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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 819-823, (2003)
© 2003 American Thoracic Society

Clinical Commentary

Aminoglycoside Prescribing and Surveillance in Cystic Fibrosis

Kelvin H.-V. Tan, Michael Mulheran, Alan J. Knox and Alan R. Smyth

Academic Division of Child Health, and Division of Respiratory Medicine, University of Nottingham; and Department of Paediatrics, Nottingham City Hospital, Nottingham, United Kingdom
Keywords:

Correspondence and requests for reprints should be addressed to Dr. K. Tan, Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: Kelvin.Tan{at}nottingham.ac.uk

Key Words: cystic fibrosis • aminoglycoside antibiotics • ototoxicity • nephrotoxicity

The potential of aminoglycoside antibiotics to cause ototoxic and nephrotoxic damage was first discovered in 1945, during early clinical trials of streptomycin (1). Despite the introduction of newer classes of antibiotics, aminoglycosides continue to be widely prescribed in cystic fibrosis (CF) clinics and are likely to retain an important role in the management of CF lung disease for the foreseeable future. They are highly active against Pseudomonas aeruginosa, display synergism with ß-lactam antibiotics (2), and effectively penetrate the sputum of patients with CF (3).

Patients with CF can now expect to live into the fourth decade and beyond, with full-time education followed by employment and an active lifestyle being attainable goals. Therefore, the role of the CF clinician when prescribing repeated courses of potentially toxic drugs is to ensure optimal efficacy with minimal cumulative toxicity. Guidance on how to prescribe aminoglycosides effectively and minimize the risks of developing toxicity is needed.

There remains controversy surrounding the prevalence, importance, and the role of surveillance of aminoglycoside-induced toxicity in CF. There have been no large studies of aminoglycoside-naive patients with CF to clarify these issues, and evidence from patients without CF may not be directly applicable. Recent consensus statements produced by the UK CF Trust (4) and the European Consensus Committee for Antibiotic Therapy in CF (5) made no reference to the controversial area of screening for aminoglycoside-induced toxicity. The North American CF Foundation (6) recommends that urine analysis, blood urea nitrogen, and creatinine should be measured after each course of intravenous administration, and audiology should be performed every two to four intravenous aminoglycoside courses, although the evidence on which these recommendations are based is unclear. This pulmonary perspective will review the literature surrounding the prescribing and monitoring of aminoglycosides and put forward suggestions regarding good clinical practice.

PRESCRIBING AMINOGLYCOSIDES IN CF

Pharmacokinetics of Aminoglycosides in CF
Aminoglycosides are highly polar cationic molecules which are relatively lipid-insoluble and highly water-soluble. When administered intravenously, they distribute almost entirely to the body's lean mass, of which 70% is body water and the remainder muscle. After intravenous administration, aminoglycosides distribute rapidly throughout the extracellular fluid compartment, with peak serum levels achieved within 30 minutes of the end of a 30-minute infusion.

Patients with CF are typically prescribed high dose prolonged courses of intravenous antibiotics based upon reports of altered pharmacokinetics (7) and due to the nature and severity of CF disease. The volume of distribution and the rate of clearance of aminoglycosides are increased, with the half-life of tobramycin between 2 and 3 hours. Aminoglycosides undergo minimal protein binding and are eliminated almost entirely by glomerular filtration.

Starting Dose
The starting dose of aminoglycosides is traditionally calculated from body surface area (60–75 mg/m2/dose) (8), body weight (3.3–5 mg/kg/dose) (9), or from past records of doses that achieved therapeutic levels. In our practice, the maximum total daily dose prescribed is 660 mg in three divided doses. Although these clinician-led techniques require only simple calculations, these methods result in widely varying peak serum concentrations. Approaches using population models, which take into account renal function, are reported to be superior (10).

Dosing Frequency and Monitoring
Aminoglycosides are most commonly prescribed thrice-daily, with peak and trough serum concentrations monitored to confirm that serum levels are within the therapeutic and nontoxic ranges, respectively. The optimum peak serum level for tobramycin or gentamicin is generally considered to be 8 to 12 mg/L 30 minutes after completion of an intravenous infusion, and < 1 mg/L for the trough (4). Our practice is to aim for peak levels closer to the upper limit of 12 mg/L, as laboratory models of P. aeruginosa sputum infection suggest that higher peak levels of tobramycin achieve more effective bacterial killing (3).

Although convenient for patients, the efficacy and safety of once- and twice-daily aminoglycoside dosing remains unproven in CF. However, in once-daily dosing, peak levels of 20–30 mg/L are typically achieved, with trough levels < 1 mg/L. Strategies that maximize the peak concentration and minimize the trough concentration of aminoglycosides may enhance bactericidal activity and reduce the risk of nephrotoxicity and ototoxicity. Because aminoglycosides demonstrate concentration-dependent killing, achieving a ratio for the peak aminoglycoside level: minimum inhibitory concentration in excess of 8 may result in improved clinical success (11). Furthermore, by increasing the interval between doses, one would expect a reduction in the basal serum aminoglycoside level, thereby reducing accumulation within the kidney and inner ear.

Active therapeutic drug monitoring optimizes the starting dose and evaluates ongoing individual pharmacokinetic parameters to maintain serum aminoglycoside levels within target ranges (12). The most widely used technique is the Sawchuk-Zaske model, although other pharmacokinetic software is available. The peak aminoglycoside concentration/minimum inhibitory concentration ratio can be maximized, which would be expected to improve clinical outcome. These methods are also reported to reduce time to achieve target levels of aminoglycosides and result in reductions of cost (13).

Adjusting Aminoglycoside Doses in Renal Failure
Toxic concentrations of aminoglycosides will develop if the dose is not adjusted in renal failure. Avoidance of aminoglycoside use is rarely an option, as the emergence of resistant strains of P. aeruginosa compel their use. Mathematical formulae (14) or nomograms (15) have been used for many years to adjust the aminoglycoside dosing regimen, to take account of renal function; e.g., the half-life of gentamicin can be estimated as a function of the serum creatinine concentration (mg/100 ml) multiplied by a factor of four. However, these formulae were originally calculated from patients without CF.

TOXICITY OF AMINOGLYCOSIDES IN CF

Nephrotoxicity
Nephrotoxicity results from a small but sizeable proportion of the administered dose being retained in the epithelial cells of the proximal tubules. Aminoglycosides bind to brush border membranes, where they are endocytosed and accumulate with phospholipid within the tubular cell lysosomes (16). Increasing accumulation of aminoglycosides results in a stepwise alteration of cell function and ultimately cell necrosis. Advancing toxicity is characterized by increased excretion of electrolytes such as magnesium, potassium, and calcium. Finally, renal failure is characterized by uremia and a high serum creatinine concentration. In clinical practice, this presents as nonoliguric renal failure with a reduction in the glomerular filtration rate. Progression to oliguric or anuric renal failure is rare, with recovery on discontinuation of aminoglycosides the most common outcome.

How Common Is Aminoglycoside-induced Nephrotoxicity in CF?
Accurate estimates of the prevalence of this condition are difficult to ascertain, as much of the literature in CF is limited to comparisons of dosing regimes and case reports. Furthermore, the prevalence of renal impairment will depend upon the markers of renal function measured and criteria used to define nephrotoxicity. However, renal failure characterized by elevated creatinine and urea concentrations does appear to be a rare complication of aminoglycoside therapy in patients with CF. In comparison, nephrotoxicity has been estimated to affect 10 to 20% of therapeutic courses of aminoglycosides in the population without CF (17).

Defining Nephrotoxicity
Clinicians commonly use serum creatinine, urea, and electrolyte concentrations as the most practical measures of renal function. Unfortunately, none of these are useful markers of early renal impairment. For example, typical definitions of nephrotoxicity include an increase in the serum creatinine of > 40 µmol/L (0.4 mg/dL) (18) or an increase in serum creatinine concentration of > 50% from baseline (19). However, the serum creatinine concentration may remain within the normal range even in the presence of a 50% drop in glomerular filtration rate. In addition, protein metabolism, the state of hydration, and the use of steroids influence the blood urea concentration. Thus, a grossly malnourished patients with CF may have a relatively normal blood urea concentration in the presence of significant renal impairment. Increased urinary losses of potassium, magnesium, and calcium, reflecting tubular dysfunction, will precede elevated creatinine and urea levels (20, 21). Hypomagnasemia in patients with CF receiving aminoglycosides is well documented, but may be multifactorial in origin, with malnutrition, malabsorption, diabetes, and secondary hyperaldosteronism being contributory factors. Recently, markers of proximal tubular function, such as N-acetyl-ß-D-glucosaminidase (NAG, a lysosomal enzyme) and ß2-microglobulin (a low molecular weight protein) have been proposed as early markers of aminoglycoside-induced tubular toxicity (22). The proximal tubule is the primary site of aminoglycoside damage, and markedly elevated levels of these proteins can be found in the urine after intravenous aminoglycoside administration. However, the clinical implication of elevated proximal tubule proteins remains unclear, and their measurement remains largely a research tool.

How to Assess Renal Function in CF
The gold standard test for assessing renal function is the glomerular filtration rate (normal range, 80–120 ml/min), a laborious investigation involving the administration of radiolabeled isotopes. A more practical assessment of renal function is the creatinine clearance, which measures the ability of the kidneys to clear creatinine from the circulation into the urine over 24 hours. However, creatinine clearance rates should be interpreted for individual patients with CF, as the serum creatinine concentration is influenced by muscle mass, which may be reduced in CF. The modified Cockroft-Gault formula (calculated after ingestion of 2.4 g of Cimetidine), calculates the creatinine clearance, correcting for age, body mass, and serum creatinine concentration.

OTOTOXICITY

It is well recognized that the use of aminoglycoside antibiotics carries a risk of auditory and vestibular toxicity. The cochlea sensory cells are divided into the outer and inner hair cells. The typical pattern of aminoglycoside-induced high frequency hearing loss results from progressive loss of function from the outer hair cells to the inner hair cells (23, 24). The mechanism involves penetration of endolymph, active uptake into hair cells, storage, and finally generation of damaging free radicals (25). If the detoxicant systems in the hair cells do not adequately deal with this challenge, then apoptotic cell death results. Experimental models suggest that the half-life of aminoglycosides in hair cells can be measured in months (26). If the interval between repeat aminoglycoside courses is less than this half-life, then accumulation of aminoglycosides in the hair cells of the inner ear will occur.

How Common Is Aminoglycoside-induced Hearing Loss in CF?
Mulheran and coworkers have reported the prevalence of hearing loss in patients with CF, using recognized protocols for audiometric testing (27). The prevalence of hearing loss in 70 young (10–18 years, n = 27) and adult (18–37 years, n = 43) patients with CF using standard and high frequency pure tone audiometry was 17%. The prevalence of hearing loss in the pediatric population is generally reported to be lower (0–6%) (28), which may reflect less aminoglycoside exposure and less environmental damage.

In comparison, several studies have investigated the prevalence of aminoglycoside toxicity in patients without CF, with estimates of hearing loss of 20% and balance dysfunction of 15% (29). Mulheran and coworkers described a per-course risk estimate for the development of ototoxicity after a course of aminoglycoside antibiotics; 7.5% in the population without CF compared with less than 2% in patients with CF. This difference in risk may suggest that patients with CF patients are less likely to develop hearing loss from a course of aminoglycosides than their counterparts without CF, which raises the possibility that patients with CF may be protected against the toxic potential of aminoglycosides antibiotics.

Defining Ototoxicity
Early hearing loss is defined as a threshold elevation at any frequency to 25dB HL, across the frequency range 250–8,000 Hz. Aminoglycosides typically produce a pattern of high-frequency, irreversible threshold elevation, which progresses to speech frequencies with continued exposure. Most patients may be unaware of high-frequency threshold elevation, as this may not present any significant difficulty in conversational speech. Early detection of minor levels of impairment may enable the prediction and prevention of clinically significant hearing loss.

Vestibulotoxicity in association with aminoglycoside infusions is commonly referred to as "dizziness." This symptom is often difficult to define, but typically refers to rotational vertigo associated with the unpleasant sensations of nausea, sweating, vomiting, and pallor that accompany excessive vestibular stimulation. Fortunately, irreversible vestibular dysfunction appears to be an uncommon side effect of aminoglycosides, although anecdotal reports of patients experiencing transient and reversible "dizziness" are well recognized. These problems are often unpredictable, although sometimes described in association with high-dose (15 mg/kg/dose), rapid infusions of aminoglycosides (30), exposure to netilmicin (31), concurrent use of nephrotoxic drugs (32), or in those who have previously experienced dizziness.

Reducing the Risk of Developing Toxicity
The risk factors for aminoglycoside-induced nephrotoxicity and ototoxicity are broadly similar. Strategies for reducing the risk of nephrotoxicity and ototoxicity are considered below.

REDUCING CUMULATIVE AMINOGLYCOSIDE EXPOSURE

The most strongly implicated risk factor for the development of toxicity is the cumulative exposure to aminoglycosides. There is a nonlinear relationship between cumulative aminoglycoside exposure and the development of toxicity, which may be exacerbated by the prolonged half-life of aminoglycosides within target cells.

Aminoglycosides remain an important antibacterial therapy in the management of CF lung disease. Therefore, recommendations to stop using them when a threshold of cumulative exposure has been reached are unhelpful. However, if patients receive frequent (every 2 months) intravenous antibiotic treatment, clinicians may consider using alternate aminoglycoside courses. By increasing the interval between aminoglycoside exposure, where clinically indicated, complete aminoglycoside clearance from the previous course may be possible.

Choosing Less Toxic Aminoglycosides
The aminoglycosides can be ranked in order of decreasing toxicity: neomycin > amikacin > gentamicin = tobramycin > netilmicin (33). Differences in nephrotoxic potential are related to increased ability to bind to the brush border membranes of the renal tubule. Experimental and clinical studies have shown that the relative risk of developing auditory toxicity from gentamicin and tobramycin is generally considered to be equivalent.

Avoiding Concurrent Use of Other Toxic Drugs
Several other drugs used in CF care have nephrotoxic and ototoxic potential. Ototoxicity resulting from the concurrent use of diuretics with aminoglycosides is well described and should be avoided where possible. Transient renal failure associated with the use of ibuprofen and aminoglycosides, interstitial nephritis associated with ceftazidime use (34), and intravenous colistin (35) or vancomycin (36) used in combination with aminoglycosides have all been reported to increase the risk of nephrotoxicity.

Unfortunately, due to the increased prevalence of resistant P. aeruginosa species, unavoidable combinations of potentially toxic antibiotics are widely used in clinical practice. Increased vigilance may help reduce the risk of side effects.

Extended-Interval Aminoglycoside Dosing
Several separate meta-analyses investigating the relationship between dosing interval and toxicity in patients without CF report that extended interval aminoglycoside dosing has less toxic potential than the standard thrice-daily regime (37–39). In three-times daily dosing, saturable accumulation of aminoglycosides in the target cells of the kidney and inner ear may occur. In the proximal tubules of the kidney, aminoglycoside accumulation slows as the serum concentration reaches 10–15 mg/L. Although once-daily dosing would produce peak levels in excess of this range, it would also increase the time available for target cells to clear aminoglycosides between doses.

However, the situation in patients with CF may be different due to differences in drug handling. A recent systematic review of once-daily dosing in patients with CF concluded that there was insufficient evidence to recommend one dosing schedule over another in terms of efficacy and toxicity (40). Of note, none of the patients in the studies included demonstrated nephrotoxicity after once- or thrice-daily dosing. There are currently two multicentre trials in the U.S.A and UK, which are designed to answer this question. Until then, the standard three-times daily dosing regimen should be used.

SPECIAL CONSIDERATIONS IN CF

Using Aminoglycosides in Pregnancy
The number of reported pregnancies among women with CF has increased markedly over the last 10 years (41). Careful planning of pregnancies is ideal, but not always possible. It is suggested that an FEV1 > 50% predicted is associated with improved outcome for the infant. However, some mothers will need antibiotic treatment during pregnancy, and the teratogenic potential of these drugs should be considered.

Tobramycin crosses the placenta, distributes to most fetal tissues, and concentrates in fetal kidneys and urine. There have been no reports of teratogenicity after the use of tobramycin in humans, although high-dose tobramycin (30–60 mg/kg/day) has been reported to cause renal toxicity in pregnant rats and their fetuses. Ototoxicity has not been reported as an effect of in utero exposure. However, in view of the theoretical risks of aminoglycosides the UK National Teratology Information Service advises that tobramycin should only be used in pregnancy if the potential benefit outweighs the potential risk to the fetus. Reassuringly, Bouget and coworkers reported no side effects in the use of once-daily (and therefore high–dose) tobramycin in pregnant women during the second and third trimester (42).

Nebulized Aminoglycosides
Many patients with CF receive nebulized aminoglycoside antibiotics as adjunct or maintenance therapy, as tobramycin levels of 1,237 mcg/g of sputum can be achieved using this route (43). These high levels are believed to enhance concentration-dependent killing. Aminoglycosides are absorbed systemically from the respiratory system, although their bioavailability is reported to be low (11.7% of nominal dose). Ramsey and colleaguesstudied intermittent administration of inhaled tobramycin in CF (44). The median tobramycin level 1 hour after administration of the first dose was 0.94 mg/L, a value of the same order of magnitude as an intravenous trough level. The median serum tobramycin level was 0.98 mg/L at Week 20. They reported no toxic effect on auditory or renal function. However, the surveillance tests used to detect toxicity were limited in sensitivity. Furthermore, patients receiving concurrent intravenous tobramycin were excluded from the toxicity analysis.

A systematic review of patients with CF receiving nebulized aminoglycosides also found no cases of adverse effects (45). However, the surveillance tests used were again not sensitive enough to detect subclinical changes in auditory and renal function. Ring and coworkers demonstrated an increase in urinary NAG in patients with CF receiving nebulized gentamicin (46). More significantly, those currently on gentamicin therapy showed a positive correlation between urinary NAG activity and cumulative dose of nebulized gentamicin. It is possible that further cumulative exposure might result in more severe renal impairment.

There is insufficient evidence regarding the toxicity of long-term nebulized aminoglycosides. Accumulation of aminoglycosides in the inner ear and kidney may occur, unless there are drug-free periods between courses of nebulized therapy. The summary of product characteristics for the currently licensed form of nebulized tobramycin recommends administration for 4 weeks followed by a 4-week drug-free period. More research is needed to guide clinical practice in this area.

GUIDELINES FOR AMINOGLYCOSIDE SURVEILLANCE IN CF

Nephrotoxicity
The UK CF Trust's Antibiotic Group recognizes that patients with CF may receive repeated courses of potentially toxic drugs such as aminoglycosides, and recommends careful monitoring of renal function (4). However, it offers no advice on which tests to perform and when, except that during intravenous therapy trough and peak levels of aminoglycosides should be measured. The North American CF Foundation recommends that urine analysis, blood urea nitrogen, and creatinine should be measured after each course of intravenous administration (6). In our clinical practice, renal function is assessed at the start and during the second week of treatment in all patients with CF receiving intravenous aminoglycosides. Serum magnesium, potassium, calcium, creatinine, and urea concentrations, together with peak and trough aminoglycoside levels, should be also measured. A random trough level in the second week of treatment would detect aminoglycoside accumulation. All tests should be interpreted with caution, as they are limited in sensitivity and must be assessed for each individual patient. More frequent and detailed assessments of renal function (creatinine clearance) should be considered in those patients with added risk factors for developing nephrotoxicity.

Ototoxicity
It would seem sensible to test all patients who complain of auditory or vestibular symptoms during treatment. In addition, we have previously demonstrated that the median number of aminoglycoside courses received in patients with CF without hearing loss is 9, and in those with hearing loss it is 20 (p = 0.006) (28). Therefore, we would suggest that all patients who have received 10 or more courses of intravenous aminoglycosides should also undergo routine audiometric assessments. A standard pure tone audiogram (250–8,000 Hz), although restricted in its sensitivity, is readily accessible in most centers and should be performed at annual assessment. This will provide a useful marker of the presence or absence of hearing loss. Although high frequency hearing loss precedes hearing loss across speech frequencies, this level of testing is only available in specialist centers. Distortion Product Otoacoustic Emissions have been proposed as an early marker of hair cell function in patients chronically exposed to aminoglycosides (47). The hair cells of the inner ear are forced to vibrate by acoustic stimuli until they distort and generate energy known as the Distortion Product Otoacoustic Emission. However, this remains an experimental tool and its use has not yet been thoroughly validated as a screening tool for aminoglycoside-induced hearing loss in CF.

CONCLUSION

The prognosis of patients with CF continues to improve, in part due to the use of timely and vigorous antibiotic regimes, which often include aminoglycosides. These antibiotics remain the treatment of choice for patients with CF chronically infected with P. aeruginosa, and so exposure to the cumulative toxic potential of these drugs will continue for the foreseeable future.

Patients with CF appear to handle repeated courses of aminoglycosides well, as the prevalence of nephrotoxicity and ototoxicity appears to be low compared with the population without CF. This protection may result from altered pharmacokinetic handling and/or the underlying abnormality of the CFTR, although further research in this area is needed. However, the prevalence of adverse effects of treatment in CF is expected to increase as survival in this condition continues to improve.

It would be useful to be able to predict early and reversible toxicity before clinically significant damage has occurred. It is now possible to detect early changes in target cell function, although these tests are limited by their applicability in routine clinical practice. Adverse effects of treatment in patients with CF will become more common unless surveillance of aminoglycoside toxicity is performed. Routine surveillance of audiometric and renal function must become standard practice if we are to reduce long-term morbidity in these patients.

FOOTNOTES

This work was made possible by a grant from the UK Cystic Fibrosis Trust.

Received in original form September 13, 2001; accepted in final form September 13, 2002

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