I have a thing about Gentamicin, I often find I am adding it to a patients’ management when I’m called out of hours. In fact my wife frequently comments that “all on call queries can be solved with a good dollop of Gentamicin!” Hmm...it’s not the only treatment I prescribe; although it has its uses… So why does it get left out of the management of patients who really need it? Often the reason is that the doctor is frightened of it causing renal failure. I find this argument really baffling and I think that in most situations they have got the balance of risk wrong.
For example, a 67 year old man is admitted to hospital with sepsis secondary to acute cholangitis. He is allergic to beta-lactams with a history of anaphylaxis. He weighs 70kg and has a creatinine of 140micromol/L. The hospital antibiotic guidelines say to use Teicoplanin PLUS Gentamicin PLUS Metronidazole but because of the renal impairment the admitting doctor omits the Gentamicin as they do not want to make the renal function worse. Is the doctor just protecting those kidneys and being safe or is their approach wrong? I believe this approach is a mistake which may lead to patient harm. Let me explain...
Why do the guidelines say to use Gentamicin?
Most intra-abdominal infections are polymicrobial, involving mixtures of bowel flora getting into sites they shouldn’t be in. This includes Gram-positive, Gram-negative and anaerobic bacteria. Combination therapy is required because each of the individual antibiotics only covers part of the flora; all are need to provide a sufficient spectrum of activity.
Why do the guidelines say to use Gentamicin?
Most intra-abdominal infections are polymicrobial, involving mixtures of bowel flora getting into sites they shouldn’t be in. This includes Gram-positive, Gram-negative and anaerobic bacteria. Combination therapy is required because each of the individual antibiotics only covers part of the flora; all are need to provide a sufficient spectrum of activity.
- Teicoplanin – Gram-positive bacteria including Enterococcus spp. and Streptococcus spp.
- Gentamicin – Gram-negative bacilli including the Enterobacteriaceae e.g. E. coli, K. pneumoniae, E. cloacae, etc.
- Metronidazole – Anaerobic bacteria including Clostridia spp. and Bacteroides spp.
In some respects this omission can be seen as not treating the patient at all and remember that sepsis has a 40% mortality at 6 hours without adequate antibiotic treatment! The patient has not been treated for the infection that is known to be present for the fear of a condition that may or may not occur. A renal physician once put it another way to me “a live patient with renal complications, was in his opinion, better than a dead patient with normal kidneys”. Maybe a bit blunt but I believe he has a point.
So why are doctors worried about renal failure and Gentamicin?
Some doctors seem to hold the opinion that every patient given Gentamicin will go in to renal failure and that it should only be used as a last resort. This is not true. Although acute kidney injury is relatively common in Gentamicin administration, occurring in about 10% of patients based upon studies conducted in the 1980s, it is rarely severe and usually recovers within 21 days of stopping the Gentamicin. Added to this is that this complication normally only occurs with courses of Gentamicin longer than 5-7 days.
Gentamicin is taken and up and concentrated in the proximal tubule cells of the kidney where it disrupts protein synthesis and mitochondrial function leading to cell damage. When it does occur, it usually presents as a nonoliguric increase in serum creatinine although electrolyte disturbances can also occur due to the failure of fluid and electrolyte reabsorption in the tubules.
Which patients are most at risk of Gentamicin induced renal failure?
There are a number of risk factors for renal failure with Gentamicin including:
NOTE: the Renal Drug Handbook by Ashley and Currie (which is commonly held to be the best source of information in the UK on prescribing in renal failure) does not restrict Gentamicin in renal failure but rather recommends appropriate dosage modification...just like almost all other antibiotics.
So you’re still worried about Gentamicin but you’re patient needs it, what should you do?
There are a number of ways in which the risk of Gentamicin induced renal damage can be reduced:
1. Use the correct dose of Gentamicin for the individual patient
The most common dosing regimen for Gentamicin is once-daily, but “old-fashioned” dosing of BD or TDS should still be used for certain patients where there are concerns about potential toxicity from single high doses, including patients with burns >20% total body surface area, ascites or those who are pregnant. I’m going to concentrate on once-daily dosing as this is by far the most common method of administration in UK hospitals.
Once-daily Gentamicin dosing should be based on the individual patient’s body weight and renal function calculated as their creatinine clearance (CrCl) using the Cockcroft-Gault equation:
So why are doctors worried about renal failure and Gentamicin?
Some doctors seem to hold the opinion that every patient given Gentamicin will go in to renal failure and that it should only be used as a last resort. This is not true. Although acute kidney injury is relatively common in Gentamicin administration, occurring in about 10% of patients based upon studies conducted in the 1980s, it is rarely severe and usually recovers within 21 days of stopping the Gentamicin. Added to this is that this complication normally only occurs with courses of Gentamicin longer than 5-7 days.
Gentamicin is taken and up and concentrated in the proximal tubule cells of the kidney where it disrupts protein synthesis and mitochondrial function leading to cell damage. When it does occur, it usually presents as a nonoliguric increase in serum creatinine although electrolyte disturbances can also occur due to the failure of fluid and electrolyte reabsorption in the tubules.
Which patients are most at risk of Gentamicin induced renal failure?
There are a number of risk factors for renal failure with Gentamicin including:
- Prolonged course of Gentamicin – renal failure usually requires 5-7 days or more of treatment with Gentamicin but repeated courses within 2-3 weeks can also cause problems
- Old age – elderly patients are unable to heal as well as younger patients and therefore they have a more limited capacity to recover from renal damage caused by Gentamicin
- Comorbidities – early studies suggested chronic renal failure as a risk factor for worsening renal function in patients given Gentamicin but these were in the days when serum concentrations could not be measured. Subsequent studies (that correct for monitoring of serum Gentamicin concentrations) have not confirmed these findings. Both diabetes mellitus and leukaemia have been associated with an increased risk of renal failure from Gentamicin but the cause is not clear
- Reduced intravascular volume – this results in reduced renal perfusion and associated ischaemia which increases the risk of Gentamicin induced renal damage; this should be corrected in septic patients where Gentamicin may be required
- Drug interactions – co-administration of Gentamicin with other nephrotoxic drugs can increase the risk of renal damage e.g. Furosemide, non-steroidal anti-inflammatory drugs (NSAIDS), Ciclosporin, Vancomycin
- High serum Gentamicin concentrations – elevated trough concentrations of Gentamicin in serum are associated with a higher risk of renal failure and so levels should be monitored in all patients except those where a single Stat dose has been given
NOTE: the Renal Drug Handbook by Ashley and Currie (which is commonly held to be the best source of information in the UK on prescribing in renal failure) does not restrict Gentamicin in renal failure but rather recommends appropriate dosage modification...just like almost all other antibiotics.
So you’re still worried about Gentamicin but you’re patient needs it, what should you do?
There are a number of ways in which the risk of Gentamicin induced renal damage can be reduced:
1. Use the correct dose of Gentamicin for the individual patient
The most common dosing regimen for Gentamicin is once-daily, but “old-fashioned” dosing of BD or TDS should still be used for certain patients where there are concerns about potential toxicity from single high doses, including patients with burns >20% total body surface area, ascites or those who are pregnant. I’m going to concentrate on once-daily dosing as this is by far the most common method of administration in UK hospitals.
Once-daily Gentamicin dosing should be based on the individual patient’s body weight and renal function calculated as their creatinine clearance (CrCl) using the Cockcroft-Gault equation:
Click for larger image
For patients whose total body weight (TBW) is "normal" e.g. within 25% of the ideal body weight (IBW), use IBW to calculate CrCl.
Male IBW = 50 + (2.3 x height in inches above 60 inches)
Female IBW = 45 + (2.3 x height in inches above 60 inches)
However:
Male IBW = 50 + (2.3 x height in inches above 60 inches)
Female IBW = 45 + (2.3 x height in inches above 60 inches)
However:
- For underweight patients, whose TBW is less than IBW, use the patients TBW to calculate renal function
- For obese patients, whose TBW is more than 25% greater than IBW, use a dosing weight calculated using: Dosing weight (kg) = IBW + [0.4 x (TBW – IBW)]
Click for larger image
2. Correct fluid and electrolyte disturbances
Patients with reduced intravascular volume should be carefully fluid resuscitated and consideration given to correcting low serum potassium and magnesium levels.
3. Limit treatment to less than 7 days, if possible
Renal failure is more common with prolonged courses of Gentamicin so try to limit the duration of treatment. In practice this shouldn’t be too difficult as very few infections require longer than this. The more difficult situation to judge is when patients receive multiple courses of antibiotics in a short period of time. In this case try to avoid giving further Gentamicin to patients who have received a course within the preceding 2-3 weeks. If in doubt this would be the ideal patient to discuss with a Microbiologist or Antibiotic Pharmacist.
4. Avoid co-administration of other nephrotoxic drugs
Where possible try to avoid other nephrotoxic drugs but don’t let that mean that you fail to treat the patient for their infection. If other nephrotoxic drugs cannot be stopped and have to be given with Gentamicin make sure you monitor renal function and serum Gentamicin concentrations carefully.
5. Monitor serum Gentamicin concentrations and renal function during treatment
In patients with stable normal renal function the serum Gentamicin level should be measured before the 3rd or 4th dose and then the dose given (without waiting for the level to come back). In this case any dose adjustments can be made prior to the next dose.
If the trough level is high then recheck the level at 24 hours and withhold the next dose. If this level is <1mg/L then redose the patient and adjust the timing of the dose on the prescription chart. If this level is >1mg/L recheck the level at 24 hourly intervals and only redose when the level is <1mg/L. Adjust the prescription to the time taken to reach <1mg/L i.e. 48, 72, 96 hourly.
If the patient is already in renal failure (CrCl <40ml/min) or their renal function is changing rapidly then check the level at 24 hours and wait for the result before redosing if the level is <1mg/L (see Gentamicin dose based on CrCl table above). If the level is >1mg/L recheck the level at 24 hourly intervals and only redose when the level is <1mg/L.
Although most doctors remember to monitor renal function during Gentamicin treatment in order to spot any renal failure that might be developing, in my experience, they tend to forget that as a patient’s renal function improves more Gentamicin may actually be needed to remain therapeutic. REMEMBER: changes in renal function, either up or down, require re-evaluation of antibiotic doses.
Summary
Gentamicin should be used to treat Gram-negative infections and sepsis, especially in patients allergic to beta-lactams. Leaving it out of these regimens is a mistake as it leaves no Gram-negative cover. Whilst reversible impairment of renal function occurs in about 10% of patients given Gentamicin, irreversible damage is rare. The risk of renal failure can be reduced by:
REMEMBER: don’t let a patient come to harm because you are worried about a side-effect that hasn’t yet happened; more patients die from sepsis than renal failure caused by Gentamicin.
Patients with reduced intravascular volume should be carefully fluid resuscitated and consideration given to correcting low serum potassium and magnesium levels.
3. Limit treatment to less than 7 days, if possible
Renal failure is more common with prolonged courses of Gentamicin so try to limit the duration of treatment. In practice this shouldn’t be too difficult as very few infections require longer than this. The more difficult situation to judge is when patients receive multiple courses of antibiotics in a short period of time. In this case try to avoid giving further Gentamicin to patients who have received a course within the preceding 2-3 weeks. If in doubt this would be the ideal patient to discuss with a Microbiologist or Antibiotic Pharmacist.
4. Avoid co-administration of other nephrotoxic drugs
Where possible try to avoid other nephrotoxic drugs but don’t let that mean that you fail to treat the patient for their infection. If other nephrotoxic drugs cannot be stopped and have to be given with Gentamicin make sure you monitor renal function and serum Gentamicin concentrations carefully.
5. Monitor serum Gentamicin concentrations and renal function during treatment
In patients with stable normal renal function the serum Gentamicin level should be measured before the 3rd or 4th dose and then the dose given (without waiting for the level to come back). In this case any dose adjustments can be made prior to the next dose.
If the trough level is high then recheck the level at 24 hours and withhold the next dose. If this level is <1mg/L then redose the patient and adjust the timing of the dose on the prescription chart. If this level is >1mg/L recheck the level at 24 hourly intervals and only redose when the level is <1mg/L. Adjust the prescription to the time taken to reach <1mg/L i.e. 48, 72, 96 hourly.
If the patient is already in renal failure (CrCl <40ml/min) or their renal function is changing rapidly then check the level at 24 hours and wait for the result before redosing if the level is <1mg/L (see Gentamicin dose based on CrCl table above). If the level is >1mg/L recheck the level at 24 hourly intervals and only redose when the level is <1mg/L.
Although most doctors remember to monitor renal function during Gentamicin treatment in order to spot any renal failure that might be developing, in my experience, they tend to forget that as a patient’s renal function improves more Gentamicin may actually be needed to remain therapeutic. REMEMBER: changes in renal function, either up or down, require re-evaluation of antibiotic doses.
Summary
Gentamicin should be used to treat Gram-negative infections and sepsis, especially in patients allergic to beta-lactams. Leaving it out of these regimens is a mistake as it leaves no Gram-negative cover. Whilst reversible impairment of renal function occurs in about 10% of patients given Gentamicin, irreversible damage is rare. The risk of renal failure can be reduced by:
- Using the correct dose for the individual patient
- Correcting fluid and electrolyte disturbances
- Limiting treatment to less than 7 days, if possible
- Avoiding co-administration of other nephrotoxic drugs, if possible
- Monitoring serum Gentamicin concentrations and renal function during treatment
REMEMBER: don’t let a patient come to harm because you are worried about a side-effect that hasn’t yet happened; more patients die from sepsis than renal failure caused by Gentamicin.
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