MDR-TB Treatment & Prevention

Taking my lead from the staff at the Southeastern National TB Center in Florida, I do administer the Aminoglycosides three times a week. The patients enjoy the break and I suspect that the break is good for the TB, allowing greater killing with the intermittent dosing. If possible, it would be good to get a peak and trough level of the drug to be sure that you attain a therapeutic and not toxic dose. Monitoring the vestibular apparatus and Creatinine should be done at least monthly if possible.

To my knowledge there is one study directly comparing the safety of thrice vs daily AG administration, that showed basically no difference in the rate of adverse events (PMID 15156439). Differences in efficacy were not assessed and are anyway very difficult to demonstrate given the intrinsic variability among MDR patients. The rationale of high-dose less-frequent administration of AG is the higher tissue concentration you can archive and the long PAE of AG. Moreover considering the relative slow doubling rate of MTB, thrice weekly adm may sound reasonable. Nevertheless, in the high-MDR setting in which I am working, we prefer to give AG daily for the entire intensive phase or for at least 6 months, in the absence of adverse events ascribable to AG and if renal function is normal. In my experience, if the dosage is correct and patient is properly monitored, the rate of adverse events is low. We have to consider that in some patients AG is the most potent drug in the regimen. To sum up, we always start with daily adm and before shifting to thrice weekly we take into account the DST of the single patient and its response to treatment at that time. Anyway ...

To my knowledge there is one study directly comparing the safety of thrice vs daily AG administration, that showed basically no difference in the rate of adverse events (PMID 15156439). Differences in efficacy were not assessed and are anyway very difficult to demonstrate given the intrinsic variability among MDR patients. The rationale of high-dose less-frequent administration of AG is the higher tissue concentration you can archive and the long PAE of AG. Moreover considering the relative slow doubling rate of MTB, thrice weekly adm may sound reasonable. Nevertheless, in the high-MDR setting in which I am working, we prefer to give AG daily for the entire intensive phase or for at least 6 months, in the absence of adverse events ascribable to AG and if renal function is normal. In my experience, if the dosage is correct and patient is properly monitored, the rate of adverse events is low. We have to consider that in some patients AG is the most potent drug in the regimen. To sum up, we always start with daily adm and before shifting to thrice weekly we take into account the DST of the single patient and its response to treatment at that time. Anyway thrice weekly adm throughout the treatment might be appropriate in different settings.

New Discussion:
Dear experts:
I need your  professional expertise on the following issues-

As we started out MDR-TB treatment in Afghanistan  only a few months back ,so we are facing some kind of  new challenges.We got one patient with its DST results performed at The Aga Khan University Hospital,karachi,Pakistan.DST results as below-
For first line drugs-

Rifampicin,Ethambutol,Isoniazid(lower concentration),Pyrazinamide and streptomycin(lower concentration) are resistant but higher concentration of isoniazid and streptomycin are sensitive.
For second line drugs-
Ofloxacin is resistant but kanamycin,amikacin,capromycin and ethionamide are sensitive.
So,may I ask you that should we start the treatment of this patient as MDR-TB under the standard MDR-TD treatment regimen or need any other special  measures?
Your kind input is highly appreciable.

Kind regards,


________________________________
Sarder Tanzir Hossain
B.Sc.(Hon's) and M.S. in Microbiology (DU)
Microbiologist, National TB Control Program,
Health Program, BRAC Afghanistan.
Website:http://www.brac.net,www.bracafg.org
 "Leader helps other people discover for themselves what they need to do"

In high HIV setting (I am talking about 5-20% of HIV prevalence in general
population), the situation is quite challenging. And most patients need at
least six months (if not more sometimes for getting delayed results of DST
in resource limited conditions). But I would like to go for eight months
daily treatment according to new WHO recommendations, which are mostly for
resource limited conditions. But I would agree with Mr./Ms. Fulvio
Salvo "Nevertheless,
in the high-MDR setting in which I am working, we prefer to give AG daily
for the entire intensive phase or for at least 6 months, in the absence of
adverse events ascribable to AG and if renal function is normal. In my
experience, if the dosage is correct and patient is properly monitored, the
rate of adverse events is low. We have to consider that in some patients AG
is the most potent drug in the regimen". Though monitoring properly (most of
the times is quite challenging) in developing world.

I think the reply of Hossain is a new question...
Ronald Karpick makes an interesting remark: "I suspect that the break is good for the TB, allowing greater killing with the intermittent dosing"
Why would you suspect greater killing with the intermittenent dose? Is that for the reason Fulvio Salvo gives: "The rationale of high-dose less-frequent administration of AG is the higher tissue concentration you can archive and the long PAE of AG"?

This query about aminoglycosides brings me back to my earlier question in July about therapeutic drug monitoring. I thank Yue Guan for the response on behalf of Charles Peloquin but I am still unclear about the science behind the increased target levels of amikacin (which seem to cause such trouble). For example if an amikacin MIC of 2 was identified what would a reasonable target plasma level be 1 hour post dose? and if the MIC were 4 would the target by extension be double? These are important, not facetious, questions as if we can prolong aminoglycoside therapy by minimising toxicity then treatment outcomes are likely to be improved. Are we sometimes using much higher doses than are necessary?

Against Gram negative and many other organisms, including TB
aminoglycosides display concentration-dependent activity. This can be shown
in vitro and in the mouse model. Maximizing the Cmax to MIC ratio and the
AUC to MIC ratio is the goal. So, in cases of higher MICs, one would need to
give a bigger dose to achieve the desired Cmax to MIC ratio of 10 to 12.
Smaller doses still may have activity, but less activiy.

For nontuberculous mycobacteria (NTM), MICs may be 4, 8, or 16. If options
are limited, and one elects to use an aminoglycoside, then doses of 25 mg
per kg would be needed to approach the desired Cmax to MIC ratio. Given
concerns about this dose daily, and given the historical use of this dose 3
times weekly, the intermittent approach is used. This is done in clinical
practice, but prospective randomized trial data for this approach with NTM
are lacking.

With TB, generally MICs for streptomycin and amikacin are 1 to 2 mcg per ml.
Thus, one does not have to use the 25 mg per kg dose to achieve the ratio.
The 15 mg per kg dose should achieve this. Another practical limitation is
that ...

Against Gram negative and many other organisms, including TB
aminoglycosides display concentration-dependent activity. This can be shown
in vitro and in the mouse model. Maximizing the Cmax to MIC ratio and the
AUC to MIC ratio is the goal. So, in cases of higher MICs, one would need to
give a bigger dose to achieve the desired Cmax to MIC ratio of 10 to 12.
Smaller doses still may have activity, but less activiy.

For nontuberculous mycobacteria (NTM), MICs may be 4, 8, or 16. If options
are limited, and one elects to use an aminoglycoside, then doses of 25 mg
per kg would be needed to approach the desired Cmax to MIC ratio. Given
concerns about this dose daily, and given the historical use of this dose 3
times weekly, the intermittent approach is used. This is done in clinical
practice, but prospective randomized trial data for this approach with NTM
are lacking.

With TB, generally MICs for streptomycin and amikacin are 1 to 2 mcg per ml.
Thus, one does not have to use the 25 mg per kg dose to achieve the ratio.
The 15 mg per kg dose should achieve this. Another practical limitation is
that intramuscular dose volumes of 1.5 ml, perhaps 2 ml, are about as much
as you can administer into a single site. In an older study by Hudson and
Sbarbaro, they gave 2 injections per dose ("1 in each cheek," according to
John S, referring to the buttocks) to administer 27 mg per kg twice weekly.

Aminoglycosides are cidal but not good sterilizing drugs. Toxicity has a
large random nature to it (probably genetic and prior organ damage are the
main components), such that "normal" concentrations still can produce
toxicity, and "high" concentrations can be well tolerated. This was shown in
our 2004 paper on aminoglycoside toxicity.

Chuck Peloquin