Single Daily Dose Regimen Research Articles

Tenofovir, Lamivudine, and Dolutegravir Among Rural Adolescents in Zimbabwe: A Cautionary Tale.

Tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) as a safe and more effective single daily dose regimen is rolling out in Africa for people living with HIV. Although access to viral load (VL) testing is improving, patients may still be transitioned to TLD with virological failure and potential drug resistance. We reviewed annual VL test results of 390 children and adolescents who had enrolled in a community-based antiretroviral therapy program in rural Zimbabwe between 2018 and 2019. VL testing was done by the near point of care simplified amplification-based assays (Diagnostics for the Real World, Sunnyvale, CA, USA) at Chidamoyo Christian Hospital and rate of virological suppression (VS) on TLD (VL <1,000 copies/mL) was assessed. Overall, 184 children and adolescents on TLD were enrolled in this study. The median [interquartile range (IQR)] age was 15 (11-19) years, above half of the participants were female (57%). Before switching to TLD, rate of VS was 76% (139/184). After a median (IQR) duration of 6.9 (5.5-9.1) months on TLD, VS was observed in 95% (174/184) of the participants. Of the 10 participants with VL ≥1,000 copies/mL on TLD, 90% (9/10) were failing on their previous regimens, 6 of 9 (67%) having been on boosted protease inhibitor-based regimens. A high rate (95%) of VS was observed among children and adolescents on TLD in rural Zimbabwe. TLD may address the problems of virological failure and emergence of resistance in Africa. However, longer follow-up might be needed to ascertain sustained VS in this vulnerable population. Randomized Control Trial NCT03986099.

Study the Effects of Anadrol Overdose on Liver Function in Male Rats

Anadrol (oxymetholone) is an active androgenic anabolic steroid that has been clinically studied in numerous diseases since the 1960s. It is used in the treatment of anemia and the replacement of male sex steroids. Unfortunately, in attempts to improve physical performance, Anadrol could be misused by athletes, that can lead to poisoning contributes to hepatotoxicity. The aim of this study was to investigate the impact of anadrol on the liver function in rat model, via assessment of liver enzymes and histopathological study. A forty male rats, weights about (200-300 gm), aged 8-12 weeks, after acclimatization, the rats were ‎randomly divided into four groups (10 rats in each group) as follow: control group (in which all rats were administered normal saline (NS) via oral gavage), anadrol 10 mg/kg (Iran-Tehran Company) group (in which all rats were administered anadrol 10mg/kg via oral gavage), anadrol 20 mg/kg group (in which all rats were administered anadrol 20mg/kg via oral gavage), and anadrol 30 mg/kg group (in which all rats were administered anadrol 30mg/kg via oral gavage), the oral administration had continued for 8 weeks in single daily dose regimen. At the end of study liver function enzymes such as alanine aminotransferase &amp; aspartate aminotransferase were measured via chemical analysis. Then histopathological study was done on the liver tissue in the four experimental groups. Male rats that treated with anadrol displayed high level of liver enzymes, including as alanine aminotransferase &amp; aspartate aminotransferase, as compared with control group. On the other hand, histopathological study exhibited significant injurious changes in the hepatic tissue in anadrol groups comparing with control. When anadrol given in high doses results in hepatic injury, that can be cleared via elevated levels of hepatic enzymes and liver histopathological changes.

Effectiveness, safety, and economic impact of the bictegravir/emtricitabine/tenofovir alafenamide regimen in real clinical practice cohort of HIV-1 infected adult patients

RESUMENIntroducciónDentro de los nuevos esquemas de tratamiento antirretroviral (TAR) destaca bictegravir (BIC), un inhibidor de la integrasa de reciente incorporación. BIC conjugado con emtricitabina (FTC) y tenofovir alafenamida (TAF) ha demostrado ser no inferior en eficacia como terapia de inicio en régimen de dosis única diaria comparado con otros TAR de inicio. El objetivo de nuestro estudio es evaluar el impacto de la inclusión de este nuevo esquema de TAR en la práctica clínica real.Material y métodosEstudio observacional, retrospectivo y descriptivo que incluyó todos los pacientes VIH adultos (edad ≥18 años) que llevaran al menos 24 semanas seguidas en tratamiento con BIC/FTC/TAF durante 1 año y medio para evaluar efectividad, seguridad e impacto económico.ResultadosSe incluyeron 115 pacientes. Los pacientes sin tratamiento previo, naive, fueron 28 (24,3%). Los pacientes pretratados presentaban una media de 42 ±9 meses de TAR previo. El porcentaje de pacientes en la semana 24 después de cambiar a BIC/FTC/TAF con carga viral plasmática suprimida fue del 88% en el grupo naive y del 94,1% en el grupo de pretratados. Se notificaron eventos adversos en 8 (7%) pacientes. El impacto económico que supuso el cambio a BIC/FTC/TAF fue de 1.202,63 €/paciente/año, representando un aumento del 9,3%. Conclusiones. Nuestros resultados se correlacionan con los resultados de dos ensayos clínicos fase 3 de no inferioridad en pacientes naive (88% y 84%) y los de un ensayo clínico fase 3 de no inferioridad en pacientes pretratados (86%). Sin embargo, observamos gran diferencia entre los altos porcentajes de pacientes que notificaron algún evento adverso en tres ensayos clínicos de fase 3 y nuestros resultados.

Gentamicin Vestibulotoxicity: Further Insights From a Large Clinical Series.

To review insights gained from a 21-year experience with gentamicin-induced vestibulotoxicity including differences in vestibulotoxicity between single daily dosing (SDD) and multiple daily dosing (MDD) regimens. Retrospective case series. Tertiary care center. Patients with gentamicin vestibulotoxicity referred to the Hertz Multidisciplinary Neurotology Clinic between January 1993 and September 2014. None. Spectrum of vestibular dysfunction measured using videonystagmography, vestibular evoked myogenic potentials, video head impulse testing, and magnetic scleral search coil testing. Of 53 patients with gentamicin-induced vestibulotoxicity, 24 received SDD and 29 received MDD treatment. The most common indications for treatment were sepsis, endocarditis, and osteomyelitis. Angular acceleration receptor function (semicircular canals) was more commonly affected than linear acceleration receptor function (otolithic organ of the saccule; 100% vs. 62%). A significant proportion of patients (53%) developed vestibulotoxicity in the absence of nephrotoxicity and 40% experienced vestibulotoxicity in a delayed fashion up to 10 days posttreatment cessation (mean 3.9 ± 0.7). Therapeutic monitoring did not necessarily prevent delayed vestibulotoxicity. Nephrotoxicity was less common for SDD compared with MDD (60% vs. 35%, p = 0.01). However, the SDD group experienced vestibulotoxicity at a lower cumulative dose (6.3 vs. 7.0 g, p = 0.04) and shorter duration of therapy (20.7 vs 29.4 d, p = 0.02). Our study further highlights important insights regarding gentamicin-induced vestibulotoxicity. While SDD is associated with decreased risk for nephrotoxicity compared with MDD, it confers a higher risk for vestibulotoxicity.

The Safety Profile of Single Daily Dose of Aminoglycosides in Comparison with Multiple Daily Dose

To overcome the problems which associated with the standard multiple daily doses (MDD)&#x0D; of aminoglycosides (AGs) like high incidence of toxicity(nephrotoxicity, ototoxicity)(5-25%) and high cost, an alternative approach was developed which was single daily dose (SDD).This new regimen was designed to maximize bacterial killing by optimizing the peak concentration/minimum inhibitory concentration(MIC)ratio and to reduce the potential for toxicity. The study includes 75 patients selected randomly, 50 of them received SDD regimen of age range of 17-79 years and the remaining received MDD regimen of age range of 13-71 years. The study was designed to evaluate the safety of SDD regimen in comparison with MDD regimen. All the patients in SDD group received a constant dose of 5-mg/kg/day of gentamicin and 20mg/kg/day of amikacin with a drug administration interval based on estimated creatinine clearance(CLcr): if ≥60 ml//min every 24 hours (q24h), 59- 40 ml/ min every 36hours and 39- 30 ml/min every 48 hours.The calculated dose was diluted with 0.9% normal saline or 5% dextrose to 50-100 ml and given as intravenous infusion over 30-60 minutes. In SDD group , the mean length of therapy was 6.4±1.73 days .Gentamicin accounted for 96% of the aminoglycoside use, and the majority(58%) of patients received the drug every 24 hours.The 36- and -48 hours intervals were used for 34 and 8% of the population, respectively.While in MDD group , the mean length of therapy was 5.0±0.91 days. Gentamicin accounted for all (100%) of aminoglycoside use, and all of the patients received the drug every 8 hours. No clinically apparent ototoxicity and nephrotoxicity were observed in the patients in the SDD group, in contrast to the patients in MDD group, in whom 4 patients (16%) were developed nephrotoxicity and 1 patient (4%) was developed ototoxicity. The obtained results indicate that SDD regimen was safer through decreasing the incidence of both nephrotoxicity and ototoxicity.For statistical analysis, ANOVA test was used with P&lt;0.01.Each mean was expressed as mean±SEM(Standard Error of Mean).&#x0D; Key words: Aminoglycosides, Single Daily Dose, Nephrotoxicity and Ototoxicity.

An Updated Review of the Optimal Lithium Dosage Regimen for Renal Protection

Despite several decades of research, there is still uncertainty regarding the optimal lithium dosage regimen associated with a decreased risk of renal effects, such as polyuria, in patients with bipolar affective disorder. We present an updated review of the literature to provide an informed dosing regimen recommendation for prescribers. Major databases MEDLINE and Embase were searched using terms, such as lithium, drug administration schedule, dose-response relationship, once daily, twice daily, and sustained release. In addition, the bibliographies of related publications were manually searched. A total of 20 trials were included. Some trials showed a reduction in urine volume with single daily dosing (SDD), while others showed no change. The only trial evaluating patients newly started on lithium found a reduction in urinary frequency with SDD after 21 days. Trials examining renal biopsy results found that multiple daily doses were associated with more pathologic damage to the kidneys. SDD regimens were generally well tolerated, and no reduction in efficacy was noted in any of the trials. The available evidence is contradictory as to whether SDD of lithium reduces polyuria; however, no trial has demonstrated any downfall of SDD in terms of prophylactic efficacy or adverse effects. Given the added benefits of SDD, such as improved compliance, we recommend patients newly started on lithium should be converted to a SDD of lithium at bedtime once an appropriate daily dose is determined.

Preliminary Data on Once-Daily IV Busulfan at 3.2 mg/kg/day Indicate That It Is Safe as a Component of the Conditioning Regimen for Hematopoietic Stem Cell Transplantation.

Busulfan is a useful chemotherapy in many stem cell transplant regimens. Data support the use of buslfan in transplant patients, especially if they have had prior treatment with radiation therapy. The dose of the busulfan used in myloablative stem cell transplantation has traditionally been sixteen oral doses of 1mg/kg/dose. The oral dosing has been limited by unreliable oral absorption of busulfan tablets. Transplant related mortality and incidence of venocclusive disease are directly related to high peak levels of busulfan. Relapse has been associated with low peak levels of busulfan.Recently, busulfan has become available as an IV preparation and preliminary data indicate that the peak busulfan levels are predictable via the IV administration route. The bulk of the data available on outcomes after transplantation using IV busulfan have used a QID dosing schedule of 0.8mg/kg/dose for sixteen doses. A smaller data base has utilized IV busulfan for stem cell transplantation as a single daily dose of 3.2mg/kg/day for 2–4 days. We present data on 19 patients treated at RMBMTP for hematological malignancies with the 3.2mg/kg/day dosing for stem cell transplantation. Sixteen of the 19 patients underwent allogeneic stem cell transplantation from related or unrelated donors from April 2003 to March 2004. Three patients underwent autologous stem cell transplants using the IV busulfan 3.2 mg/kg/day with cyclophosphamide 120 mg/kg total dose. None of the autologous transplant patients developed VOD or death during the first 100 days. 8 of the 16 patients undergoing allogeneic stem cell transplant have died: 4 patients died of relapsed disease, 2 died of GVHD, 1 patient died of sepsis, and 1 died of GVHD, relapse and a fungal infection. No autologous or allogeneic stem cell transplant patients died of regimen related toxicity.This single daily dose regimen has been well tolerated with no increase in transplant related mortality or VOD. The 3.2 mg/kg/day dose appears adequate to assure engraftment of allogeneic stem cells. The patients presented had high-risk hematological malignancies. Although the followup is short, the OS survival of 100% for the autologous stem cell transplants and 50% for the allogeneic stem cell transplantation is consistent with published data for transplantation of high-risk hematological malignancies. There does not appear to be a higher transplant related mortality, GVHD or VOD rate for patients treated with busulfan at 3.2 mg/kg/day as a single dose.

Aminoglycoside antibiotics and post-antibiotic effects

Man has been fighting diseases for centuries. One of the major battles is against microorganisms and diseases they cause. A health education course was organized on prescribing aminoglycoside antibiotics and postantibiotic effect. The aim of the course was to change the prescription habits in our colleagues. The postantibiotic effect of aminoglycoside antibiotics as well as impact of subinhibiting doses on duration of postantibiotic effect requires modification of previous therapeutic protocols. Single daily dose has the same or even greater effect than multiple daily doses. The toxicity of aminoglycosides is not increased and remains the same or smaller in single daily regimens. The single daily dose regimen of aminoglycosides has been used in 63.6% of cases in Clinic for Infectious Diseases of the Clinical Center of Novi Sad, 41.2% in Outpatient Health Care Center of Novi Sad "Liman" and this regimen has not been used in General Practice Department, Children's Health Care Department and Ear, Nose and Throat Clinic at all. The twice daily regimen has been used instead. Doctors are aware of the postantibiotic effect, but vast majority are still bound to their old habits in regard to prescribing antibiotics. Our educational course failed to achieve its goal.

The Aminoglycosides

Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with β-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens. Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with β-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens.

The Aminoglycosides

Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with beta-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens.

Strategies for Cost-Containment: Once-Daily Ceftriaxone Plus Amikacin as Empiric Therapy for Febrile Granulocytopenic Children with Cancer

Administration of broad-spectrum antibiotics as empiric therapy to febrile granulocytopenic patients has become a widely accepted practice. In order to evaluate the cost-effectiveness of ceftriaxone plus amikacin in single daily doses as empiric treatment for febrile granulocytopenic children with cancer, a retrospective review (January-December 1996) of all febrile episodes at our institution was carried out. Overall, 101 febrile episodes in 89 granulocytopenic children with cancer were empirically treated with a once-daily ceftriaxone plus amikacin combination. 59/101 (59%) patients had absolute granulo-cyte count lower than 100/mm3 at entry; 46 (45%) were affected by solid tumors, 16 (15%) by Hodgkin's disease or lymphoma, and 30 (30%) patients underwent bone marrow transplantation. The ceftriaxone plus amikacin combination was effective in 72/101 (72%) patients with a median time to defervescence of 3 days (range, 1-4). We also evaluated the economic advantages of the ceftriaxone plus amikacin once-daily regimen when compared with another treatment regimen such as ceftazidime plus amikacin requiring three daily doses. Compared with the multiple daily dose regimen of ceftazidime plus amikacin, there is a cost saving of US 11 (17,500 Italian liras) and US 66 (105,000 Italian liras) for both 1-day and 6-day treatments, respectively, by using the single daily dose regimen of ceftriaxone plus amikacin. The potential of ceftriaxone to lower costs in hospitalized patients depends upon its comparable efficacy with other extended-spectrum beta-lactams, in which case it can reduce overall treatment costs because of its once-daily administration schedule.

Omerprazole and other proton pump inhibitors: pharmacology, efficacy, and safety, with special reference to use in children.

Omerprazole and other proton pump inhibitors: pharmacology, efficacy, and safety, with special reference to use in children.

Strategies for Cost-Containment: Once-Daily Ceftriaxone Plus Amikacin as Empirical Therapy for Febrile Granulocytopenic Children with Cancer

Administration of broad-spectrum antibiotics as empiric therapy to febrile granulocytopenic patients has become a widely accepted practice. In order to evaluate the cost-effectiveness of ceftriaxone plus amikacin in single daily doses as empiric treatment for febrile granulocytopenic children with cancer, a retrospective review (January-December 1996) of all febrile episodes at our institutions was carried out. Overall, 101 febrile episodes in 89 granulocytopenic children with cancer were empirically treated with a once-daily ceftriaxone plus amikacin combination. 59/101 (59%) patients had absolute granulo-cyte count lower than 100/mm3 at entry; 46 (45%) were affected by solid tumors, 16 (15%) by Hodgkin's disease or lymphoma, and 30 (30%) patients underwent bone marrow transplantation. The ceftriaxone plus amikacin combination was effective in 72/101 (72%) patients with a median time to defervescence of 3 days (range, 1-4). We also evaluated the economic advantages of the ceftriaxone plus amikacin once-daily regimen when compared with another treatment regimen such as ceftazidime plus amikacin requiring three daily doses. Compared with the multiple daily dose regimen of ceftazidime plus amikacin, there is a cost saving of US 11 (17,500 Italian liras) and US 66 (105,000 Italian liras) for both 1-day and 6-day treatments, respectively, by using the single daily dose regimen of ceftriaxone plus amikacin. The potential of ceftriaxone to lower costs in hospitalized patients depends upon its comparable efficacy with other extended-spectrum beta-lactams, in which case it can reduce overall treatment costs because of its once-daily administration schedule.

Single daily dosing of aminoglycosides in immunocompromised adults: a systematic review.

We examined the efficacy and toxicity of single daily dosing (SDD) of aminoglycosides for febrile, immunocompromised adults by systematically reviewing four randomized, controlled trials of SDD vs. standard dosing regimens. We assessed the methodological quality of each study and extracted data pertaining to efficacy and toxicity outcomes. Pooled risk ratios for the efficacy outcomes were bacteriologic cure, 1.00 (95% confidence interval [CI], 0.86-1.16); clinical cure, 0.97 (95% CI, 0.91-1.05); and mortality, 0.93 (95% CI, 0.62-1.41). The pooled nephrotoxicity risk ratio was 0.78 (95% CI, 0.31-1.94). Only one study assessed ototoxicity. Although our study was limited by the small number of trials available for review, the results suggest that SDD of aminoglycosides may be efficacious for febrile, immunocompromised patients. Additional studies are necessary for more precise quantification of the mortality and toxicity risk ratios.

Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

Busulfan Pharmacokinetics Using a Single Daily High-Dose Regimen in Children With Acute Leukemia

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aeruginosa

A novel, in vitro, pharmacodynamic comparison of single and divided daily dosing regimens of aminoglycosides is described. Experiments were conducted to evaluate the impact of gentamicin and tobramycin concentration on the time required for the MICs for five Pseudomonas aeruginosa strains to revert to their original values (MIC reversion time [MRT]) following single and multiple 2-h aminoglycoside exposures to 8 and 24 mg/liter. Single 2-h aminoglycoside exposures to 8 mg/liter produced culture MRTs (gentamicin, 21.5 +/- 4.0 h; tobramycin, 22.3 +/- 2.8 h) that were significantly (P < 0.05) shorter than those measured following identical exposures to 24 mg/liter (gentamicin, 28.9 +/- 3.8 h; tobramycin, 26.8 +/- 3.1 h). However, three sequential 2-h exposures to 8 mg/liter, one exposure every 8 h, produced MRTs following the third exposure (gentamicin, 68.1 +/- 5.2 h; tobramycin, 77.8 +/- 7.8 h) that were significantly longer (P < 0.005) than those determined following three 2-h exposures to 24 mg/liter, one exposure every 24 h (gentamicin, 36.1 +/- 3.0 h; tobramycin, 34.5 +/- 3.0 h). In addition, the once-daily exposure regimen to 24 mg/liter consistently produced cultures with significantly (P < 0.005) higher aminoglycoside concentration/MIC ratios compared with those for cultures reexposed to 8 mg/liter once every 8 h. These data support the concept of once-daily aminoglycoside dosing.

Simplified monitoring of aminoglycosides.

For many years it has been standard practice to give aminoglycosides in divided daily doses monitored by serum aminoglycoside assays. Recent experience indicates that aminoglycosides can be given as a single daily dose with equal or better efficacy and equal or less toxicity. The single-daily dose regimen is both cheaper and more convenient. Recommended serum aminoglycoside concentrations immediately before the next dose, or 8 h later, vary according to whether a single daily dose or divided dose schedule is used. This is seldom realized in practice. Estimated creatinine clearance enables better prediction of the daily dose than was formerly recognized, and is to be preferred. Earlier fears of giving aminoglycosides as a bolus intravenous injection have not been substantiated. After more than 40 years of use, we are beginning to learn how to monitor these potentially toxic drugs.

Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy.

Azithromycin is an acid stable orally administered macrolide antimicrobial drug, structurally related to erythromycin, with a similar spectrum of antimicrobial activity. Azithromycin is marginally less active than erythromycin in vitro against Gram-positive organisms, although this is of doubtful clinical significance as susceptibility concentrations fall within the range of achievable tissue azithromycin concentrations. In contrast, azithromycin appears to be more active than erythromycin against many Gram-negative pathogens and several other pathogens, notably Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Urea-plasma urealyticum and Borrelia burgdorferi. Like erythromycin and other macrolides, the activity of azithromycin is unaffected by the production of beta-lactamase. However, erythromycin-resistant organisms are also resistant to azithromycin. Following oral administration, serum concentrations of azithromycin are lower than those of erythromycin, but this reflects the rapid and extensive movement of the drug from the circulation into intracellular compartments resulting in tissue concentrations exceeding those commonly seen with erythromycin. Azithromycin is subsequently slowly released, reflecting its long terminal phase elimination half-life relative to that of erythromycin. These factors allow for a single dose or single daily dose regimen in most infections, with the potential for increased compliance among outpatients where a more frequent antimicrobial regimen might traditionally be indicated. The potential disadvantage of low azithromycin serum concentrations, however, is that breakthrough bacteraemia may occur in patients who are severely ill; nevertheless, animal studies suggest that tissue concentrations of azithromycin are more important than those in serum when treating respiratory and other infections. The clinical efficacy of azithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (the latter including paediatric patients), skin and soft tissues (again including paediatric patients), in uncomplicated urethritis/cervicitis associated with N. gonorrhoeae, Chlamydia trachomatis or U. urealyticum and in the treatment of early Lyme disease. Azithromycin was as effective as erythromycin and other commonly used drugs including clarithromycin, beta-lactams (penicillins and cephalosporins), and quinolone and tetracycline antibiotics in some of the above infections. Some patients with acute exacerbations of chronic bronchitis due to H. influenzae may be refractory to therapy with azithromycin (as is the case with erythromycin) indicating the need for physician vigilance, although it should be noted that azithromycin is of equivalent efficacy to amoxicillin in the treatment of such patients. In the therapy of urethritis/cervicitis associated with C. trachomatis, N. gonorrhoea or U. urealyticum, a single dose azithromycin regimen offers a distinct advantage over currently available pharmacological options, while providing effective therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Challenging conventional aminoglycoside dosing regimens: The value of experimental models

Although newer antimicrobials look promising for the treatment of serious gram-negative infections, aminoglycosides still remain part of the mainstay of their therapy. Traditional intermittent therapy is based upon the premise that high serum aminoglycoside concentrations are toxic. However, the rate of bacterial killing for aminoglycosides is also a concentration-dependent phenomenon. Two animal models of Pseudomonas pneumonia were utilized to examine the efficacy of non-traditional aminoglycoside dosing regimens, i.e., single, high daily doses versus the conventional, intermittent low doses of aminoglycosides. Other recent data suggest that toxicity might also be less with the large, single daily dose regimen. The current dosing strategy used for aminoglycosides may not be maximizing their therapeutic potential, nor minimizing their toxicities.