An initiative of NSW Clinical Pharmacologists & Pharmacists Funded by the NSW Department of Health

AMINOGLYCOSIDE DOSAGE REGIMENS

A Position Statement of the NSW Therapeutic Assessment Group Inc.

December 1996

Mr William Montgomery, St Vincents Hospital Sydney Dr Thomas Gottlieb, Concord Hospital, Sydney Ms Lynn Weekes, NSW Therapeutic Assessment Group Inc
This review was prepared by the authors in consultation with members of the NSW Therapeutic Assessment Group Inc.

This work is copyright of the NSW Therapeutic Assessment group Inc and NSW Health department. Apart from any use as permitted under The Copyright Act 1968, no part of this information may be reproduced by any process without written permission. Whilst the information contained in this document has been presented with all due care, and the information is considered to be true and correct at the date of publication, changes in circumstances after publication may impact on the accuracy of the information. This document represents expert consensus opinion and should not be relied upon as professional advice other than in this context. The information provided should not be regarded as a substitute for detailed expert advice in individual cases. NSW Therapeutic Assessment Group Inc will accept no responsibility for any loss, claim or damage suffered or caused by any person acting or refraining from action as a result of any material in this document.

EXECUTIVE SUMMARY
Once daily aminoglycoside dosage regimens have become standard in many hospitals in Australia. This paper reviews the evidence for once daily compared with multiple daily dosage regimens. Consideration is also given to how these new aminoglycoside dosage regimens should be monitored and how and when dosage individualisation should be undertaken. Theoretically once daily aminoglycoside dosage regimens ensure high peak plasma concentrations and longer drug free periods between dosing. High peak plasma concentrations are desirable because the rate and extent of bactericidal effect is dependent on the initial concentration of aminoglycoside. Longer drug free periods may improve efficacy by allowing time for resolution of the adaptive resistance reported with aminoglycosides and take advantage of the post antibiotic effect. Clinically, once daily dosage regimens have been associated with at least equal efficacy to multiple daily dosing regimens with some studies reporting better efficacy. Nephrotoxicity may be reduced with once daily regimens. The evidence is not as convincing for reduced ototoxicity. Once daily dosage regimens may not be suitable for all patients. Toxicity does still occur and changes in renal function and clinical status, as well as plasma aminoglycoside concentrations should be monitored. All patients who are expected to require an aminoglycoside for more than 48 hours or in whom the duration of therapy is unknown should have a plasma concentration taken after the first dose. Dosage adjustments will be required for patients with renal impairment (including the elderly) who may require extended dosage intervals and patients with enhanced elimination who may require higher doses (mg/kg) every 24 hours. The AUC method is recommended as the preferred method for dosage adjustment in those institutions with the facilities and staff to support it. In other institutions, the method described in the Antibiotics Guidelines is the preferred option. Monitoring trough levels is considered to be an inferior alternative but is superior to no monitoring and may be considered in situations where the preferred options are not achievable.

INTRODUCTION

There has been a debate in recent years on the adoption of once daily dosing (ODD) of aminoglycosides for everyday clinical use. A substantial amount of prospective data has now accumulated to make ODD of aminoglycosides the accepted standard of care in many institutions. This change of practice has brought with it a new set of problems related to optimising the dosing and monitoring of aminoglycosides. The aminoglycosides remain important bactericidal antibiotic agents despite their recognised narrow therapeutic range. In the mid-1980s it was commonly believed that the aminoglycosides would be gradually phased out; it was felt that because of their toxicity, the aminoglycosides would be replaced by the broad spectrum third generation cephalosporins. The current worldwide concern over the emergence of gram-negative pathogens resistant to the third generation cephalosporins has been associated with a resurgence of interest in aminoglycoside use. Certain strains of bacteria, in particular constitutive cephalosporinase producers such as Enterobacter sp. and Klebsiella pneumoniae isolates, producing extended-spectrum beta-lactamases, have emerged under the selective pressure of third generation cephalosporins. Control of outbreaks of extended-spectrum beta-lactamase strains in intensive care units has at times required total withdrawal of third generation cephalosporin use. The emergence of resistance to aminoglycosides has been far less predictable. Despite over thirty years of gentamicin use, resistance is relatively uncommon. Most commonly encountered gram-negative clinical isolates remain susceptible. As aminoglycosides require an alkaline pH for maximal activity, their utility is far lower in an established abscess and tissue infections unless there is concomitant bacteraemia present. Similarly, because of low intra-cellular pH they are rarely effective against intra-cellular pathogens. It is therefore prudent for aminoglycosides to be used for established indications such as endocarditis and febrile neutropenia. Empiric use should be considered in the presence of suspected gram-negative bacteraemia, particularly in the 48-72 hours required for the bacterial pathogen and its susceptibility to be determined. The parenteral aminoglycoside antibiotics in current clinical use in Australia include amikacin, gentamicin, netilmicin and tobramycin. Streptomycin, the first available aminoglycoside, is now difficult to obtain and is rarely used in clinical practice. This paper will consider: The evidence to support once daily dosing (ODD) versus multiple daily dosing (MDD) regimens. Dosage regimens (on a mg/kg basis). Therapeutic monitoring of plasma aminoglycoside levels and dosage adjustment

PHARMACOKINETIC PROPERTIES OF AMINOGLYCOSIDES

The aminoglycosides are highly polar cations with poor bioavailability after oral administration 1. All are absorbed rapidly into the systemic circulation after intramuscular injections with peak concentrations occurring after 30 to 90 minutes. In critically ill patients, particularly those in shock, absorption from an intramuscular site may be reduced because of poor perfusion 2. Due to their polar nature the aminoglycosides are confined mainly to the extracellular space which corresponds to a volume of distribution of approximately 0.2 L/kg. They penetrate well into synovial, peritoneal, ascitic and pleural fluids and poorly into the central nervous system and the eye. High concentrations are found in the renal cortex and in the endolymph and perilymph of the inner ear. Penetration into respiratory secretions is poor. Inflammation increases the penetration of aminoglycosides into peritoneal and pericardial cavities. Penetration into the cerebrospinal fluid (CSF) is limited, with less than 10% of the corresponding plasma concentration being achieved in the absence of inflammation although this may approach 20% in meningitis. Since aminoglycosides are minimally distributed into fatty tissue the lean or ideal body weight should be used when calculating the dose on a mg/kg basis. During gram-negative sepsis, dehydration or shock can cause contraction of the extracellular fluid compartment and hence a reduced volume of distribution. Certain groups of patients may have an increased volume of distribution, including those with congestive heart disease or peritonitis and patients who are postpartum or receiving parenteral nutrition. The measured volume of distribution has been shown to have wide interpatient variability 3 and this has been one argument for monitoring plasma concentrations to optimise aminoglycoside dosing. The aminoglycosides are excreted almost entirely by glomerular filtration with renal clearance approximately 80% of the simultaneous creatinine clearance. The plasma elimination half life of aminoglycosides is usually 2-4 hours in adults with normal renal function although wide interpatient variation in elimination has been shown 1. Aminoglycosides are removed by both haemodialysis and peritoneal dialysis. Approximately 50% of the administered dose is removed by one cycle of haemodialysis. Peritoneal dialysis is less effective than haemodialysis at removing aminoglycosides 1. The rate of intravenous infusion does not appear to affect the elimination half life or clearance of aminoglycosides 4.

2.1

Pharmacokinetic Models to Describe Aminoglycoside Disposition

The aminoglycosides demonstrate linear pharmacokinetics. Pharmacokinetic studies have shown the aminoglycosides have tri-phasic disposition characteristics. The first phase approximates the initial distribution and occurs within minutes, the second is the elimination phase from the vascular compartment which occurs over some hours and the third phase represents redistribution from deep tissue sites and subsequent elimination.

In practice a one compartment model provides clinically useful information for dosage prediction 1. The use of a simpler pharmacokinetic model that adequately describes the distribution of aminoglycosides during multiple dose administration has the advantage that it only requires 1- 2 plasma concentrations for optimisation of dose requirements 3. More complex models, although theoretically more relevant, require up to six samples for dose optimisation which is not practical in a clinical setting.

TOXICITY OF AMINOGLYCOSIDES

Ototoxicity and nephrotoxicity are the most serious adverse events associated with aminoglycoside therapy. Less common adverse reactions include neuromuscular blockade, other neurotoxic effects, peripheral neuropathy, hypersensitivity reactions, nausea and vomiting, blood dyscrasias and transient rises in liver function tests. Aminoglycoside toxicity will develop predictably in all patients with prolonged exposure (weeks of therapy) even when levels are kept within the therapeutic range of < 2mg/L for thrice daily dosing.

3.1

Ototoxicity

Aminoglycosides have been shown to cause eighth cranial nerve damage leading to vestibular symptoms (dizziness, vertigo and ataxia) and auditory symptoms such as tinnitus and varying degrees of deafness. Deafness and vestibular damage may be permanent if the damage is extensive. There are no overall accepted prevalence rates for the incidence of aminoglycoside ototoxicity. Clinically evident ototoxicity is estimated for gentamicin and amikacin to be approximately 1-2% and less for tobramycin in patients with normal renal function. Netilmicin may be the least ototoxic aminoglycoside 5. Apparent differences between the ototoxicity and vestibular toxicity of the different aminoglycosides remain unexplained. Amikacin is predominantly ototoxic whereas gentamicin and tobramycin affect hearing and vestibular function equally. A recent study by Halmagyi et al 6 found no safe dose and no safe plasma concentration for avoiding vestibular toxicity but there was a higher risk in patients who developed nephrotoxicity.

3.2

Nephrotoxicity

Nephrotoxicity results from the accumulation of the aminoglycoside in the proximal renal tubular cells. Aminoglycoside nephrotoxicity may be evidenced by tubular necrosis, increases in plasma urea and creatinine, decreases in urine specific gravity and creatinine clearance, proteinuria, or cells or casts in the urine. Most patients with aminoglycoside nephrotoxicity develop non-oliguric azotemia; oliguria rarely occurs. Rarely, the aminoglycosides can cause an electrolyte wasting syndrome with clinical signs of calcium, magnesium and potassium depletion. Aminoglycosideinduced nephrotoxicity is usually reversible following discontinuation of the drug, however irreversible renal impairment has been reported. The relative nephrotoxicity of the aminoglycosides in humans has not been definitively established.

Positive correlations have been found between development of nephrotoxicity and the presence of aminoglycoside trough levels > 2-4 mg/L, older age, greater than 10 days therapy and other nephrotoxic drugs 7.

3.3

Nervous System Effects

The aminoglycosides can produce varying degrees of neuromuscular blockade. Netilmicin is probably the strongest neuromuscular blocking agent of the aminoglycosides. The blockade is usually dose related and self-limiting. Neuromuscular effects are most likely to occur when the drug is applied to serosal surfaces or when administered to patients with neuromuscular disease, hypocalcaemia or receiving general anaesthetics, neuromuscular blocking agents or massive transfusions of citrated blood 8.

4 4.1

THEORETICAL SUPPORT FOR ONCE DAILY DOSING Post Antibiotic Effect

The Post Antibiotic Effect (PAE) is defined as the period of suppression of bacterial growth after cessation of exposure of the bacteria to the antibiotic. It is thought to be the result of irreversible drug binding to bacterial ribosomal subunits causing non-lethal damage to the bacteria 9. In vitro, aminoglycosides exhibit rapid concentration dependent killing of gram negative bacteria, followed by a prolonged period of suppression of bacterial growth. Experimental evidence has shown that the duration of the PAE is proportional to the peak plasma concentration achieved. The PAE for aminoglycosides has been reported to last 2-7 hours against E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa 9. In general, maximal effects in vitro occur after 2 hour exposures to drug levels 5 to 10 times the MIC. This effect has been shown to last longer in vivo than in vitro 9. An acidic environment may shorten the PAE against gram-negative bacteria, including Pseudomonas sp 10. It was previously accepted that the post antibiotic effect was partially neutrophil dependent, however neutropenic animal models 11,12 have shown the post antibiotic effect is retained in neutropenia and studies in patients have confirmed clinical efficacy 13.

4.2

Concentration Dependent or Dose Dependent Killing

There is a considerable amount of in vitro and in vivo evidence to support the concept of concentration dependent killing of susceptible bacteria by aminoglycosides. The rate and extent of bacterial killing are a function of the concentration of the aminoglycoside 14,15. Moore et al 16 showed that achieving adequate peak concentrations of aminoglycosides was the most important factor for resolution of gram-negative pneumonia in the patients they studied. The same group subsequently showed a graded relationship between increasing maximal-peakconcentration/MIC ratios and clinical response for a range of gram negative infections and aminoglycosides 17. A peak/MIC ratio of 10 was found to have relative odds >8 of achieving a clinical response.

It has been proposed that self-promoted internalisation of ionically bound aminoglycoside accounts for the early drug-concentration-dependent rapid bactericidal action of aminoglycosides 15. The extent of uptake of the aminoglycoside may be genetically determined 18 and differences in the extent of concentration dependent killing have been described for different aminoglycosides 19. Evidence from experimental models suggests that while both peak concentrations (Cmax) and area under the curve (AUC) were factors determining gentamicin activity that Cmax was an independent determinant of effect 20. Most of the Enterobacteriaceae have gentamicin MICs below 0.5 - 1.0 mg/L, a majority of Pseudomonas aeruginosa isolates have MICs < 1-2 mg/L. Peak plasma gentamicin levels of 10-15 mg/L or higher can be predictably achieved with a single gentamicin (cf. tobramycin, netilmicin) dose of 4.5-5 mg/kg, and amikacin dose of 15 mg/kg, but cannot with three times daily intermittent dosing. Regimens that provide peak serum concentrations less than 10 times the MIC have been associated with emergence of antimicrobial resistance in experimental models 21,22.

4.3

Adaptive Resistance

In vitro several susceptible organisms display a temporary adaptive resistance to aminoglycosides. First exposure to the drug is not lethal and the cell down-regulates its uptake of aminoglycoside for a period of time. This unstable form of resistance was found to be enhanced by continuous exposure to antibiotic and could be reversed by several hours of growth in drug-free media 23. Following brief exposure to an aminoglycoside, refractoriness to its bactericidal effects develops within 1-2 hours and persists for 6-7 hours during growth in a drug free medium. During constant exposure adaptive resistance persists and increases over time 24. An in vitro model which mimics the in vivo pharmacokinetics of gentamicin in humans was used to investigate the degree of adaptive resistance expressed by Pseudomonas aeruginosa upon exposure to different concentrations of gentamicin 25. The degree of adaptive resistance was greater and the duration longer with higher initial concentrations of gentamicin. Full recovery occurred at approximately 36, 39 and 43 hours following exposure to concentrations of 2.5, 8 and 25mg/L respectively. These workers concluded that extended aminoglycoside dosing intervals may improve efficacy by allowing time for adaptive resistance to resolve.

4.4

Toxicity

Animal studies have shown the renal cortex uptake of gentamicin, netilmicin and gentamicin is saturable and a function of steady-state plasma concentrations 26,27 while uptake of tobramycin is linearly related to plasma concentrations 28. Continuous infusions of aminoglycosides resulted in 3050% higher renal cortex concentrations than when single bolus doses were used 29. In rats, uptake of aminoglycoside into inner ear tissue is dose-dependent and saturable. Less uptake has been reported with single bolus dosing than with continuous infusion 30. The clinical relevance of these findings is yet unclear but the higher peaks and longer relatively drug free periods associated with ODD should theoretically produce less toxicity than similar AUCs from thrice daily dosing.

5 EXPERIMENTAL AND CLINICAL EVIDENCE FOR ONCE DAILY DOSING 5.1 Animal Models of Infection

Marked interspecies difference exist in aminoglycoside pharmacokinetics and caution should be exercised in interpretation of results. Zhanel et al 31 reviewed much of the work relating to the efficacy of aminoglycosides in animal models of infection. The majority (but not all) of the animal studies have demonstrated equal or greater efficacy with ODD compared to conventional dosing strategies. Regimens which resulted in high Cmax and AUC have shown the best antibacterial efficacy 26. The efficacy of ODD aminoglycosides in animal models is augmented by addition of betalactam antibiotics 32,33.

5.2

Clinical Studies

A summary of the clinical studies which have compared once daily dosing of aminoglycosides with conventional dosing is provided in Table 1. Once daily regimens consistently resulted in higher peak plasma concentrations and lower trough concentrations. In spite of these pharmacokinetic effects, the majority of studies did not show a difference in clinical or bacteriological response although there were trends for greater efficacy with ODD. Similarly, both nephrotoxicity and ototoxicity were still reported with ODD and most studies did not show a reduced incidence compared with MDD regimens. The majority of studies have excluded patients with renal impairment. Of 211 patients enrolled to receive netilmicin 6mg/kg/day either once daily or three time a day 34, 197 were evaluated for clinical response and toxicity. Seven of the 14 patients who dropped out of the study had a trough concentration > 2mg/L after the first dose of netilmicin; all these patients were randomised to the once daily group. No difference was found between once daily and thrice daily regimens for clinical response (93% vs 96%), or auditory (1 patient vs 3 patients), vestibular (1 patient in each group) or nephrotoxicity (9 patients vs 10 patients). Toxicity was shown to positively correlate with age, severity of disease, mean netilmicin peak concentration and mean netilmicin trough concentration. Patients with intra-abdominal infections admitted to eight hospitals in six Asian countries were randomised to receive netilmicin 300mg once daily or 100mg three times daily by either intramuscular injection or intravenous infusion 35. Approximately half the patients in each group received concomitant antibiotics (selection of antibiotics was at the discretion of the investigator). Of 185 evaluable patients, a clinical cure was achieved in 88% of patients on ODD and 68% of patients on MDD however the causative microorganism was eliminated or the infection site healed in 90% and 88% of patients respectively. No statistics were quoted for these results. There was a low incidence of nephrotoxicity noted in this study which was not associated with the dosage regimen. Marik et al 36 published one of the few reports to find a significant difference in efficacy and toxicity of once daily versus thrice daily aminoglycoside. Once daily amikacin in adults (20mg/kg/day patients > 1 year of age) and children (15mg/kg/day - patients < 1 year of age) was compared with the same dose given twice daily in 348 critically ill adults and children with a documented Gram
8

negative infection. The study found a significantly higher clinical response rate in the once daily group (83% vs 66%; P=0.001) and a higher bacteriological response rate (81% vs 58%; P=0.005). Sub-group analysis of paediatric patients found a significant difference in clinical response, although similar analysis of adult patient results showed a trend but not a statistically significant difference. Plasma creatinine rose in 21% of patients in the once daily group compared with 35% in the twice daily group (P=0.05). No difference in auditory toxicity was found. A study by Prins et al 37 of once versus thrice daily gentamicin in 123 patients with serious infections reported clinical response rates of 91% in the once daily and 78% in the thrice daily groups, however the confidence intervals for this 13% difference were very broad (-6.4% to 26.7%). High tone audiometry found at least one manifestation of ototoxicity in 58% (7/12) of the once daily and 55% (6/11) of the three times daily group. Nephrotoxicity occurred in 24% of patients in the three times daily group compared with 5% in the once daily group (P=0.016). This difference is partly explained by the longer duration of therapy in the once daily group (16 vs 6.7 days). It is important to note that patients in this study were not equally matched for severity of disease with more patients in the once daily group having urinary tract infections. A significantly higher proportion of patients with suspected or documented gram negative infections achieved clinical cure with once daily gentamicin than thrice daily (42/48 vs 36/52; P<0.05) 38. The microbiological cure rate was also better in the once daily group but this difference was not statistically significant. It should be noted that only 75% and 73% of patients in the once daily and thrice daily treatment groups had documented bacterial infections. Ter Braak et al 39 compared once daily netilmicin plus ceftriaxone 2g daily and multiple (2-3) daily dosing of netilmicin plus ceftriaxone. Patients were mainly elderly (mean age 71years) with severe bacterial infection. Netilmicin doses were individualised for all patients using a nomogram based on sex, weight, age and renal function. In the MDD group the target concentrations were peak concentrations between 6-12 mg/L and troughs <2 mg/L. A relatively high incidence of nephrotoxicity (16% in both groups) was reported and hearing loss occurred in one patient on MDD and two patients on ODD. Nephrotoxicity was significantly associated with elevated trough concentrations in patients who receive once daily netilmicin. The mean netilmicin trough concentrations in patients suffering nephrotoxicity were 2.8 mg/L in the ODD group (compared with 1.1mg/L for other patients; P<0.001) and 2.7 mg/L in the MDD group (compared with 2.4 mg/L for other patients; P= ns). No association was found between peak concentrations and toxicity. Nicolau et al 40 reported on their clinical experience of 2184 patients who were given 7mg/kg gentamicin (94%) or tobramycin (5%) or 15mg/kg amikacin in once daily dosage regimens. Dosage was adjusted to achieve peak concentrations to MIC ratios of 10 (by nomogram) and for impaired renal function. Patient groups excluded from this open observational study included pregnant women, children, patients with burns (>20% of body) or ascites and dialysis patients. The reported toxicity in this study was very low; 3 patients were reported to have clinical manifestations of ototoxicity and there was a 1% incidence of nephrotoxicity. The approach of observational toxic event monitoring may have biased the results and led to a lower estimation of the incidence of nephrotoxicity.

Once daily aminoglycosides have been studied in febrile neutropenic patients 41,42 with clinical response rates of around 70 % reported with both once daily and conventional dosing. The study by Rodzdzinski et al 41 using netilmicin 6mg/kg/day found no difference in either rates of clinical response or toxicity between once and thrice daily dosing. However multivariate analysis found that neither the dosage regimen nor peak concentrations were determinants of a favourable response. The EORTC trial 42 of once daily amikacin plus ceftriaxone and twice daily amikacin plus ceftazidime in 677 patients with cancer and granulocytopenia found similar efficacy and toxicity in both treatment arms. Moreover there was no difference in the time to defervescence. It should be noted in both these studies that a range of betalactam antibiotics were used, making direct comparison of efficacy more difficult. Several groups 36,43-5 have reported use of once daily aminoglycosides in neonates and children. No difference in efficacy or toxicity has generally been reported with good rates of clinical cure achieved with either regimen.

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Table 1
Study
de Vries 34 Elhanan 44 EORTC 42 Fan 46 Giamarellou 47 Hollender 48 Maller 49 Maller 50

Summary of clinical studies of once daily aminoglycosides

Infection Drug (route) Dosage Regimen (no. patients) Mean total dose (mg)
5,343 5,289 9.6 10.4 8.7 8.8 -

Days of therapy
6.5 6.6 6.8 5.8 8.5 8.0 -

Mean Cmax mg/L

21.1 10.0 a 13.9 5.7 a 46 21 4.76 13.76 a 45-52 28-31 12.45 5.06 42 55 33 32.7 40.1 43.4 24.2 24.1 24.9 32.6 17.6 a 35.6 20.4 a 13.0 4.0 13.3 6.9 41 32 51 4 10.2 5.2 a 8.7 4.6 a 15.2 5.7 a 19 7.5 a 12.9 6.4 a 20.3 6.2 53.8 26.4

Mean Cmin mg/L

1.3 2.3 a 0.2 0.5 a 0.9 2.0 2.0-3.5 2.8-3.2 1.22 1.17 b 1.2 1.3 3.7 3.3 2.0 1.3 4.9 3.3 2.2 0.6 3.86 a 0.8 3.74 a -

Maraucher 35 Marik 36

Nordstrom 51

Powell 52

Prins 37 Raz 38 Rozdzinski Skopnik 45 Sturm 53 Ter Braak 39 Tulkens 54

41

Van der Auwera 55

6mg/kg od (98) 2mg/kg tds (99) Diverse Gentamicin (IVI) 4.5mg/kg od (32) (3mth-16yrs) 1.5mg/kd tds (31) Neutropenia Amikacin (IVI) 20mg/kg od (249) 6.7mg/kg tds (256) Intra-abdominal Netilmicin (IMI) 1.5mg tds (20) 4.5mg od (20) Diverse f Amikacin (IVI) 15mg/kg od (30) 7.5mg/kg bd (30) Intra-abdominal Netilmicin (IMI or 4.5mg/kg od (57) IVI) 1.5mg tds (55) Diverse Amikacin (IVI) 11mg/kg od (16) 15mg/kg od (14) 7.5mg/kg bd (15) Diverse Amikacin (IVI) 7.5 mg/kg od (18) 11 mg/kg od (49) 15 mg/kg od (66) 3.25 mg/kg bd (16) 6.5 mg/kg bd (69) 7.5 mg/kg bd (49) Intra-abdominal Netilmicin 300mg od (92) (IMI or IVI) 100mg tds (93) Pneumonia or Amikacin (IVI) 20mg/kg od (67) e surgical sepsis 10mg/kg bd (65) e 15mg/kg od (88) 7.5mg/kg bd (80) Diverse Gentamicin 4.5mg/kg od (14) (IMI or IVI) 1.5mg/kg tds (14) Netilmicin 4.5mg/kg od (15) (IMI or IVI) 1.5mg/kg tds (13) Cystic Fibrosis Tobramycin all individualised f (IVI) od (15) od (11) od (10) continuous inf (16) Diverse Gentamicin (IVI) 4mg/kg od (59) 1.33mg/kg tds (64) Diverse Gentamicin (IVI) 4.5mg od (48) 1.5mg tds (52) Febrile Netilmicin (IVI) 6mg/kg od (71) Neutropenia 2mg/kg tds (72) Diverse (neonates) Gentamicin 3.5-4mg/kg od (223) Tobramycin (IVI) 2-2.5mg/kg bd (79) Bacteraemia Netilmicin (IVI) 6mg/kg od (36) 2mg/kg tds (36) Diverse Netilmicin (IVI) all individualised 3.9mg/kg od (69) 3.8mg/kg/day bd-tds (72) Pelvic Netilmicin od (19) d (IVI) tds (19) Amikacin od (20) (IVI) bd (20) Urinary Tract Netilmicin 6mg/kg od (30) (IMI or IVI) 2mg/kg tds (30)

Intra-abdominal

Netilmicin (IVI)

2,040 2,670 -

6.9 8.8 8.6 8.0 7.0 6.8 -

99/kg 90/kg 180/kg 121/kg 1590 1672 4,800 4,880 1982 1775 2700 2456 5518 5654 11 10 12 11 7.0 7.4 8 8 5.4 5.3 8.6 8.1 7.1 7.3 7 7 -

0.9 2.5 a 0.7 1.1 a 0.2 0.9 a 0.5 0.9 a 1.3 2.5 a -

Vigano 43

Pyelonephritis Netilmicin (IMI) 5mg/kg od (74) 10 9.8 0.5 (children) 2mg/kg tds (70) 10 5.1 a 0.9 a a Difference was statistically significant b Trough levels <1 were calculated as =1 c Patient groups were poorly matched for severity of infection - more patients with URTI in bd group, more UTI in od group d Dosage appears to have been individualised e Children (< 1 year) received 20mg/kg/day, all other patients received 15mg/kg/day f Patients were randomised to receive a continuous infusion (n=16); or od tobramycin(n=15) to achieve conc 4mg/L; or od administration (n=11) to achieve 4mg/L and ototoxicity assessment; or od administration (n=10) to achieve conc 5.2mg/L

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5.3

Meta -Analyses of Clinical Studies

Four meta-analyses have assessed the relative efficacy and toxicity of aminoglycosides given in once daily or multiple daily dosage regimens. An analysis by Galle et al 56 compared any publications (searched electronically through Index Medicus and through lists of references) in which patients were randomised to receive single or multiple daily doses of an aminoglycoside. From 16 studies, they concluded that the relative chance of cure of single dose compared to multiple dose regimens was 1.03 (95% CI: 0.993-1.06), avoidance of nephrotoxicity was 1.00 (95% CI: 0.98-1.02) and avoidance of ototoxicity was 1.00 (95% CI: 0.986-1.02). A subsequent analysis 57 of 21 randomised controlled studies identified through MEDLARS (1966-1995) and lists of references reported a trend toward fewer antibiotic failures with once daily dosing. This difference was not statistically significant, however, when the random effects model was used (risk ratio 0.83; 95% CI 0.57-1.21; P=0.32). The analysis found significant heterogeneity across the 21 trials. The overall rate of nephrotoxiciy was 5.5% for single daily regimens and 7.7% in the multiple daily dose regimens. The risk ratio estimate was 0.78 (0.57-1.07) with the random effects model and 0.78 (0.54-1.00; P<0.05) with the fixed effects model. Risk assessments across studies were homogeneous and the confidence intervals between fixed and random effects models were similar. Further analysis found that other factors including control rate of nephrotoxicity, frequency of multiple daily dosing, use of concurrent antibiotics and duration of therapy were not associated with the relative risk of toxicity. Sub-group analysis showed a trend in favour of single daily dose regimens for avoidance of nephrotoxicity in febrile neutropenic and paediatric patients. The two treatment regimens showed no difference for ototoxicity or overall mortality. A third meta-analysis 58 of 13 independent studies , involving 1625 patients, considered only studies which were of randomised controlled design, compared intravenous dosage regimens and enrolled infected immunocompetent adults (thus, excluding surgical prophylaxis) of whom < 50% had a urinary tract infection. All studies reported the following outcome measures: bacteriological or clinical cure, mortality, nephrotoxicity or ototoxicity. Significant heterogeneity existed among the individual risk ratios for clinical cure but not other outcome measures. For pooled efficacy, the risk ratio for bacteriological cure was 1.02 (95%CI: 0.99-1.05) and the risk ratio for mortality was 0.91 (95%CI: 0.63-1.31). For the pooled toxicity outcomes, the risk ratio for nephrotoxicity was 0.87 (95%CI:0.60-1.26) and for ototoxicity was 0.67 (95%CI: 0.35-11.28). No statistically significant efficacy or toxicity advantages were found in this analysis, however there was a trend for reduced nephrotoxicity with once daily dosage regimens. Munckhof, et al. 59 undertook an analysis of 19 publications up to November 1994. Studies were included in the meta-analysis if the study objective was to compare safety and efficacy of an aminoglycoside used for treatment, the treatment was randomly

assigned, there were two or more comparative arms, the total daily dose of aminoglycoside in each arm was equivalent, the aminoglycoside was given for at least 72 hours and at least one outcome was reported. There was a small but statistically significant difference (3.5%; 95% CI 0.5% to 6.5% ) in clinical efficacy across the pooled results of the 19 studies in favour of ODD (84.9%) compared with MDD (81.4%; P=0.027). There was a trend for better bacteriological efficacy with ODD (85%) compared with MDD (81.5%) but the difference (3.4%; 95% CI: -0.9% to 7.7%) was not significant (P=0.137). Pooled data from the 15 studies which reported nephrotoxicity as an outcome, gave a nephrotoxicity rate of 4.7% for ODD and 5.9% for MDD. The difference (1.3%; 95% CI -3.1% to 5%) was not statistically significant (P=0.199). Audiometry was reported for 597 patients in 10 studies with 6.2% of patients on ODD and 5.5% of patients on MDD having detectable audiometric toxicity (95% CI -3.1% to 4.5%; P=0.845). Clinical auditory toxicity was reported in 0.4% of patients after ODD and no patients after MDD (95% CI -0.2% to 0.9%; P=0.489). There was no difference in the reported rates of vestibular toxicity for the two dosage regimens.

MONITORING AND DOSAGE ADJUSTMENT

It is evident from the clinical studies of once daily aminoglycoside use that toxicity remains a problem with these new regimens. Establishing new monitoring guidelines has proved problematic which is not surprising given the limited evidence for validity of the therapeutic range for conventional three times daily dosage regimens 7. Most clinical studies of once daily dosing have used 4.5-6mg/kg/day gentamicin, netilmicin or tobramycin or 11-15mg/kg/day amikacin. Generally, they have not individualised once daily doses and most have excluded patients with renal impairment. Konrad, et al 60 found that to achieve a peak concentration of 25mg/L and a trough of 0.5mg/L with once daily netilmicin in a group of surgical ICU patient with normal renal function that doses of 5.00-11.54 mg/kg (mean 7.86) were required. However in patients with serum creatinine > 120mol/L doses of 1.28-6.62 mg/kg/day (mean 2.67) were given to ensure trough levels were not excessive. Two studies 34,39 reported nephrotoxicity secondary to netilmicin was positively correlated with elevated netilmicin trough concentration. In one of these studies 34 but not the other, peak netilmicin concentrations were also shown to be associated with toxicity. One of the difficulties of monitoring trough concentrations with once daily dosing is that dosage adjustment will be delayed until the third dose, 48 hours after the first dose. In order to adjust the second dose, plasma sampling must occur before the end of the 24 hour interval. There is also inadequate evidence of what aminoglycoside trough concentrations have increased risk of toxicity with once daily dosing. Ter Braak 39 found that patients with trough levels of 2.8mg/L had a significantly greater incidence of nephrotoxicity than those with levels of 1.1 mg/L. Ototoxicity has not been shown to correlate with either peak or trough concentration in once daily dosing studies.

14

6.1

Published Dosage and Monitoring Methodologies

Nicolau et al 4o designed a protocol that utilised a fixed dose and varied the dosing interval according to the patients calculated creatinine clearance. The graphical method recommended is based on pharmacokinetic data from only 20 patients and requires a single random, but accurately timed, plasma sample taken between 6 and 14 hours after the first or second dose of the aminoglycoside. The dose is administered as a one hour infusion and sampling time is measured from the start of the infusion. If the level measured falls in the area designated q24h then the dose interval is 24 hours. If it falls in the q36h or q48h the interval is 36 hours or 48 hours respectively. This method, because of the large fixed dose (7mg/kg of gentamicin, netilmicin or tobramycin and 15mg/kg of amikacin), may be hazardous if the patients renal function declines between plasma concentration measurements and may expose patients with poor renal function to excessively high concentrations for prolonged periods. The methods developed by Begg et al 61 are based on the assumption that by achieving the same AUC as conventional therapy a once daily regimen will be no more toxic and at least as effective. They contend that the traditional target peak and trough levels for aminoglycosides are not appropriate for once daily aminoglycoside dosing in patients with moderate to normal renal function. They recommend a starting dose of 57mg/kg/day and exclusion of certain patient groups from once daily regimens due to the lack of appropriate clinical data: children and patients with endocarditis or creatinine clearance <20ml/min. Two methods are described that aim to achieve a target area under the concentration-time curve (AUC) typical of that which would be expected in a patient with mean population values for volume of distribution and elimination half-life. The first of these requires a peak level and second sample 6-18 hours after the first dose of the aminoglycoside. The calculations subsequently required would most efficiently and practically be achieved with computer assistance. Dosing in patients with renal impairment relies on achieving the target AUC; for patients with a creatinine clearance < 40mL/min the dose is decreased but the interval remains at 24 hours. The second method for patients with normal renal function requires a single plasma concentration 6-14 hours after the end of the infusion. The result is compared with the concentration at the same time point on a graph of a concentration-time curve below which drug accumulation is unlikely and above which a decrease in dose is recommended. A simplified approach to monitoring aminoglycoside therapy based on the relationship between creatinine clearance and aminoglycoside clearance has been described 62. The total daily dose can be administered as a single dose or in divided doses if preferred. The dose should be monitored according to the plasma creatinine which should be measured three times weekly. Measurement of serum aminoglycoside concentrations are recommended in certain cases eg. children, patients with anuria or muscular dystrophy and in patients being dialysed. The clinical appropriateness of this approach has not been tested to date. The Antibiotic Guidelines of the Victorian Medical Postgraduate Committee 63 recommend a starting dose of up to 7mg/kg/day of aminoglycosides and a single plasma concentration taken 6-14 hours after the end of the infusion. The plasma level result can

15

then be plotted on a nomogram which is adapted from the simple graphical model described by Begg et al. 61 It has been argued 64 that as single trough levels are more practical in most clinical settings this method of monitoring should not be hastily discarded. The sensitivity of trough measurements can be increased by use of a reverse dilution protocol 65 which allows aminoglycoside plasma concentrations of as low as 0.2mg/L to be measured. It has been suggested that taking the trough level 1-2 hours before the next dose is due would result in little change to the trough concentration observed and allow time for the level to be measured and interpreted. This method has not been compared with AUC methods and there are concerns that low levels of drug accumulation may not be recognised. It is however probably the method in most widespread clinical use at present. In patients with renal impairment or failure, there has been debate about the choice between reducing the dose of aminoglycoside given every 24 hours or maintaining the dose (mg/kg) and extending the dosing interval. It has been proposed that the ODD dose should be reduced to 2-3mg/kg depending on renal function which will ensure the AUC and trough concentration are acceptable at 24 hours 61. The problem with this approach is that the peak concentration and the peak concentration : MIC ratio may not be sufficiently bactericidal. The alternative is to give an equivalent dose of aminoglycoside (mg/kg) to that recommended in ODD regimens but to extend the dosage interval until trough concentrations of <0. 5Mg/L ( or < 1mg/L for amikacin) are achieved. Dosing with aminoglycosides has not been assessed for periods greater than 24 hours and theoretically this could leave a patient without gram negative cover for a prolonged period. In practice, however, aminoglycosides have been given for many years as stat doses to patients with renal failure with subsequent doses withheld until the plasma concentration has fallen to a predetermined level but almost always in conjunction with another antibiotic. There is certainly more clinical experience with this method of dosage adjustment than with the AUC method.

7 7.1

RECOMMENDATIONS Dosage

Once daily aminoglycoside regimens appear to be at least as efficacious as traditional dosage regimens and there is limited evidence that they may cause less nephrotoxicity. There is adequate evidence to support the use of once daily aminoglycosides in most patients with serious gram negative infections although further experience is required in patients with bacterial endocarditis, cystic fibrosis, burns and possibly neutropenia before it can be routinely recommended in these groups. Doses of 7mg/kg/day have been used in some studies but these studies have not included data on the elderly or patients with multiple medical complications, including renal impairment. Considering that for most enteric bacteria, other than P. Aeruginosa and Acinetobacter sp., effective peak : MIC ratios are achievable with ODD of 4-5mg/kg,
16

these doses should not be exceeded in the elderly. These doses are likely to be insufficient in paediatric patients and in burns and cystic fibrosis patients all of whom have higher rates of aminoglycoside elimination. Experience of once daily regimens in children is increasing and many units will feel comfortable adopting this as standard therapy. Doses of 5-7mg/kg are more likely to be applicable for these groups as well as for young adults. Use in neonates who have significantly different kinetics, however, requires more work before once daily therapy can be recommended routinely. For certain documented infections such as P. Aeruginosa septicaemia, associated with poor prognosis, and where susceptibility is intermediate (MIC 1-4mg/L), higher doses of 5-7mg/L should be considered despite the increased risk of toxicity.

7.2

Monitoring

Plasma concentrations should be measured if the patient is anticipated to require more than 48 hours of aminoglycoside therapy. If the length of therapy is uncertain, plasma levels should be monitored in the first 24 hours. Plasma samples should be taken early (in the first 24 hours) and concentrations should be used to individualise subsequent dosing. Subsequent plasma levels should be required only once or twice weekly in haemodynamically and clinically stable patients. Haemodynamically unstable patients, particularly those with changing renal function need to be monitored more frequently. Serum creatinine should be monitored closely in patients continuing on aminoglycosides more than 72 hours. Deteriorating renal function should be a strong inducement for withdrawal of the aminoglycoside. When continuation of therapy is deemed necessary daily monitoring of plasma levels is likely to be required with appropriate dosage adjustments. Early deterioration of renal function (within the first five days of therapy) is usually related to the underlying illness and is unlikely to be indicative of aminoglycoside toxicity. Dosage adjustment will still be necessary, however. All patients should be monitored clinically for signs of auditory and vestibular toxicity. Impairment is often irreversible and current practice probably under detects this adverse outcome. Patients receiving prolonged courses of aminoglycosides should be assessed either at the bedside or more formally for development of toxicity. Effective monitoring of aminoglycoside plasma concentrations requires accurate information on the time of sampling, time of dosage and patient characteristics (serum creatinine, age, weight, height) to assist appropriate interpretation of the level.

7.3

Dosage Adjustment

Several approaches for adjustment of aminoglycoside dosages have been described: measurement of an aminoglycoside area under the plasma concentration versus time curve (AUC); plasma levels taken at a specified time (6-14 hours) post dose and adjusted
17

according to a nomogram; and plasma trough concentrations taken at 24 hours or immediately prior to the next dose. From a practical viewpoint, the method must allow for any plasma concentrations to be rapidly acted upon to allow dosage adjustment before subsequent doses are given. The best tested of the monitoring and dosage adjustment procedures is the AUC method proposed by Begg et al 66. This is the recommended method in hospitals with the staff and facilities (probably including a computer program to facilitate calculation of the new dosage) to make it a practical option. Consistently obtaining two plasma samples (a peak and another at 6-14 hours) after the dose may prove difficult in many institutions. Unfortunately many hospitals will not find the AUC method practical for their institution and the method described in the Antibiotic Guidelines 64 is then the recommended option. For the latter to be effective, it is important that the plasma sampling time is accurately recorded - this is more likely in normal working hours and in intensive care and high dependency units. In units with lower staff to patients ratios, accurate information on dosage time can be compromised by recording of administration at a set time rather than when the drug was actually given. In these circumstances it will be difficult for the blood collector to know the exact time of dosing and an over-estimation by one to two hours can substantially affect interpretation of the plasma concentration result. Blood collections are less easily obtained outside normal working hours and outside the times designated for routine blood collection rounds. While monitoring trough concentrations appears to be a third choice alternative, accurate sampling is more easily ensured than with the other options. This method of monitoring is preferable to no monitoring at all and should be encouraged if the preferred options discussed above are not achievable. Patients with renal failure should be dosed according to the AUC method described by Begg 62 or with stat 5mg/kg every 36-72 hours as determined by plasma concentrations, usually with an additional antibiotic given concurrently. Further studies of once daily dosing are required to clarify the optimum dosage regimens for patients with renal impairment. All aminoglycoside dosage regimens should be given for the shortest period possible, preferably for less than 10 days in all patients.

18

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35. Mauracher EH, Lau W, Kartowisastro H, Ong K, Ganato V, et al. Comparison of once daily and thrice daily netilmicin regimens in serious systemic infections: a multicentre study in six Asian countries. Clin Ther 1989; 11: 604-13 36. Marik PE, Lipman J, Kobilski S, Scribante J. A prospective randomised study comparing once- versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Ther 1991; 28:753-764 37. Prins JM, Bller HR, Kuijper EJ, Tange RA, Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341: 335-9 38. Raz R, Adawi M, Romano S. Intravenous administration of gentamicin once daily versus thrice daily in adults. Eur J Clin Microbiol Infect Dis 1995; 14: 88-91 39. Ter Braak E, de Vries PJ, Bouter KP, Van der Vegt SG, Dorrestein GC, et al. Oncedaily dosing regimen for aminoglycoside plus -lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone. Am J Med 1990; 89: 58-66 40. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once daily aminoglycoside program administered to 2,184 patients. Antimicrob Agents Chemother 1995; 39: 650-655. 41. Rozdzinski E, Kern WV, Reichle A, Moritz T, Schmeiser T, et al. Once daily versus thrice daily dosing of netilmicin in combination with -lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother 1993; 31: 585-98 42. The International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Ann Intern Med 1993; 119: 584-593 43. Vigano A, Principi N, Brivio L, Tammasi P, Stasi P, Dalla Villa A. Comparison of 5 milligrams of netilmicin per kilogram of bodyweight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram negative pyelonephritis in children. Antimicrob Agents Chemother 1992; 36: 1499-1503 44. Elhanan K, Siplovich L, Raz R. Gentamicin once daily versus thrice daily in children. J Antimicob Chemother 1995; 35: 327-32 45. Skopnik H, Heimann G. Once daily aminoglycoside dosing in full term neonates. Pediatr Infect Dis J 1995; 14: 71-2 46. Fan ST, Lau WY, Teoh-Chan CH, Lau KF, Mauracher EH. Once daily administration of netilmicin compared with thrice daily both in combination with metronidazole in gangrenous and perforated appendicitis. J Antimicrob Chemother 1988; 22: 69-74 47. Giamarellou H, Yiallouros K, Petrikkos G, Moschovakis E, Vavouraki E, et al. Comparative kinetics and efficacy of amikacin administered once or twice daily in the treatment of systemic gram negative infections. J Antimicrob Chemother 1991; 27(suppl C): 73-9 48. Hollender LF, Bahnini J, de Manzini N, Lau WY. Fan ST, et al. A multicentre study of netilmicin once daily versus thrice daily in patients with appendicitis and other intra-abdominal infections. J Antimicrob Chemother 1989; 23: 773-83 49. Maller R, Isaksson B, Nilsson L, Soren L. A study of amikacin given once versus twice daily in serious infections. J Antimicrob Chemother 1988; 22: 75-9
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50. Maller R, Ahrne H, Holmen C, Lausen I, Nilsson LE, et al. Once- versus twice- daily amikacin regimen: efficacy and safety in systemic gram negative infections. J Antimicrob Chemother 1993; 31: 939-48 51. Nordstrom L, Ringberg H, Cronberg S, Tjernstrom O, Walder M. Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity. J Antimicrob Chemother 1990; 25: 159-173 52. Powell SH, Thompson WL, Luthe MA, Stern RC, Grossniklauss DA, et al. Once daily vs continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin and tobramycin. J Infect Dis 1983; 147: 918-32 53. Sturm AW. Netilmicin in the treatment of gram negative bacteraemia: single daily versus multiple daily dosage. J Infect Dis 1989; 159: 931-7 54. Tulkens PM. Pharmacokinetic and toxicological evaluation of a once daily regimen versus conventional schedules of netilmicin and amikacin. J Antimicobial Chemother 1991; 27(suppl C): 49-61 55. Van der Auwera P, Meunier F, Ibrahim S, Kaufman L, Derde MP, Tulkens PM. Pharmacodynamic parameters and toxicity of netilmicin given once daily or in three divided doses to cancer patients with urinary tract infection. Antimicrob Agents Chemother 1991; 35: 640-7 56. Galle AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? Eur J Clin Pharmacol 1995; 48: 39-43 57. Barza M, Ioannidis JPA, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. Br Med J 1996; 312: 338-43 58. Hatala R, Dinh T, Cook D. Once daily aminoglycoside dosing in immunocompetent adults: a mete-analysis. Ann Intern Med 1996; 124: 717-25 59. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37: 645-63 60. Konrad F, Wagner R, Neumeister B, Rommel H, Georgieff M. Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intens Care Med 1993; 19: 215-20 61. Begg EJ, Barclay ML, Duffull SB. A suggested approach to once- daily aminoglycoside dosing. Br J Clin Pharmacol 1995; 39: 605-609 62. Cronberg S. Antimicrobial practice - Simplified monitoring of aminoglycosides. J Antimicrob Chemother 1994; 34: 819-827 63. Antibiotic Guidelines Sub-Committee, Victorian Drug Usage Advisory Committee. Antibiotic Guidelines, 9th edition, Victorian Medical Postgraduate Medical Committee Inc, 1996 64. DeWit D, Once daily aminoglycosides, Personal Communication, 1996 65. White Lo, MacGowan AP, Louering AM, Holt HA, Reeves DS, Ryder D. Assay of low trough serum gentamicin concentrations by fluorescence polarisation immunoassay. J Antimicrob Chemother 1994; 33: 1068-1070 66. Barclay ML, Duffull SB, Begg EJ, Buttimore RC. Experience of once-daily aminoglycoside dosing using target area under the concentration-time curve. Aust NZ J Med 1995; 25: 230-235

22

Appendix One

Once Daily Dosing Nomogram 1

8

Aminoglycoside concentration (mg/L)

Maximum

3 Minimum 2

0 6 7 8 9 10 11 12 13 14 Time (hours) post dose

Data based on population pharmacokinetics for 4mg/kg (lower line) and 7mg/kg (upper line). Reprinted with permission of Therapeutic Guidelines from Antibiotic Guidelines, ninth edition, VMPF Therapeutics Committee, Melbourne, 1996. 23