Zithromax

[Debbie1]

We were at the peds office today for a check up. My son is not on Zithromax (he is on prophylactic amox), but we once again had the Zithromax discussion. My ped just doesn't understand why it works. He says its an extracellular drug. Does anyone know of any research that may provide some explanation for him?

 

Thanks,

Debbie

[sf_mom]

Debbie: I have my own theory and I'm definitely not a Dr. but I believe it is a really difficult strain of strep to eradicate. If you look closely at the information regarding the coccoid strain it is encapsulated making it resistant to certain drugs. Based on conversations with Diana Polhman of PANDAS Network and her visit with Madeleine Cunningham penicillin will just roll right of certain strains of strep in a petri dish. I think azithromycin has the ability to penetrate the encapsulation.

 

Taken from Wikipedia

 

Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, bile soluble diplococcus aerotolerant anaerobe and a member of the genus Streptococcus.[1] A significant human pathogenic bacterium, S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century and is the subject of many humoral immunity studies.

Despite the name, the organism causes many types of pneumococcal infection other than pneumonia, including acute sinusitis, otitis media, meningitis, bacteremia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess.

 

S. pneumoniae is the most common cause of bacterial meningitis in adults and children, and is one of the top two isolates found in ear infection, otitis media.[2] Pneumococcal pneumonia is more common in the very young and the very old.

 

S. pneumoniae can be differentiated from other members of Viridans Streptococci, some of which are also alpha hemolytic, using an optochin test, as S. pneumoniae is optochin sensitive. S. pneumoniae can also be distinguished based on its sensitivity to lysis by bile. The encapsulated, gram-positive coccoid bacteria have a distinctive morphology on gram stain, the so-called, "lancet shape." It has a polysaccharide capsule that acts as a virulence factor for the organism; more than 90 different serotypes are known, and these types differ in virulence, prevalence, and extent of drug resistance.

 

Clinical significance of Coccoid Bacteria

 

Important human pathogens caused by coccoid bacteria include staphylococci infections, some types of food poisoning, some urinary tract infections, toxic shock syndrome, gonorrhea, as well as some forms of meningitis, throat infections, pneumonias, and sinusitis.[4]

[EAMom]

Here is Dr. Ed Kaplan's paper on intracellular strep. Of the antibiotics studied in the paper, Azith. was most effective at erradicting intracellular strep. http://www.journals.uchicago.edu/doi/pdf/1...773?cookieSet=1

 

Here is another article (I post this one a lot) on Amoxcillin failure in strep throat. It discusses intracellular strep and coaggregation...2 reasons why amoxcillin might not work to erradicate strep in the human body (which is different from a test tube!) http://www.entrepreneur.com/tradejournals/.../169459644.html

[Debbie1]

Thanks SF Mom and EA Mom. (EA Mom - I was not able to launch the articles you attached, but I will keep trying)

[sf_mom]

The article EAMom provided is much more helpful than my theory. 'Amoxicillin failure in strep throat.'

 

A pair of newly detected actions of Group A streptococci may offer clues as to why penicillin and amoxicillin of ten fail to eradicate streptococcal pharyngitis in children and adults, and why cephalosporins or macrolides may be better treatment options.

 

Penicillin failure in eradicating strep throat has been increasingly documented beginning in the 1980s, rising from just 5% in the 1950s to approximately 35% today. My colleague Dr. Janet R. Casey and I have published a series of articles over the years documenting this phenomenon, as have other researchers worldwide. In 2004, Dr. Casey and I conducted two separate meta-analyses demonstrating the clear superiority of cephalosporins--mainly azithromycin and clarithromycin--over penicillin in treating strep throat, both in children (Pediatrics 2004;113:866-82) and adults (Clin. Infect. Dis. 2004;38:1526-34).

 

Traditional antibiotic resistance does not appear to be the reason. In fact, there is absolutely no in vitro resistance of group A streptococci (GAS) to penicillin or amoxicillin (or cephalosporins).

 

Some people have theorized that the inadvertent inclusion of strep carriers in many of the studies explains the eradication failure with penicillin, but that has never made sense to me. Why would such inclusion have increased since the 1950s? In fact, the opposite has happened: Efforts have been made in more recent studies to exclude carriers. Our meta-analyses showed that the failure rate remained pretty much rocksolid at 35%, even when we looked at only the 12 most recent studies that did a fantastic job of excluding carriers.

 

I think the answer lies in considering mechanisms of "resistance" beyond those involving a particular bacterium resisting a particular drug in a test tube. There are two newly appreciated phenomena that I categorize as "in vivo resistance" because they result from a fundamental interaction with the host and can't be measured by a lab test.

 

About 5 years ago, several researchers published studies showing that streptococci were capable of entering and living inside the epithelial cells of the upper respiratory tract, a process dubbed "internalization." Prior to that time, GAS was thought to be a strictly extracellular pathogen.

 

Then, just last year, Dr. Edward L. Kaplan of the University of Minnesota and his associates showed for the first time that internalization was a likely explanation for the treatment failure of penicillin and amoxicillin, which are incapable of penetrating the cell wall. In contrast, erythromycin and azithromycin, which enter cells easily, were the most effective at GAS eradication while the first-generation cephalosporin cephalothin and clindamycin had intermediate efficacy (Clin. Infect. Dis. 2006;43:1398-406).

 

A second mechanism of in vivo resistance, known as "coaggregation," was first described in 2004 by Dr. Eric R. LaFontaine and his associates at the University of Toledo (Ohio). They found that the pathogens Streptococcus pyogenes and Moraxella catarrhalis colonize overlapping regions of the human nasopharynx, and that M. catarrhalis can dramatically increase the adherence of S. pyogenes to human epithelial cells (Infect. Immun. 2004;72:6689-93).

 

Subsequent to that paper, my laboratory group completed a study in which we confirmed Dr. LaFontaine's finding regarding coaggregation of S. pyogenes with M. catarrhalis, and also for the first time demonstrated the same phenomenon with S. pyogenes and Haemophilus influenzae.

 

With coaggregation, the GAS bacteria acquire the ability to attach themselves to the M. catarrhalis or H. influenzae that already colonize the throat at various times during childhood and adulthood (H. influenzae is about 5-6 times more common than M. catarrhalis). While these two organisms have long been known to become pathogenic in certain settings, we are now realizing that they also may serve to enhance the attachment of GAS to throat cells.

 

Indeed, coaggregation is a likely explanation for why some children--such as those more frequently colonized with M. catarrhalis or H. influenzae--are more vulnerable to strep throat than others. Moreover, it also explains our finding that an individual who is colonized with one of those two organisms and then is exposed to streptococcus has a 10-fold increased likelihood of developing strep throat.

 

It also helps explain the differential treatment effect of penicillin/amoxicillin versus other antibiotic classes. Both M. catarrhalis and H. influenzae produce beta-lactamase, which inactivates penicillin and amoxicillin. Cephalosporins, on the other hand, have greater activity in the presence of beta-lactamase, while macrolides such as azithromycin are completely immune to the enzyme.

 

Thus, it appears that beta-lactamase production, a well-described mechanism for in vitro antimicrobial resistance, is being enhanced by this additional coaggregation mechanism.

 

Based on this new information, my practice now uses cephalosporins as first-line treatment for strep throat. Cephalexin is a good option because it's generic, and it's first-generation, so it is not as broad-spectrum. We prescribe it twice daily for 10 days.

 

Second choice would be either a second-or third-generation cephalosporin or azithromycin, depending upon the degree of macrolide resistance in your community. Here in Rochester, where macrolide resistance is about 8%, we normally go with cefprozil, cefdinir, or cefpodoxime. All three are generic, although they're still not cheap--there's currently only one distributor. Cefprozil is the least expensive of the three, and there also is evidence that it eradicates the strep carrier state as well as the active infection (Clin.Ther. 2001;23:1889-900).

 

The Infectious Diseases Society of America is planning to issue new guidelines for the treatment of streptococcal pharyngitis sometime in 2008. Dr. Kaplan is the chairman of the writing committee, and Dr. Casey is a member. The American Academy of Pediatrics" 2006 Red Book still recommends amoxicillin as first-line therapy, but I'm guessing that will not be the case in the next edition, due out in 2009. I have no financial conflicts that are relevant to this article.

 

DR. PICHICHERO, a specialist in pediatric infectious diseases, practices in Rochester, N.Y. He is also professor of microbiology, immunology, pediatrics, and medicine at the University of Rochester. Write to Dr. Pichichero at our editorial offices (pdnews@elsevier.com).

[sf_mom]

Part of the other article.

 

Reduced Ability of Penicillin to Eradicate

Ingested Group A Streptococci from Epithelial Cells:

Clinical and Pathogenetic Implications

Edward L. Kaplan,1,a Gursharan S. Chhatwal,2 and Manfred Rohde2

1

Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota; and 2Department of Microbial Pathogenesis;

Helmholtz Centre for Infection Research, Braunschweig, Germany

Background. Group A streptococci (Streptococcus pyogenes; GAS) invades human epithelial cell lines. Failure

of penicillin to eradicate GAS from the throats of patients, especially those who are GAS “carriers,” has been

increasingly reported. However, there has been no comprehensive evaluation of how effectively antibiotics that are

used to treat GAS enter upper respiratory tract epithelial cells and kill internalized GAS. We examined the viability

of ingested, intracellular GAS after epithelial cell exposure to antibiotics commonly recommended for therapy of

GAS infections.

Methods. A human laryngeal epithelial cell line (HEp-2) was used. Three techniques were used to study

antibiotic (penicillin V, erythromycin, azithromycin, cephalothin, and clindamycin) killing of ingested GAS: ex-

amination by electron microscopy of ultrathin sections of ingested GAS, qualitative determination of intra–epithelial

cell antibiotic, and special stain evaluation of intracellular GAS viability after epithelial cell exposure to antibiotics.

Results. GAS survived intracellularly despite exposure of the GAS-containing epithelial cells to penicillin. In

contrast, there was killing of ingested GAS after exposure of epithelial cells to either erythromycin or azithromycin.

Electron microscopy confirmed a lack of intracellular GAS fragmentation (cell death) after exposure of epithelial

cells to penicillin in contrast to obvious GAS fragmentation after epithelial cell exposure to erythromycin or

azithromycin. Cephalothin, a cephalosporin, and clindamycin were more effective in killing ingested GAS than

was penicillin, but they were less effective than erythromycin or azithromycin.

Conclusions. These observations strongly suggest that if the GAS upper respiratory tract carrier state results

from intra–epithelial cell GAS survival, the failure of penicillin to kill ingested GAS may be related to a lack of

effective penicillin entry into epithelial cells. These unique observations may have clinical implications for un-

derstanding GAS respiratory tract carriers and managing GAS infections.

[Debbie1]

Thanks SF Mom. I am going to give this to my doctor.

[colleenrn]

Yes, Zithromax is the best at reaching intracellular strep, but it also has properties that are beneficial to children with PANDAS, that most antibiotics do not have.

 

Zithromax is an immune modulator, so it helps to modulate the immune system.

 

Zithromax has anti-inflammatory properties which helps children with PANDAS b/c their basal ganglia is inflamed.

 

Colleen

[EAMom]

Yes, our immulologist (Stanford) agrees with this theory about Azith. being anti-inflammatory/immune-modulating and that is one reason it is so helpful for us.

[Megs_Mom]

Yes, Zithromax is the best at reaching intracellular strep, but it also has properties that are beneficial to children with PANDAS, that most antibiotics do not have.

 

Zithromax is an immune modulator, so it helps to modulate the immune system.

 

Zithromax has anti-inflammatory properties which helps children with PANDAS b/c their basal ganglia is inflamed.

 

Colleen

 

Ok - I totally get the intracellular part - this is very helpful - thank you, everyone! Does anyone have studies on Zithromax as Immune modulating & anti-inflammatory? I have also heard this, including from our Neurologist. However, we are losing our Neurologist, and all our other docs want her to "come off" to see what happens. She is on extremely low does, and I have a script for another 4 months, so I have plenty of time - but I'd love to be sure I am ready to have this argument if necessary.

[colleenrn]

Here are some abstracts talking about Zithromax being anti-inflammatory and immune modulating. They are mostly used with cystic fibrosis.

 

 

http://linkinghub.elsevier.com/retrieve/pi...548276604000275

 

http://erj.ersjournals.com/cgi/content/abstract/24/5/834

 

http://ajrccm.atsjournals.org/cgi/content/short/170/12/1331

 

http://www.sciencedirect.com/science?_ob=A...e0d863a9412d79e

 

Colleen

[EAMom]

Here's one: http://jpet.aspetjournals.org/cgi/reprint/292/1/156.pdf

 

There's also a lot if you google Azithromycin, anti-inflammatory, and cystic fibrosis http://www.ncbi.nlm.nih.gov/pubmed/12383667

 

However, we are losing our Neurologist, and all our other docs want her to "come off" to see what happens.

 

Grrrrrrrrrrr. Tell them you are not interested in running that experiment on your daughter...and if she decompensates b/c they refuse to keep her on antibiotics (as your previous neurologist had recommended) you will hold them responsible. Perhaps it might also help if you look at them as if they are completely insane for even suggesting she go off antibiotics. And ask them, what makes you think she would react any differently once she gets another strep infection? You should also insist they take the time to consult with Dr. Latimer (also a neurologist, who actually know PANDAS) if they are confused about treatment, instead of putting your dd at risk.

[Megs_Mom]

Here are some abstracts talking about Zithromax being anti-inflammatory and immune modulating. They are mostly used with cystic fibrosis.

 

 

http://linkinghub.elsevier.com/retrieve/pi...548276604000275

 

http://erj.ersjournals.com/cgi/content/abstract/24/5/834

 

http://ajrccm.atsjournals.org/cgi/content/short/170/12/1331

 

http://www.sciencedirect.com/science?_ob=A...e0d863a9412d79e

 

Colleen

 

Thanks - this makes sense to me, and matches what we saw when we started giving her very low does of Zith - it was like her mind calmed. I imagined that either the antibodies that were pelting her brain were being smacked down, or that her brain was litterally closing a hole so nothing could get in. It was not a cure, but it was a clear difference that then allowed her to control her mind without such high levels of anxiety. Before the Zith, it almost looked like she would get punched internally, and her entire body would change in front of our eyes. I think we may be on too low of a dose for true preventative care. We'll see, our last meeting with the Neuro is next week, before he moves.

 

So is the hypothesis that if she ever came off, that the inflamation would come right back? Or after some period of time, do they think the brain heals once it has been allowed not to be inflamed? Or is this completely hypothetical? I have no problem leaving her on it indefinitely. And I do have a some time to convince others to renew that prescription (or maybe fly to Nebraska twice a year ). I am putting together a short document that has Megan's history and what we are doing & why, with attachments to the key studies. I always felt like Azith was doing something to her that has nothing to do with anti-biotics or titers, but did not know how to explain myself. Thanks Colleen & EAMom.

[Megs_Mom]

Here's one: http://jpet.aspetjournals.org/cgi/reprint/292/1/156.pdf

 

There's also a lot if you google Azithromycin, anti-inflammatory, and cystic fibrosis http://www.ncbi.nlm.nih.gov/pubmed/12383667

 

However, we are losing our Neurologist, and all our other docs want her to "come off" to see what happens.

 

Grrrrrrrrrrr. Tell them you are not interested in running that experiment on your daughter...and if she decompensates b/c they refuse to keep her on antibiotics (as your previous neurologist had recommended) you will hold them responsible. Perhaps it might also help if you look at them as if they are completely insane for even suggesting she go off antibiotics. And ask them, what makes you think she would react any differently once she gets another strep infection? You should also insist they take the time to consult with Dr. Latimer (also a neurologist, who actually know PANDAS) if they are confused about treatment, instead of putting your dd at risk.

 

That is EXACTLY how I feel - how come you are willing to experiment to the negative with my child and not to the positive!!! If they were to live in her shoes (nevermind mine) for a week, they would get it. We did the phone consult with Latimer a month ago, and are hoping to receive the follow-up from her soon so that we can use this with other doctors.

 

In the meantime, I'll ask next week for an extension of the prescription, and at least that will give us a low dose option!

[colleenrn]

You are most welcome! I completely agree with EAMom about not being willing to take Meg off the Zith to "see what happens". Some doctors just don't get it.

 

That would be, IMO, the same as a doctor telling you to stop giving antibiotics to your child with rheumatic fever and let's "see" if they get strep again that attacks their heart.

 

Colleen