Once daily aminoglycoside dosing: maintained efficacy with reduced nephrotoxicity?

β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis

Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twice- or thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5% vs. 84.7%, p < 0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day.

AimIntravenous gentamicin is given as a 5 day course to paediatric patients who have undergone abdominal surgery. There was an impression that the multiple daily dosing regimen in use at...

Once versus individualized multiple daily dosing of aminoglycosides in critically ill patients

Aminoglycosides are among the first-choice antibiotics for routine clinical use. However, dose-limiting factors such as ototoxicity and nephrotoxicity are considered as serious complications of aminoglycosides. In this systematic review, the main goal was to investigate the efficacy and incidence of nephrotoxicity and ototoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of aminoglycosides through available randomized controlled trials (RCTs). We performed a literature-based research in relevant databases, including EMBASE, MEDLINE, and SCOPUS published between 1987 and 2023 using the keywords "aminoglycosides", "pharmacokinetics", "ODD", "MDD", "once daily", "multiple daily", "dosing regimen", "nephrotoxicity", "ototoxicity", "efficacy", "safety", and "toxicity". As so told, the results of this article were limited to papers available in English. Our initial search yielded 1124 results. After a review of the titles and abstracts of the articles, 803 articles were excluded from this study because they did not address the toxicity and effectiveness of ODD versus MDD of aminoglycosides. A total number of 20 studies on gentamicin, tobramycin, netilmicin, and amikacin met the inclusion criteria for the efficacy of aminoglycosides and their role in ototoxicity and nephrotoxicity were included in this review. Studies recruited different age classes, and the age of relevant cohorts varied from only a few days to more than 70 years. The most common clinical condition in the included studies was cystic fibrosis. In most studies, there were no significant differences between the two regimens regarding ototoxicity. In addition, the ODD regimens were safer than MDD concerning nephrotoxicity.

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.

To determine the incidence of nephrotoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of tobramycin in critically ill patients. Randomized, prospective clinical trial. : Adult intensive care units at two university hospitals. Fifty-eight critically ill patients with a suspected or documented aerobic Gram-negative infection. Patients were randomized to receive tobramycin by ODD (7 mg/kg) or MDD. Baseline urine aliquots and 24-hr urine collections were collected on days 3, 7, and 11 during therapy and on days 3, 7, and 11 following discontinuation of therapy for measurement of alanine aminopeptidase (AAP), N-acetyl-beta-d-glucosaminidase (NAG), and creatinine. Fifty-four patients were evaluable (ODD n = 25; MDD n = 29). The groups were similar with regard to demographic and clinical variables. The tobramycin dose was higher in the ODD group compared with the MDD group (425 +/- 122.5 mg vs. 312.8 +/- 116.6 mg, p <.001). Patients in the MDD group received a mean of 3.89 +/- 1.14 mg.kg(-1)day(-1) at intervals of 11.92 +/- 3.12 hrs. In the ODD group, patients had a higher measured creatinine clearance at the end of therapy compared with MDD group (70 +/- 18.6 vs. 64.8 +/- 17.5 mL/min, p =.047). Fewer patients in the ODD group developed nephrotoxicity than the MDD group (5 vs. 12, p =.142). Although there were increases in urinary enzymes in both treatment groups (AAP, 8.7 +/- 2.9 vs. 5.2 +/- 2.1 units/24 hrs, p <.01 MDD vs. ODD; NAG, 14.7 +/- 4.9 vs. 6.8 +/- 3.1, p <.01 MDD vs. ODD), the increases in the ODD group were significantly lower than in the MDD group. : The ODD tobramycin regimen appeared to be less nephrotoxic than the MDD regimen despite significantly higher doses. Tobramycin administered by ODD may be the preferred dosing method in selected critically ill medical patients to reduce the incidence and extent of renal damage.

Background and aims: Once daily dosing (ODD) of aminoglycosides has been shown to be less toxic and as efficacious as multiple daily dosing regimens. There is a lack of pharmacokinetic (PK), safety, and efficacy data for aminoglycoside ODD in critically ill paediatric patients. Aims: To evaluate the proposed exclusion criteria for use of ODD gentamicin by examining gentamicin PK disposition in patients excluded from ODD therapy, and to adapt the criteria as appropriate. Methods: A retrospective chart review (approved by Research and Ethics Board) of 176 critically ill paediatric patients excluded from ODD therapy was done. PK parameters were calculated based on available therapeutic drug monitoring (TDM) levels. Extrapolated serum gentamicin levels achieved using a dose of 9 mg/kg were calculated and used to determine whether an excluded patient would have adequately cleared ODD gentamicin. Exploratory analyses were done to assess other characteristics that may predict if a patient will adequately clear ODD gentamicin despite prior exclusion. Results: The majority of patients (56%) were excluded from ODD therapy based on having a weight of ≤5 kg. Thirty-nine percent of patients excluded due to weight may have been able to adequately clear ODD gentamicin based on extrapolated PK parameters. Of these patients, 53% were estimated to achieve target Cmax, and 97% were estimated to achieve target drug-free interval. Conclusions: Patients with a weight of ≤5 kg can potentially be considered a conditional exclusion criterion, whereupon critically ill pediatric patients started on gentamicin for non-cardiac indications can be subsequently switched to gentamicin ODD if TDM levels show adequate clearance.

TherapeuticsJuly 1, 1996Meta-analysis: A single daily dose of aminoglycosides is as effective as multiple daily dosing with less nephrotoxicityPeter S. Millard, MD, PhDPeter S. Millard, MD, PhDFamily Practice Residency Program, Bangor, Maine, USA (P.S.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-1996-125-1-010 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail Source CitationBarza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ. 1996 Feb 10;312:338-45. https://pubmed.ncbi.nlm.nih.gov/8611830References1 Levison ME. New dosing regimens for aminoglycoside antibiotics. Ann Intern Med. 1992;117:693-4. Google Scholar2 Hatala R, Dinh TT, Cook DJ. Single daily dosing of aminoglycosides in immunocompromised adults: a systematic review. Clin Infect Dis. 1997;24:810-5. Google Scholar3 Tan K, Bunn H. Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 201(2):CD002009 (latest version 18 Aug 2000.) Google Scholar Author, Article, and Disclosure InformationAffiliations: Family Practice Residency Program, Bangor, Maine, USA (P.S.M.) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails July 1, 1996Volume 125, Issue 1Page: 10KeywordsAntibioticsClinical trialsCreatinineDatabasesDrugsEpidemiologyInformation storage and retrievalProphylaxisPseudomonas infectionsSystematic reviewsToxicity ePublished: 9 March 2020 Issue Published: July 1, 1996 Copyright & PermissionsCopyright © 1996 by American College of Physicians. All Rights Reserved.Loading ...

Background: Bacterial sepsis is highly prevalent among premature infants. Amikacin is an antibiotic widely recommended for the treatment of neonatal sepsis, one of the consequences of which might be nephrotoxicity. The present study aimed to compare the efficacy and nephrotoxicity of multiple daily dosing (MDD) and once-daily dosing (ODD) of amikacin in preterm infants suspected of sepsis. Methods: This triple-blind, randomized, controlled clinical trial was conducted on 40 premature infants suspected of sepsis, who were randomly divided into two groups. In addition to ampicillin, one group was administered with the standard daily dose, and the other group received an ODD of intravenous amikacin. Maximum and minimum serum levels of amikacin and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured in both groups. Data were extracted and analyzed based on the research hypothesis and literature review. Results: No significant differences were observed between the study groups in terms of gender, gestational age, mode of delivery, birth weight, and Apgar score. After the intervention, mean plasma creatinine reduced in both groups, while the mean reduction was significantly higher in the group administered with the ODD of amikacin (P=0.0001). However, mean changes in the urine NGAL had no significant difference between the groups (P=0.635). Minimum and maximum serum levels of amikacin in the study groups indicated a more significant reduction in mean level of the infants administered with the ODD of amikacin compared to the MDD group (P=0.0001). Conclusion: Considering the higher maximum and lower minimum levels of amikacin in the neonates receiving the daily dosage regimen, it seems that this regimen is more effective in the treatment of sepsis in preterm infants. Moreover, no significant difference was observed in the efficacy and nephrotoxicity of the daily amikacin dosing in the premature infants suspected of sepsis compared to those treated by multiple doses of amikacin.

Objectives:Previous studies have examined renal safety of once daily intravenous tobramycin in individuals with cystic fibrosis. This has been mainly in combination with ceftazidime in an adolescent or adult population. In this report, we describe our institutional experience of once daily intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics in children with cystic fibrosis.Methods:We present a retrospective review including children with cystic fibrosis, who were admitted for a pulmonary exacerbation from January 2009 to December 2011, and treated using intravenous tobramycin. A literature review of once daily intravenous aminoglycoside dosing in cystic fibrosis was performed to compare our results to existing literature.Results:A total of 35 subjects were divided into once daily dosing (n = 20) versus multiple daily dosing (n = 15) groups. Mean age was 11.3 years (± 5.7) for the once daily dosing group and 13.1 years (± 4.4) for the multiple daily dosing group (p = 0.34). All subjects had normal baseline serum creatinine at admission (once daily dosing 0.49 ± 0.14 mg/dL vs multiple daily dosing 0.62 ± 0.23 mg/dL, p = 0.07). All subjects received intravenous tobramycin, and most received piperacillin-tazobactam as their second anti-pseudomonal antibiotic (once daily dosing 45% and multiple daily dosing 40%). There was no significant change in serum creatinine in either group during antibiotic treatment (once daily dosing 0.08 ± 0.12 mg/dL vs. multiple daily dosing 0.06 ± 0.10 mg/dL, p = 0.43). All subjects had significant improvement in lung function following intravenous antibiotic therapy.Conclusion:We show that both once daily dosing and multiple daily dosing of intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics were safe in terms of nephrotoxicity in children with cystic fibrosis. These findings are important given existing literature mainly examines once daily tobramycin in combination with ceftazidime, a cephalosporin, and the majority of our patients were on tobramycin with piperacillin-tazobactam, an extended spectrum penicillin plus beta-lactam. This contributes new information not previously examined in a pediatric cystic fibrosis population.

To compare efficacy and safety of single daily dosing (Single-DD) vs multiple daily dosing (Multiple-DD) regimens of psychotropic drugs, the authors conducted a systematic review and meta-analysis. A systematic literature search of MEDLINE and Embase was conducted with keywords related to dosing regimens and psychotropic drugs (last search: December 30, 2019). Randomized controlled trials comparing clinical outcomes between Single-DD and Multiple-DD of the same formulation of the same psychotropic drugs in patients with psychiatric disorders were included. Data on study discontinuation, psychopathology, and treatment-emergent adverse events (TEAEs) were extracted. A total of 32 studies with 34 paired comparisons involving 3,142 patients met the eligibility criteria and were included in the meta-analysis. Various types of psychotropic drugs were examined: antidepressants (22 comparisons), antipsychotics (7 comparisons), benzodiazepines (2 comparisons), mood stabilizers (2 comparisons), and antidepressant-benzodiazepine combination (1 comparison). There was no significant difference in study discontinuation due to all causes (30 comparisons, N = 2,883, risk ratio [RR] = 1.01, 95% CI = 0.94 to 1.09, P = .77), lack of efficacy (22 comparisons, N = 2,307, RR = 1.06, 95% CI = 0.84 to 1.33, P = .62), or adverse events (25 comparisons, N = 2,571, RR = 0.93, 95% CI = 0.75 to 1.14, P = .47) between the Single-DD and Multiple-DD groups. No significant difference was found in changes in psychopathology (8 comparisons, N = 1,337, standardized mean difference = 0.00, 95% CI = -0.11 to 0.11, P = .99) between the 2 groups. These results were also true for any type of psychotropic drugs. In terms of TEAEs, however, there were significant differences in anxiety (4 comparisons, N = 347, RR = 0.53, 95% CI = 0.33 to 0.84, P = .007) and sleepiness (3 comparisons, N = 934, RR = 0.82, 95% CI = 0.68 to 0.99, P = .04) in favor of the Single-DD group. The findings suggest Single-DD can be clinically adopted regardless of type of psychotropic drugs in patients with psychiatric disorders in general.

Tinidazole, a synthetic imidazole derivative, has been used in the oral treatment of several protozoal infections - trichomoniasis, giardiasis and amoebiasis. Among the protozoal organisms inhibited by tinidazole are Trichomonas vaginalis, Trichomonas foetus, and Entamoeba histolytica. In vitro, tinidazole has been shown to possess antiprotozoal activity at least comparable to, and in some cases greater than, metronidazole. Tinidazole also has activity against some Gram-negative anaerobic bacilli, including Bacteroides spp. Following oral administration of a 2g dose, like metronidazole serum levels peak in about 2 hours but persist for longer. Any clinical significance of the longer plasma half-life (tinidazole 12.5h; metronidazole 7.3h) has yet to be demonstrated. Tinidazole is approximately 20% bound to plasma proteins. Only unchanged drug has been found in the plasma and urine of tinidazole-treated subjects, although metabolites have been detected in animal studies. A single 2g dose of tinidazole has been shown to be effective therapy in vaginal trichomoniasis and in urogenital trichomoniasis in males. Single-dose therapy in general offers advantages in regard to convenience, and in the treatment of a sexually transmissible disease such as trichomoniasis, single-dose therapy facilitates compliance of patient and sexual partner. In comparative studies, tinidazole, in both single-dose and traditional multiple-dose regimens, has been shown to be equivalent and often superior to other antitrichomonal agents, including metronidazole. In intestinal amoebiasis, tinidazole has been evaluated after both once-a-day and multiple daily dose regimens, with the former giving slightly better results. When both metronidazole and tinidazole were administered in multiple daily dose regimens, the two agents yielded similar cure rates; in one study fewer tinidazole-treated patients required a second course. Tinidazole has also been successful in some cases of amoebic liver abscess, but an advantage over metronidazole has not been demonstrated. Results in the treatment of giardiasis, especially with the single-dose regimen, are promising, and in one study, tinidazole proved effective in infections resistant to metronidazole. Even in large doses, tinidazole has been well tolerated, although rarely vomiting may occur and the patient may need to be re-treated with a multiple dose regimen.

To review the feasibility and effectiveness of single daily dosing of lithium in patients with affective disorder and to discuss advantages and disadvantages of this schedule of administration. A comprehensive search of the literature was conducted using a combination of electronic databases and a search of reference lists and relevant journals. English-language articles were selected for the review if they discussed the issues comparing multiple and single daily dosing schedules of lithium. We found 9 comparative studies. Single daily dosing of lithium causes transient higher peak lithium concentrations; however, no comparative study revealed a significant difference in side effects between multiple and single daily dosing groups. Numerous reports concluded that taking lithium in a single dose prevents, or at least limits, the increase in urine output (and the reduction of osmolality) and subsequent thirst. There is no evidence that a single lithium dosing schedule preserves glomerular function. According to the presented data, it could be reasonable to use lithium as a single evening dose in patients who can tolerate this schedule because no studies have suggested any benefit from administration of multiple daily doses. Possible advantages of single daily dosing, especially in improved compliance, could not be veiled by disadvantages of transient and mild postabsorptive side effects.

Pituitary conditions are associated with several physical, psychological, and social symptoms. Treatment involves surgery, medical treatment, and/or radiotherapy. Most patients with pituitary conditions have permanent hypopituitarism (congenital or acquired) and require lifelong hormone replacement therapy. Polypharmacy with multiple daily dosing and complex treatment regimens are common and patients may often require more than five different medications daily.