In vitro and ex vivo antibacterial activity of levofloxacin against Pasteurella multocida and Escherichia coli isolated from rabbits (Oryctolagus cuniculus) - A preliminary study.

Levofloxacin veterinary formulations are available in Argentina, China and India for the use in dogs, cattle, pig and sheep, but not currently in the rabbit. Only the extra-label use in rabbits is possible. Levofloxacin is not labelled for veterinary use in the EU or the USA. The activity of levofloxacin against rabbit pathogens Pasteurella multocida (P. multocida) and Escherichia coli (E. coli) was evaluated. Minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined in broth and serum for 10 P. multocida isolates and 5 E. coli isolates from rabbits. One isolate of each bacterial species was used for the time-killing curve study in vitro and ex vivo. In vitro AUC24 /MIC ratios were used for building the inhibitory pharmacodynamic Imax model. The P. multocida MIC were 0.008-0.5 µg/mL, MBC - 0.015-0.5 µg/mL. Escherichia coli MIC was 0.008-0.03 µg/mL and MBC - 0.03-0.25 µg/mL. Bacterial counts were reduced to the limit of detection after 24 h with levofloxacin concentrations of 2 MIC and higher. All serum samples from rabbits treated with levofloxacin eliminated the bacteria within 24 h. AUC24 /MIC ratios for bacteriostatic, bactericidal and bacterial elimination effects for P. multocida and E. coli isolates were 21, 29 and 75 h and 27, 32 and 60 h, respectively. Proposed daily doses against P. multocida (MIC = 0.015 µg/mL) and E. coli (MIC = 0.03 µg/mL) isolates were calculated as ≤0.91 and ≤1.43 mg/kg, respectively. Fluoroquinolones are categorized by WHO as 'highest priority critically important antimicrobials'. Considering the increasing importance of antimicrobial stewardship, antimicrobials from a lower importance category that are active against the isolate of interest should be used in preference to fluoroquinolones. Fluoroquinolone use in veterinary medicine should be based on antimicrobial susceptibility testing in order to mitigate the risk to public health and prevent the spread of bacterial resistance.

Colistin co-administration with other nephrotoxins: experience of teaching hospital of Latvia.

Background Colistin is a potentially nephrotoxic antibiotic used for the management of multidrug-resistant bacterial infections in critically ill patients. Co-administration with other nephrotoxins was reported as a potentially modifiable risk factor of colistin acute kidney injury. Objective To establish the role of colistin dosing and co-medications in development of colistin kidney injury. Setting Community teaching hospital in Latvia. Method Adult patients from intensive care units with diagnosed Gram-negative bacterial infections, undergoing colistin treatment for longer than 72 h, and not receiving renal replacement therapy were included in this retrospective study. Main outcome measure Colistin nephrotoxicity was defined as an increase in the serum creatinine level by at least 50% from the baseline after ≥ 48 h. Results In 73 of 87 cases, Acinetobacter baumannii pneumonia was diagnosed. The nephrotoxicity rate was 27.6% with a median onset of 8 days. In 79% of the cases, colistin was co-administrated with at least one potentially nephrotoxic agent. The most used nephrotoxins were loop diuretics (44 cases), non-steroidal anti-inflammatory drugs (19 cases) and vancomycin (11 cases). The use of nephrotoxins was similar in patients with colistin nephrotoxicity (group-1) and without it (group-2). Carbapenems were more common in group-2 (37% vs 62%, p = 0.004) and a colistin loading dose of 9 MU in group-1 (87% vs 62%, p = 0.027). However, in the multifactor regression analysis, the protective role of carbapenems was not confirmed. Conclusion Potentially nephrotoxic agents are commonly co-administrated with colistin. This study failed to prove their role in the development of acute kidney injury.

Pharmacokinetic profiles of levofloxacin after intravenous, intramuscular and subcutaneous administration to rabbits (Oryctolagus cuniculus).

Levofloxacin pharmacokinetic profiles were evaluated in 6 healthy female rabbits after intravenous (I/V), intramuscular (I/M), or subcutaneous (S/C) administration routes at a single dose of 5 mg/kg in a 3 × 3 cross-over study. Plasma levofloxacin concentrations were detected using a validated Ultra Performance Liquid Chromatography method with a fluorescence detector. Levofloxacin was quantifiable up to 10 h post-drug administration. Mean AUC0-last values of 9.03 ± 2.66, 9.07 ± 1.80, and 9.28 ± 1.56 mg/h*L were obtained via I/V, I/M, and S/C, respectively. Plasma clearance was 0.6 mL/g*h after I/V administration. Peak plasma concentrations using the I/M and S/C routes were 3.33 ± 0.39 and 2.91 ± 0.56 µg/mL. Bioavailability values, after extravascular administration were complete, - 105% ± 27% (I/M) and 118% ± 40% (S/C). Average extraction ratio of levofloxacin after I/V administration was 7%. Additionally, levofloxacin administration effects on tear production and osmolarity were evaluated. Tear osmolarity decreased within 48 h post-drug administration. All 3 levofloxacin administration routes produced similar pharmacokinetic profiles. The studied dose is unlikely to be effective in rabbits; however, it was calculated that a daily dose of 29 mg/kg appears effective for I/V administration for pathogens with MIC < 0.5 µg/mL.

Colistin Use in Patients with Extreme Renal Function: From Dialysis to Augmented Clearance.

Background and objectives: Colistin is used for the treatment of multidrug-resistant (MDR) Gram-negative bacteria infection in critically ill patients. It is recommended to adjust the dose in cases of renal impairment but not in cases of augmented renal clearance (ARC). The aim of this study was to determine colistin use pattern in patients with different renal functional states. Materials andMethods: Adult patients admitted to intensive care units of single Latvian hospitals in the years 2015⁻2017 with an MDR Gram-negative bacterial infection and at least 72 h colistin therapy were included in this study. Data were collected retrospectively from medical notes. Colistin use pattern and outcomes were analyzed in patients with different renal function prior to colistin therapy: normal, ARC, impaired, and on renal replacement therapy (RRT). Results: 100 cases of colistin use met the inclusion criteria. The study group was heterogeneous, and patients had different renal function states prior to colistin therapy-from continuous RRT (18 cases) to ARC (16 cases). The standard colistin dose of 9 million units (MU) daily was the most common dose among the patients. In many cases (43%), colistin dose adjustment did not follow the recent recommendations of drug manufacturers-this was mainly in patients with renal impairment prior to colistin therapy. Eighteen cases of colistin acute kidney injury (AKI) were detected, mostly (10 cases) in patients with normal renal function and without ARC prior to colistin therapy. No patients with colistin AKI needed RRT. Conclusions: Colistin doses varied greatly among patients, and in patients with renal function impairment it was commonly not in accordance with the summary of product characteristics (SPC). Patients with ARC mostly received a standard colistin daily dose of 9 MU daily, but the cumulative dose had a tendency to be higher and duration of colistin therapy was longer in comparison with other patient groups. ARC's role in the development of colistin nephrotoxicity is still unclear.

Characteristics of clinical trials in rare vs. common diseases: A register-based Latvian study.

BACKGROUND: Conducting clinical studies in small populations may be very challenging; therefore quality of clinical evidence may differ between rare and non-rare disease therapies. OBJECTIVE: This register-based study aims to evaluate the characteristics of clinical trials in rare diseases conducted in Latvia and compare them with clinical trials in more common conditions. METHODS: The EU Clinical Trials Register (clinicaltrialsregister.eu) was used to identify interventional clinical trials related to rare diseases (n = 51) and to compose a control group of clinical trials in non-rare diseases (n = 102) for further comparison of the trial characteristics. RESULTS: We found no significant difference in the use of overall survival as a primary endpoint in clinical trials between rare and non-rare diseases (9.8% vs. 13.7%, respectively). However, clinical trials in rare diseases were less likely to be randomized controlled trials (62.7% vs. 83.3%). Rare and non-rare disease clinical trials varied in masking, with rare disease trials less likely to be double blind (45.1% vs. 63.7%). Active comparators were less frequently used in rare disease trials (36.4% vs. 58.8% of controlled trials). Clinical trials in rare diseases enrolled fewer participants than those in non-rare diseases: in Latvia (mean 18.3 vs. 40.2 subjects, respectively), in the European Economic Area (mean 181.0 vs. 626.9 subjects), and in the whole clinical trial (mean 335.8 vs. 1406.3 subjects). Although, we found no significant difference in trial duration between the groups (mean 38.3 vs. 36.4 months). CONCLUSIONS: The current study confirms that clinical trials in rare diseases vary from those in non-rare conditions, with notable differences in enrollment, randomization, masking, and the use of active comparators. However, we found no significant difference in trial duration and the use of overall survival as a primary endpoint.

Impact of orphan drugs on Latvian budget.

BACKGROUND: Number of orphan medicinal products on the market and number of rare disease patients, taking these usually expensive products, are increasing. As a result, budget impact of orphan drugs is growing. This factor, along with the cost-effectiveness of orphan drugs, is often considered in the reimbursement decisions, directly affecting accessibility of rare disease therapies. The current study aims to assess the budget impact of orphan drugs in Latvia. METHODS: Our study covered a 5-year period, from 2010 to 2014. Impact of orphan drugs on Latvian budget was estimated from the National Health Service's perspective. It was calculated in absolute values and relative to total pharmaceutical market and total drug reimbursement budget. A literature review was performed for comparison with other European countries. RESULTS: Orphan drug annual expenditure ranged between EUR 2.065 and 3.065 million, with total 5-year expenditure EUR 12.467 million. It constituted, on average, 0.84 % of total pharmaceutical market and 2.14 % of total drug reimbursement budget, respectively. Average annual per patient expenditures varied widely, from EUR 1 534 to EUR 580 952. The most costly treatment was enzyme replacement therapy (Elaprase) for MPS II. Glivec had the highest share (34 %) of the total orphan drug expenditure. Oncological drugs represented more than a half of the total orphan drug expenditure, followed by drugs for metabolic and endocrine conditions and medicines for cardiopulmonary diseases. Three indications: Ph+ CML, MPS II, and PAH accounted for nearly 90 % of the total orphan drug expenditure. CONCLUSIONS: Budget impact of orphan drugs in Latvia is very small. It increased slightly over a period of five years, due to the slight increase in the number of patients and the number of orphan drugs reimbursed. Current Latvian drug reimbursement system is not sufficient for most orphan drugs.

Acute psychosis due to non-paraneoplastic anti-NMDA-receptor encephalitis in a teenage girl: Case report.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a disease occurring when antibodies produced by the body's own immune system attack NMDA-type glutamate receptors in the brain. Most anti-NMDAR encephalitis cases are associated with paraneoplastic syndrome. We analyze the case of a 15-year-old girl who was hospitalized in a child psychiatry clinic in Riga, Latvia, with de novo acute polymorphic psychotic disorder gradually progressing to a catatonic state. The patient received antipsychotic and electroconvulsive therapy with no beneficial effect. The council of doctors discussed differential diagnoses of schizophrenia-induced catatonia and the autoimmune limbic encephalitis-induced catatonic condition. When the diagnosis of anti-NMDAR autoimmune encephalitis was finally confirmed by repeated immunological assays (specific immunoglobulin [Ig] G and IgM in her blood serum and cerebrospinal fluid), and a paraneoplastic process was ruled out, she was started on immunomodulating therapy (methylprednisolone, Ig, plasmapheresis, rituximab), which changed the course of her disease. On immunomodulating treatment, her physical and mental health have gradually improved to almost complete reconvalescence. Psychiatrists should consider anti-NMDAR encephalitis as a differential diagnosis in first-episode psychosis patients presenting with disorientation, disturbed consciousness, pronounced cognitive deficits, movement disorder, dysautonomia, or rapid deterioration, and test for specific IgG NR1 autoantibodies, even if there are no specific findings on routine neuroimaging, electroencephalography (EEG), or cerebrospinal fluid tests.

Rare diseases and orphan drugs: Latvian story.

BACKGROUND: Ten years have passed since Latvia became a Member State of the EU in 2004. As a result European regulations, including those related to rare diseases and orphan drugs, have been applied to Latvian legislative system. Orphan diseases have been recognized as a priority area for action in the public health system, though there are significant differences in the national healthcare services for rare diseases among the EU States. This study aims to determine situation in the field of rare diseases in Latvia and compare it with other European countries. METHODS: We used the national plan for rare diseases, EUCERD reports, Orphanet data, Latvian and European regulations, publicly available data from the state agencies, and directly contacted drug manufacturers and wholesalers. RESULTS: National plan for rare diseases was developed and approved in 2013. Although there are no official designated centers of expertise as well as no specific register for rare diseases. Newborns are screened for only two disorders: phenylketonuria and congenital hypothyroidism. Currently 34 orphan drugs are available on Latvian market. Three medicines (8.8%) are included in the reimbursement drug list, all indicated for Ph + CML. 15 drugs (44.1%) were reimbursed within the framework of individual reimbursement system, and five drugs (14.7%) were provided within the program of medicinal treatment of rare diseases in children. CONCLUSIONS: Majority of orphan drugs authorized in the EU are not available in Latvia, moreover those drugs that are available are often not accessible because they are insufficiently reimbursed. Besides, approval of the national plan might be an important step towards improving situation in the field of rare diseases.

Homocysteine and MTHFR C677T polymorphism in children and adolescents with psychotic and mood disorders.

BACKGROUND: High level of homocysteine (Hcy) is risk factor of schizophrenia and mood disorders. AIM: The aim was to detect a serum level of Hcy, examine the associations between the level of Hcy, methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and clinical properties for patients with schizophrenia, mood disorders and in a control group. MATERIAL AND METHODS: There were 88 patients with schizophrenia, 28 with affective disorders and 94 from the control group. The Hamilton Anxiety Scale (HAM-A) was performed to study anxiety, the Hamilton Depression Scale (HAM-D) to study depression and the Brief Psychiatric Rating Scale (BPRS) to study severity of schizophrenia. The level of Hcy was stated by isocratic high-performance liquid chromatography (HPLC) system with fluorometric detection. DNA isolation from venous blood was performed by the phenol-chloroform method. RESULTS: The levels of B12 vitamin and folic acid were within normal limits for all the patients. The average level of Hcy was 11.94 ± 5.6 µmol/l for patients with schizophrenia and 11.65 ± 3.3 µmol/l for patients with affective disorders, vs. 6.80 ± 2.93 µmol/l in a control group. The highest level of Hcy has been observed in patients with an episodic-recurrent course of schizophrenia, paranoid schizophrenia-continuous, particularly in patients with CT genotype (r = - 0.58; P < 0.01). In the given diagnostic groups, the highest level of anxiety was observed. CONCLUSIONS: The level of Hcy is higher in the blood of a heterozygotic person who becomes ill with schizophrenia, and the process of the illness is more serious and with more typical affective disorders.

Elevated serum levels of homocysteine as an early prognostic factor of psychiatric disorders in children and adolescents.

Background and Goal. The aim was to examine the serum levels of homocysteine (Hcy) and their associations with the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with schizophrenia and mood disorders as well as controls. Materials and Methods. There were 198 patients: 82 with schizophrenia spectrum disorders, 22 with mood disorders, and 94 controls. The level of Hcy was determined by an isocratic high-performance liquid chromatography system. MTHFR C677T polymorphism was analysed using the restriction fragment length polymorphism-polymerase chain reaction method. Results. The average level of Hcy was 11.94 ± 5.6 µmol/L for patients with schizophrenia, 11.65 ± 3.3 µmol/L for patients with affective disorders, versus 6.80 ± 2.93 µmol/L in a control. The highest level of Hcy has been observed in patients with episodic-recurrent course of schizophrenia (11.30 ± 7.74 µmol/L), paranoid schizophrenia continuous (12.76 ± 5.25 µmol/L), and in patients with affective disorders (11.65 ± 3.26 µmol/L). An association between the MTHFR gene C677T polymorphism and Hcy level was found by linear regression analysis (r = 1.41, P = 0.029). Conclusions. The data indicate a link between Hcy levels and schizophrenia and mood disorders. No associations between the level of Hcy in patients with schizophrenia and mood disorders and the MTHFR C677T polymorphism were found.