months. The end of six months therapy also coincided with resolution of clinical and radiological parameters in all cases. In conclusion, (99m)Tc scan is a promising tool for monitoring drug response in osteoarticular tuberculosis; however, due to the small sample size, studies with a large number of patients might be of help.
Subject(s)
Antitubercular Agents/therapeutic use , Ciprofloxacin/analogs & derivatives , Drug Monitoring/methods , Organotechnetium Compounds , Radiopharmaceuticals , Tuberculosis, Osteoarticular/diagnostic imaging , Tuberculosis, Osteoarticular/drug therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Prospective Studies , Radionuclide Imaging , Time Factors , Treatment Outcome , Young AdultABSTRACT
This article presents some experience obtained by applying capillary gas chromatography coupled with thermal conductivity detection (GC/TCD) to the determination of water in substances for pharmaceutical use. This technique represents a useful, orthogonal tool complementary to water determination methods based on volumetric or coulometric titration. It can also represent an alternative technique when such titrations are not applicable. This article presents the preliminary results obtained in a number of case studies where a GC/TCD procedure was applied in comparison with pharmacopoeial methods to substances with different water contents.
Subject(s)
Pharmaceutical Preparations/analysis , Water/analysis , Amoxicillin/analysis , Anti-Bacterial Agents/analysis , Chromatography, Gas/methods , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/analysis , European Union , Indicators and Reagents , Solvents , Spectinomycin/analysis , Theophylline/analysis , Thermal ConductivityABSTRACT
OBJECTIVE: To investigate the diagnostic efficacy of indigenously developed single vial kit preparation of Tc-ciprofloxacin (Diagnobact) for the detection of orthopedic infections. METHODS: Seventy-seven patients [25 with clinical suspicion of diabetic foot osteomyelitis (DFOM), 25 with orthopedic device-related infection (ODRI) and 27 with tubercular bone infection] underwent three-phase Tc-methylenediphosphonate bone scintigraphy followed by static Tc-ciprofloxacin imaging at 1, 4 and 24 h. Imaging (anterior and posterior views) was performed under a dual-head gamma-camera using a low-energy, high-resolution, parallel-hole collimator. The lesion-to-background ratio (LBR) of the radiotracer was calculated on the static isotime Tc-ciprofloxacin images using semiquantitative analysis. Scintigraphic (Diagnobact) results were compared with the histopathological and/or culture/PCR analysis as a gold standard. RESULTS: The mean LBR of the radiotracer (Tc-ciprofloxacin) in the positive scans (n=29; 16 ODRI, 13 DFOM) was > or =2.0 at 1 h postinjection and remained consistent till 24 h. In contrast, the mean LBR in the negative scans (n=21; 12 DFOM, nine ODRI) was < or =1.5 at 1 h and declined significantly (P<0.05) at 24 h. The observed trend in the mean LBR in positive (n=18) and negative (n=9) scans for tubercular osteomyelitis was identical to that seen in the nontubercular bacterial infections. CONCLUSION: The management protocol for patients with suspected bony infection may include a three-phase bone scan followed by Tc-ciprofloxacin scan. An LBR of > or =2.0 at 1 h that remained consistent till 24 h on Tc-ciprofloxacin scan is indicative of active bacterial infection. However, resistance to ciprofloxacin at the bacterial cell membrane may be a limitation of this technique.
Subject(s)
Bacterial Infections/diagnostic imaging , Bone Diseases, Infectious/diagnostic imaging , Ciprofloxacin/analogs & derivatives , Medicine, Traditional , Organotechnetium Compounds , Adolescent , Adult , Bacterial Infections/diagnosis , Bacterial Infections/etiology , Bone Diseases, Infectious/diagnosis , Bone Diseases, Infectious/etiology , Diabetic Foot/diagnostic imaging , Diagnosis, Differential , Female , Humans , Image Processing, Computer-Assisted , India , Inflammation/diagnosis , Inflammation/diagnostic imaging , Male , Middle Aged , Orthopedic Fixation Devices/adverse effects , Osteomyelitis/diagnostic imaging , Radioactive Tracers , Radionuclide Imaging , Tuberculosis, Osteoarticular/diagnostic imaging , Young AdultSubject(s)
Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/analogs & derivatives , Escherichia coli Infections/veterinary , Fluoroquinolones/therapeutic use , Puerperal Disorders/veterinary , Sheep Diseases/drug therapy , Uterine Diseases/veterinary , Animals , Anti-Bacterial Agents/administration & dosage , Antibiotic Prophylaxis/veterinary , Case-Control Studies , Ciprofloxacin/administration & dosage , Ciprofloxacin/therapeutic use , Escherichia coli Infections/drug therapy , Female , Fluoroquinolones/administration & dosage , Pregnancy , Puerperal Disorders/drug therapy , Sheep , Sheep Diseases/pathology , Uterine Diseases/drug therapyABSTRACT
Orbifloxacin tablets were administered orally to 23 dogs with superficial and/or deep staphylococcal pyoderma. Response to therapy was excellent in 95.6% of the dogs. Duration of therapy varied from 21 to 40 days (average 29 days) for dogs having only superficial infections, and from 25 to 150 days (average 72 days) for dogs having deep infections. Relapses occurred in 18% of the dogs within a 3-month period. One dog developed a presumed adverse cutaneous drug reaction. Under the conditions of this study, orbifloxacin was an effective, safe, and convenient antibiotic for the treatment of superficial and deep staphylococcal pyoderma in dogs.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/analogs & derivatives , Dog Diseases/drug therapy , Staphylococcal Infections/veterinary , Animals , Anti-Bacterial Agents/adverse effects , Ciprofloxacin/adverse effects , Ciprofloxacin/therapeutic use , Dogs , Female , Male , Pyoderma/drug therapy , Pyoderma/veterinary , Staphylococcal Infections/drug therapy , Time Factors , Treatment OutcomeABSTRACT
DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by a common three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(DeltaE) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclear envelope. Therefore, suppressing torsinA(DeltaE) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(DeltaE) and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immunodeficiency virus effectively silenced torsinA(DeltaE) in a neural model of the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstrating significant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease.
Subject(s)
Dystonia/drug therapy , Gene Silencing/physiology , Lentivirus/physiology , Molecular Chaperones/metabolism , RNA, Small Interfering/therapeutic use , Animals , Blotting, Western/methods , Cell Count/methods , Cells, Cultured , Cerebral Cortex/cytology , Chlorocebus aethiops , Ciprofloxacin/analogs & derivatives , Cloning, Molecular/methods , Doxycycline , Dystonia/metabolism , Embryo, Mammalian , Fluorescent Antibody Technique/methods , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Gene Silencing/drug effects , Green Fluorescent Proteins/metabolism , Humans , Interferons/pharmacology , Mice , Molecular Chaperones/genetics , Mutagenesis/physiology , Neurons/drug effects , Neurons/metabolism , Organotechnetium Compounds , RNA, Small Interfering/genetics , Sequence Deletion/physiology , Transfection/methodsABSTRACT
The use of radiolabelled antibiotics is fast emerging as a promising diagnostic test for the detection of infective lesions, because of their specific binding to the bacterial component. Ciprofloxacin is a broad-spectrum antibiotic that has been used as a radiolabelled antibiotic in both the diagnosis of infections in rabbits and in clinical trials on humans. The diagnosis of skeletal microbial infections remains a challenge, especially in orthopaedic patients with implants. We present a case report of a patient with undiagnosed and unrelenting pain in the lower third of the left leg, which had persisted for 6 months. A novel scintigraphy, which was developed in-house using a 99mTC ciprofloxacin single vial kit, was used for diagnosing the active bacterial infection. A 99mTC methylene diphosphonate bone scan was also performed to locate precisely the site of the lesion. Gradually increasing concentrations of both the radiotracers confirmed the presence of active bacterial infection in the distal third of the left tibia. Follow-up scanning after antibiotic therapy showed the disappearance of the pooling of 99mTC ciprofloxacin, indicating a good response. Therefore, 99mTC ciprofloxacin has good diagnostic and prognostic applications in deep-seated covert skeletal microbial infections. However, the persistence of a focal concentration detected by the 99mTC methylene diphosphonate scan was attributed to the inflammatory and not the infective pathology.