Notes on Oral Antibiotics

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Biaxin (clarithromycin)
Our little guy has been on Biaxin a couple of times. It’s a fairly new drug and the liquid version is pretty messy. However, it seems to work well (better than the Septra he had been given first) and doesn’t produce any noticeable side effects.

I recently used Biaxin for the first time and had good results. My Doctor prescribed it against Staph Aureus. I don’t know if it is effective against Pseudomonas (I’m not saying it’s not, just that I don’t know).

(My child) has taken Biaxin (clarithromycin) 500 mg. bid,, and (my other child’s) doctor prescribed it for her for tonsillitis last fall (she’s allergic to penicillin). The literature that I have on Biaxin says: Do not miss dosages but if you do – Don’t double the drug – just resume schedule. If moderate to severe diarrhea occurs during or after treatment, contact your doctor. DO NOT TAKE SELDANE or HISMANAL while taking Biaxin. Possible side effects that may go away during treatment – diarrhea, nausea, vomiting, bad taste in mouth, indigestion, abdominal pain or discomfort, or headache. I don’t recall either of my kids having any side effects.

I am currently taking Biaxin (500mg. BID) for 2 weeks for a sinusitis. It really started to kick in after 72 hours…….I do not have CF (my son does), but I have a lifelong history of cough-variant asthma/chronic sinusitis. My experience has been excellent with this med.

Biaxin and its cousins (Zithromax is one) do NOT directly kill Pseudomonas; these enzymes are the things that chew up lung tissue and that PWCF have, so it can be beneficial in more than one way.

I took Biaxin several years ago and it worked great the first time. I think I was on it for about 3 weeks. Unfortunately, like most antibiotics, it lost its silver bullet effect after I took it several more times. I did take Biaxin over a year after I had been off it, but it didn’t seem to have anything close to the great affects like the first time.

According to the PDR, Biaxin (clarithromycin) is active against:

  • Staphylococcus aureus (common CF bug)
  • Streptococcus pneumoniae
  • Streptococcus pyogenes (good old ‘strep throat’)
  • Haemophilus influenzae (common CF bug)
  • Moraxella catarrhalis (seen in otitis media, sinusitis, bronchitis)
  • Mycobacterium avium (in AIDS/immunocompromised people)
  • Mycobacterium intracellulare (in AIDS/immunocompromised people)

It has possible (i.e., not yet tested thoroughly in clinical studies) activity against:

  • Listeria monocytogenes
  • Streptococcus agalactiae
  • Strep groups C, F, G
  • Bordetella pertussis
  • Campylobacter jejuni
  • Legionella pneumophila
  • Neisseria gonorrhoeae
  • Pasteurella multocida
  • Chlamydia trachomatis
  • Clostridium perfringens
  • Peptococcus niger
  • Propionibacterium acnes, and
  • Bacteriodes melaninogenicus.

So it is a good drug which might become great, when more is known. The same goes for azithromycin, a similar drug. Both of these are Biaxin nor Zithromax cause the amount of GI upset that straight erythromycin does. Biaxin is given twice daily, and Zithromax once daily (very nice for those of us who can barely remember to brush our teeth twice daily, let alone take a pill!).

Cipro (ciprofloxacin)
I had been on Cipro for nearly three years before I had home i.v. treatment a month and a half ago. (My doc) told me if I started coughing up any yellowish-green mucus or blood again to take Cipro for 10-14 days. Needless to say it didn’t do the trick. My pseudomonas seems to be resistant to it. His sputum cultures shows I’m not completely resistant but it doesn’t get rid of the bacteria–just slows down the process I guess.

My experience with Cipro has been very similar to yours. Over the years my cultures have indicated a sensitivity to it, but when I have taken it, it doesn’t seem to do any good.

Cipro–often the very first time it’s used, it’s a miracle drug; every time afterward, the effect is less and less, and eventually it doesn’t help and every bug is resistant to it. What really scares me about Cipro is an article I found recently on the Net (look for PharmInfoNet, or Medical Sciences Bulletin), and I quote: “Results of this study show that ciprofloxacin could promote low-level bacterial resistance to antibiotics that are structurally unrelated to ciprofloxacin or each other and that have different modes of action. This finding emphasizes the need for appropriate use of ciprofloxacin.” (Fung-Tomc J et al., Antimicrob Agents Chemother., 1993; 37:1289-1296).

These researchers tested Pseudomonas and MRSA (a resistant staphylococcus) cells exposed to different concentrations of Cipro, then tested sensitivities of the exposed cells to different antibiotics: amikacin, cefepime, tetracycline, imipenem, fusidic acid, gentamicin. More exposure to Cipro increased the resistance of the bugs to the other “not-related-in-structure-or-mode-of-action drugs. For me, this explains why my patients who have never been on any IV drugs are suddenly resistant to all kinds of drugs that they’ve never been exposed to, and I’m more leery about the general use of Cipro for virtually anything that ails you.

Now: “THE DISCLAIMER One study does not a truth make. DON’T stop taking your Cipro, everybody! But you might want to ask your doc if he/she has seen this information (the journal indicated is read mostly by infectious disease/medical microbiology types, not practicing pulmonologists), and should you REALLY be on Cipro for two weeks every month? Just ask.

Colistin (11/97)
(brand name), Colymicin (generic), or “Coly” (slang)

How Is Colistin Used? (11/97)
It is an older antibiotic that fell out of favor as an IV antibiotic when newer, safer antibiotics came down the road. As an inhaled antibiotic it is very safe and doesn’t normally lead to resistant bacteria (a common dose is 75-150mg/day). It is rarely used by IV because it has serious side effects when used this way. Also daily blood draws are needed to monitor levels. It is often used, in CF, to restore sensitivity to other antibiotics. A drawback to inhaled colistin is that it is prepared with chemical preservatives (for when it is used via IV) and this causes some lung irritation and the nasty foaming people have discussed. PathoGenesis is in the process of producing and offering for phase one trial a non-foaming, specific for inhalation, form of colymicin (colistin). When some use inhaled colistin, they mix the antibiotic with albuterol to help offset any bronchospasm or irritation.

At the October, 1997 CF conference in Nashville, it was mentioned that inhaled colistin is currently being used in Denmark with very good results. However, it’s been stressed by my doctor and others that it works best by initially doing a 2-week IV course of Tobra with cipro and/or ceftazadime followed by inhaled colistin or Tobra one month on/one month off. The point being that one wants to have the lungs as clear as possible before maintaining that clearance with inhalation therapy. I know with the TOBI studies they are utilizing 300 mg Tobra, twice daily for one month and then off one month. In Denmark they use colistin for maintenance and some doctors here in the states use colistin as IV therapy. In the Denmark study the one month on/off cycle is used with those who have not yet cultured P.A. Once cf adults culture pseudomonas a. then daily inhalation use of colisitin was used following IV therapy. Colistin was used on a daily basis for maintenance with no interruption and, apparently, there have been no cases of resistance as yet! The study is still in progress.

One Experience (11/97)
We began the transplant evaluation process 2 years ago at Shands Hospital at the University of Florida in Gainesville. At the time, the PWCF was told he was a good candidate but not quite ready for the transplant and they have continued to see him about every six months. About 3 months ago, he was told it was time to go on the list since his FEV1 was consistently at 20 and he was constantly on IVS. The only problem was his antibiotic sensitivities, or lack of them. The PWCF was culturing 4 strains of PA and the only class of drugs he was sensitive to was aminoglycosides. Shands told him he had to be sensitive to at least 2 classes before he could be listed. They suggested he discontinue all antibiotics and use Colistin for inhalation as it seems to work fairly well on the bugs but also lets some sensitivities return.

We went to the hospital here and did his first inhalation with his doctor present since the PWCF had had an allergic reaction many years ago when given this drug IV. He nearly died a few years ago from an anaphylactic reaction to Piperacillin – he was at home and fortunately so was I and neither one of us cared to go through that again.

Everything went OK. After 1 month, the PWCF was down to 3 strains and some sensitivities looked like they were trying to come back. After 3 months, he only cultured 1 strain and it showed sensitivities to 3 drug classes. Apparently the Colistin worked and Shands is listing him pending insurance approval. Fortunately Shands is in plan and has worked with my insurance company before on other transplants.

Now the PWCF begins the wait. He will have to go to pulmonary rehab 3 times a week until the transplant which may be up to a year. He also has to decrease the prednisone and take Fosamax to strengthen his bones. The hemoptysis will probably increase and he is already having to use oxygen more often. The good news is we can stay right here in Jacksonville until he gets the call since Gainesville is only 1 « hours away. As a bonus, I attended the University of Florida and we are avid Gator fans.

Anyway, for those of you considering Colistin, try it – it may not work for everyone, but it worked for the PWCF.

Frequency of Treatment (11/97)
To answer the question about frequency of colistin courses, my regimen has been, for the past 3 years, doing colistin for the first 15 days of each month regardless of exacerbation. Let me qualify this by saying that it is rare for me to go more then 15 days off of colistin without having an exacerbation of some sort. and usually every 3-4 months I find that it does not work, and have to go in to the club for a course of IVS. I reconstitute my coly with 2-3 ccs of normal saline, and aerosolize it in an ultrasonic nebulizer…DEVILbiss Aerosonic model 5000… with very negligible foaming if any.

To Stop Colistin Foaming (11/97)

Method 1a – Sterile Water Handled Carefully

I have had success with Colistin this way: Inject 3cc of sterile water into a 150mg vial of Colistin slowly! and tilt it on its side when doing so. Hold the Colistin vial and swirl it gently, do not shake, until contents are dissolved. Draw up the prescribed amount (if 150 mg, use the entire vial, if 75 mg. use 1.5 cc and refrigerate the remainder).

Slowly empty the colistin in syringe into the nebulizer which is tilted on its side (allow the medicine to run down the side of the nebulizer cup slowly). Add the saline, 1 or 2 cc depending on what the MD suggested and how long you want your treatment to last.

They probably do this as an entrance to Bomb Squad School.

Method 1b – Sterile Water Handled Carefully Plus Peri Jet Neb

hi, I use coly too and I found the trick to prevent foaming!!! The trick is to mix the sterile water with the coly really slowly. What I do is this: While I breathe my first aerosol, I draw out a syringe of 2ccs of sterile water. then I stick the syringe in the bottle of coly and leave it there. the vacuum in the coly slowly pulls the sterile water into it, very slowly, like an iv drip. after about 1 min or more, the syringe empties (sometimes I have to push the rest in) and I let it sit for 10 min or so to dissolve. then, without shaking it, (just roll it, if its still not dissolved) draw out the coly. there may be some residual foam but most of it shouldn’t be. Now , to prevent foaming as you put it into the nebulizer, inject slowly !!! Sound anal? Well, it is, but it works best for me. … I use peri jet nebulizers and they seem to be more effective in misting than the disposable kind. but I need to rinse my nebs after or else the coly clogs it up. kind of sucks since they’re expensive.

Method 2 – Ethyl Alcohol and Pari-Neb

I have been using colistin for two years and have had no problems with it foaming up. I do 75mg. twice a day. I do however mix it differently:

I use 2 ml of 50% ethyl alcohol to reconstitute the coly-mycin. I then draw out 1 ml saving the other 1 ml for my next dose. I put the 1 ml. into my nebulizer and then add 4 drops of polysorbate 80 (tween 80) and add 1-2 ml saline. I also use a pari-neb nebulizer because it make smaller particles which helps get the colistin deeper into the lungs.

I have never had any foaming. but when I rinse it out with water after my treatment I see a lot of foaming which causes me to think that the colistin must react with water.

You might ask your doctor about this as I can guarantee it won’t foam. And if I only use 1 ml of colistin + 4 drops of tween 80 + 1 ml saline it only takes me about 15-20 minutes to do it (which isn’t that bad when your watching the news or checkin’ your e-mail).

Method 3 – Sterile water and Ultrasonic Neb

I’ve been using colistin for 8 months, with variably good results. I developed an intolerance to Tobra and switched to inhaled colistin. I use it in an ultrasonic nebulizer and don’t have a problem with it foaming. I reconstitute it with sterile water (from my pharmacy).

Method 4 – Chill Before Reconstituting

Chilling the ingredients before reconstituting them seems to help stop foaming.

Comment – Method 1

At the home infusion office I work at, we have several patients on coly inhalation. Our pharmacy mixes it with Everclear which is pure alcohol (yes, the Dr. orders it this way). Our pharmacy tech actually goes to the liquor store and buys it for mixing. I guess it doesn’t get the kids drunk, but keeps all the foaming down.

Comment – Method 2

The official word from the UK distributor is that for nebulization, the colistin should be dissolved in physiological saline if there are problems with frothing. The usual volume for dissolution is 2-4 ml for 1-2 MU, i.e., 80-160 mg. The larger the volume, the less chance of frothing. We do not recommend using ethanol as a solvent, and it does not seem a good idea to inhale nebulized ethanol, as it would probably be absorbed through the lungs.

Comment – Method 3

What are you administering the colistin with????? When I used my Pulmo aid I had more foaming problems then you could imagine. It could go for an hour and still not use all the medication. I went out and bought an Ultrasonic Nebulizer. There are many types available. The ultrasonics don’t cause the foaming, but can’t be used for pulmozyme because it breaks it up too much to be effective. There is one last thing, When you reconstitute it you should be using sterile water NOT saline. Saline makes everything worse.

Sidestream Neb

We have not had foaming problems. If you try it, I suggest you get a Sidestream nebulizer as I think this is the main factor in our case in preventing foaming. Also chilling the colistin before nebulizing helps. The PWCF uses albuterol mixed in with the colistin as she has sometimes felt some chest tightness when inhaling it. This hasn’t been a significant problem however, and in her case, she has an overall benefit from using it.

My Experience

I also use Colistin inhales. I rotate them with Tobra. I use a dose of 150mg BID for the Colistin, I squirt about 2 cc of saline into the vial, and then shake it up until all the powder and the foam dissolves. It is easiest to take if it is further diluted with about 2 more cc of saline when you are ready to nebulize it. I find that it is effective and I like it better than Tobra, as I find that Tobra causes hemoptysis.

Price (11/97)
Around here, a dose of 75 mg twice daily (or 1 150 mg powder vial per day) costs around $850 per month, $29/vial. Note that for purposes of restoring sensitive organisms, U Pittsburgh showed good success at a dose of 30 mg twice daily, less than half the cost. Reconstituted drug can be refrigerated for up to 48 hours, so you can use the whole vial or 5 treatments per vial at that low dose (doing the math gets 12 vials per month, around $350).

Needle Size and Technique (11/97)
Also, I’m wondering if you have too small a needle. The ones I’ve found most satisfactory are 18 gauge. I’ve had trouble getting 22’s or 25’s through the rubber, and the withdrawal is more difficult.

Another thing that might help (if you are unused to dealing with syringes like this) is to, before withdrawing the liquid from a vial, withdraw the plunger of the empty syringe to about the level you wish to fill it (say 3cc) then access the stopper and inject the air into the vial, while keeping the plunger depressed, turn the vial upside down and keep the needle tip covered with the liquid. When you release the plunger it will fill by itself because of the pressure of the injected air to approximately the correct level..

I make up 5 vials at a time and keep them in the refrigerator as it seems easier to batch the process like this.

Also the nebulizer makes a difference. The one we particularly like for low-foaming is called the Sidestream.

Mode of Action (11/97)
Colistin in fact appears to mimic a group of natural antimicrobial substances called defensins. Defensins in CF recently came to prominence because of a recent suggestion concerning why P.aeruginosa is so prevalent in CF. It has been suggested that a small antimicrobial peptide (beta defensin) secreted from the lung epithelial cells is inactivated by the elevated salt levels in the fluids in the respiratory tract. Thus this defect in the natural immune surveillance allows P.aeruginosa to more readily colonize the lung. (I have to say that I do not altogether subscribe to this theory).

Beta defensin and other similar molecules appear to disrupt the integrity of the bacterial cell wall. Colistin has a similar mode of action but has the advantage that its activity is UNAFFECTED by elevated salt concentration. Exactly how it (and defensins) work is still a matter of debate. I recently saw an electron micrograph of P.aeruginosa after 5 minutes exposure to colistin. Its relative smooth outer coat had changed into what could best be described as the appearance of cobbled pavement.

One final point that perhaps should be mentioned. B.cepacia is naturally resistant to these antimicrobial peptides. Colistin is therefore of little value in controlling this infection.

Two Recent Studies (11/97)

  • USE OF AEROSOLIZED COLISTIN SODIUM IN CYSTIC FIBROSIS PATIENTS AWAITING LUNG TRANSPLANTATION by Bauldoff GS. Nunley DR. Manzetti JD. Dauber JH. Keenan RJ., Transplantation. 64(5):748-752, 1997 Sep 15.
  • Abstract
    Background. In patients with cystic fibrosis (CF) who are awaiting lung transplant, prolonged exposure to systemic antibiotics has frequently led to airway colonization with resistant isolates of Pseudomonas. This resistance limits the arsenal of effective antimicrobials available for infections after the initiation of immunosuppression and has been considered a theoretical deterrent to lung transplantation.

    Methods. Twenty CF transplant candidates with ”pan-resistant” Pseudomonas received maintenance antibiotic therapy with aerosolized colistin sodium (75 mg b.i.d.), and intravenous antibiotics were eliminated. Ten other CF candidates did not use colistin sodium. Sputum cultures and antibiotic sensitivities were followed every 3-6 weeks.

    Results. All 20 candidates (100%) who used aerosolized colistin sodium became colonized with sensitive isolates of Pseudomonas in an average of 45.1 +/- 20.2 days. In contrast, only 3 of 10 CF transplant candidates (30%) who did not use colistin sodium later became colonized with sensitive isolates. The mean time to spontaneous emergence of sensitive organisms was 144.6 +/- 48.0 days in candidates who did not use colistin sodium and was significantly longer than in the candidates who used colistin sodium (P=0.007). The occurrence of redeveloping sensitive isolates of Pseudomonas was significantly greater in the candidates who used colistin sodium(P