Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment

Circulation. 2001 Sep 25;104(13):E75.

Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment.

Gieffers J, Fullgraf H, Jahn J, Klinger M, Dalhoff K, Katus HA, Solbach W, Maass M.

Institute of Medical Microbiology and Hygiene, Medical University of Lubeck, Lubeck, Germany.

BACKGROUND: Recovery of the intracellulari bacterium Chlamydia pneumoniae from atherosclerotic plaques has initiated large studies on antimicrobial therapy in coronary artery disease. The basic concept that antibiotic therapy may eliminate and prevent vascular infection was evaluated in vitro and in vivo by examining the antibiotic susceptibility of C pneumoniae in circulating human monocytes, which are thought to transport chlamydiae from the respiratory tract to the vascular wall. METHODS AND RESULTS: Blood monocytes (CD14+) from 2 healthy volunteers were obtained before and after oral treatment with azithromycin or rifampin and then inoculated with a vascular C pneumoniae strain and continuously cultured in the presence of the respective antibiotic. Progress of infection and chlamydial viability was assessed by immunogold-labeling and detection of C pneumoniae-specific mRNA transcripts. Circulating monocytes from patients undergoing treatment with experimental azithromycin for coronary artery disease were examined for C pneumoniae infection by cell culture. Antibiotics did not inhibit chlamydial growth within monocytes. Electron microscopy showed development of chlamydial inclusion bodies. Reverse transcription-polymerase chain reaction demonstrated continuous synthesis of chlamydial mRNA for 10 days without lysis of the monocytes. The in vivo presence of viable pathogen not eliminated by azithromycin was shown by cultural recovery of C pneumoniae from the circulating monocytes of 2 patients with coronary artery disease. CONCLUSIONS: C pneumoniae uses monocytes as a transport system for systemic dissemination and enters a persistent state not covered by an otherwise effective antichlamydial treatment. Prevention of vascular infection by antichlamydial treatment may be problematic: circulating monocytes carrying a pathogen with reduced antimicrobial susceptibility might initiate reinfection or promote atherosclerosis by the release of proinflammatory mediators.

PMID: 11157684 [PubMed - indexed for MEDLINE]

What's it mean:
vocabulary: in vivo means in the body or organism as opposed to in a petri dish in the lab, in vitro means in the lab
What happened here is that people have noticed that CPn is present in atherosclerotic plaques yet studies seem not to find abxi helpful. The researchers wanted to know if persistence was at fault. What they found was that monocytes (a white blood cell which is part of your immune system) carried CPn inside where it stayed inside an inclusion body (a bubble if you will inside the cell where in it is protected) and that after 10 days of treatment the ey were still able to find CPn evidence with PCRi analysis and immunogold labeling. The conclusion is that CPn is able to resist abxi considered to be effective against CPn and that treatment of CPn with abx is going to be problematic due to this issue. This explains some of the problems with culturing CPn and treating it in illness. Unless you account for this and have a thoughtful antimicrobial plan, then this is the outcome: insufficient treatment, reinfection, and treatment failure. The Wheldon and VU protocols use multiple agents to beat the bacteria at every stage and lifeform. Once again we see how it can be that people in medicine struggle with the new concepts of a bacteria that has multiple innovative ways of resisting treatment. These people are still discussing how it can be that 10 days of a single antibiotic is not effective and demonstrating how it can be that CPN is still culturable at that point. This kind of academic argument is useful to establish the facts about things, but do know that he VU and Wheldon protocls already accounts for this by using several agents and using flagyl to kill the bacteria outright. This is more support for the approach we are using
Marie

Comments

Living in the Phagosome-
I agree with you, Marie. It is unwise to treat chronic intracellulari infections with a single static agent; that's a recipe for the emergence of resistance. The good thing about using doxycycline plus either roxithromycin or azithromycin is that these agents act on close steps in the bacterial protein-synthesis pathway. This combination can be thought of a kind of biological 'lock-nut'.
A parallel example of a chronic and often intracellular infection which needs long-term combined treatment is tuberculosis. So real is the risk of resistance by poor compliance that in rescidivists the antibiotics are checked to destination.
There are big parallels between cpn and TB. Both go dormant inside macrophages in the presence of IFN-gamma. And there is evidence that both resort to an anaerobic state and become sensitive to metronidazolei. See this excellent paper for a study of how M tuberculosis copes with the unpleasantness of living in dungeon of the phagosome: [Schnappinger D, Ehrt S, Voskuil MI et al. (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198:693-704]
One of the few trials of (very briefly administered) antibiotics in coronary heart disease was based in London: [Stone AF et al., Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibioticsi in Myocardial Infarction and Unstable Angina. Circulation 2002 Sep 3;106(10):1219-23] these authors found that antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes. Interestingly, this trial used a combination of antibiotics, including metronidazole. Tantalizing.
David W
D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazolei. No medication now. Morning BP typically 110/75]

Marie- this one should definitely be linked to the Physicians page. It helps them to appreciate the scope of the persistencei problem. 

On Wheldon/Stratton protocol for Cpni in CFSi/FMSi since December 2004.

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Ten days!? Okay, they proved ten days is not enough treatment.  Doesn't it occur to anyone to extend the study to thirty, ninety and one hundred-eighty days?  Goodness, even my science fair experiments in grade school emphasized thinking a BIT outside the box and showing the effectiveness of developments over time! 

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

More than ten days?  No.  That is an eternity to most physicians.  One hundred and eighty days?  No way!!  Of course, I'm not really here:  I'm just a ghost, having been poisoned by these "nasty antibioticsi."  Ho, hum!..........Sarah
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

Yes, cool huh? Here is a link to the full text Dr Wheldon mentions above...HERE< This article talks about mycobacterium TB and how it survives inside the cell. It's technical and long for the science crowd. I'll link it to the physicians page also...
Marie

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

Sarah, not only you are just a ghost. Our family consists of three ghosts.

Jan, Prague, The Czech Republic

Date Started CAPi's:
12/01/2005

On CAPs:12/01/2005 till March 2013; 20 years CFSi,IBSi, fibromyalgiai; about 10 years chronic sinusitis, laryngotracheitis, from 2002 hoarseness; from 2003 - v.s. lumbosacral meningoradiculitis, hypertension">i... 

 Ah yes, ghosts have pre-existing non-conditions, as Ron has pointed out. You certainly fit that now sarah!

David- This is another case of the links being obvious to a microbiologist, but not to physicians in general, who actually know a lot about very little or is it vice versa?

Combined Antibiotic Protocol for Chlamydia pneumonia in Chronic Fatigue Syndromei &amp; Fibromyalgiai- Currently: 150mg INHi, Doxycycline/Zithromycin, Tinidazole pulses. Northern Ohio, USA

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

 As a doctor with a sense of humor said:  As the specialties become more and more so, you learn more and more about less and less until after while you know everything there is about nothing al all.

Rica        EDSSi 6.7 at beginning - now 2
Ignorance is voluntary bad luck.  Lauritz S.   A true Viking
If you come to a fork in the road, take it. Yogi Berra

3/9 Symptoms returning. Began 5 abxi protocol 5/9 Rifampin 600, Amox 1000, Doxyi 200, MWF Azith 250, flagyli 1000 daily. Began Sept 04 PPMSi EDSSi 6.7 Now good days EDSS 1 Mind, like parachute, work only when open. Charlie Chan  In for the duration.

Maybe we should rename this site Ghost House, as non of us are really here (from a medical standpoint).

Michele:  on Wheldon protocol since 1st May 2006 for a variety of long standing ailments, also spokesperson for Ella started Wheldon protocol 17th March 2006 for RRMSi<

Sussex, UK

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

Jim, I think most general physicians know very little about an awful lot, but specialists know an awful lot about very little, apart from a few exceptions, and I'm married to one.  Rica's doctor with a sense of humour is right there.  My neuroi's gem was, on seeing my new scans all laid out on the radiologists desk, was "Oh, I can't see that!"  I think he must really have meant, "Oh, I can't look at that!"  Probably meaning, "But I don't believe in ghosts!"
Sarah

An Itinerary in Light and Shadow  Berger. Started the Wheldon regime in August 2003, due to very aggressive SPMSi.  Moved to intermittent therapy after one year.  In May 2006 still take this, two weeks every two months.  EDSSi was about 7, now less than 2.

Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

I suppose, the way my hypertension was going, that I could soon be qualified as a ghost. It would be fascinating to know whether the atheroma and other pathology vanish. My BP was 107 / 78 this morning. I still find this astonishing. (After measuring their blood-pressure the two ghosts sat down and ate strawberries and Greek yoghurt for breakfast.)

D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazolei. No medication now. Morning BP typically 110/75]

David- I thought that, by definition, ghosts had low blood pressure.

Yes, the continued normal blood pressure findings for another treatable but "incurable" condition (hypertension">i) is astonishing. That your initial observation of this phenomenon has turned out to be generalizable, as witnessed by Ron's survey results, is even more astonishing. And now, Rica's husband being a good example (as were you come to think of it), that these results seem to be effective for hypertension not due to obvious Cpni related disease is more than astonishing. That no one has observed antibiotics effecting BP before in this way is indicative of the brilliance of the VU research finding the key in metronidazolei, because it appears that significant effects on BP-- if I'm reading Ron's survey results right-- don't happen until pulses have been acheived on the CAPi.

If this is accurate, David, do you have any notions about why this is so, ie why regular abxi alone don't seem to impact  the affect of Cpn on the arterial system?

Combined Antibiotic Protocol for Chlamydia pneumonia in Chronic Fatigue Syndromei &amp; Fibromyalgiai- Currently: 150mg INHi, Doxycycline/Zithromycin, Tinidazole pulses. Northern Ohio, USA

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

 But CAPi DID have an almost immediate effect on Dr R's bp  After about 6 weeks it dropped from 139/89 with 3 bp meds to as low as 108/70 with the same bp meds.  When he hit his first flagyli pulse last weekend it flucuated from 112 to 137 but as of 2 days ago the norvasc has been dropped entirely.  The nausea from the flagyl (his main symptom) finally stopped yesterday.

Rica        EDSSi 6.7 at beginning - now 2
Ignorance is voluntary bad luck.  Lauritz S.   A true Viking
If you come to a fork in the road, take it. Yogi Berra

3/9 Symptoms returning. Began 5 abxi protocol 5/9 Rifampin 600, Amox 1000, Doxyi 200, MWF Azith 250, flagyli 1000 daily. Began Sept 04 PPMSi EDSSi 6.7 Now good days EDSS 1 Mind, like parachute, work only when open. Charlie Chan  In for the duration.

All this interesting evidence! We are living in remarkable times. I guess the answer as to why no-one knew that a few months of combined bacterial protein-synthesis inhibitors would dramatically affect hypertension">i is due to a number of factors: - People with hypertension are unlikely to be given these agents for any length of time; it is most unusual in antimicrobial practise to combine tetracyclines and macrolides; perhaps blood-pressure drops following treatment and the link isn't seen. I wonder what proportion of hypertensives are likely to be helped by treatment?

Jim - I think a lot of ghosts are ex-hypertensives.

D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazolei. No medication now. Morning BP typically 110/75]

Deleted dup post.

This study clearly shows that 10 days of treatment is not enough. But how does that prove that CAPi is needed instead of just a longer treatment with azi or rifampin? I'm not trying to argue against the idea. I'm just trying to find supporting evidence for CAP as opposed to just longer treatment with a single antibiotic.

Asthmai, chronic sinusitis/rhinitis, chronic tendonitis, hypothyroid. Jan 9, '08 started Azithromycin 1000mg/week.

Its all a question of preventing the development of resistance to a single antibiotic, and the prevention of replication until Flagyl can be tolerated well enough to begin to reduce the load.  

Two bacteriastatic antibioticsi are needed to stop replication.  

The rationale behind the treatment can be found in the handbook.

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse. Zoo keeper for Ella, RRMSi, At worse EDSSi 9, 3 months later 7 now 5.5 Wheldon CAP 16th March 2006

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

There have been a bunch of studies in different contexts that have shown viable Cpni even after months of monotherapy. The persistance of Cpn is well known, although a lot of physicians doing the studies don't seem to know why that is so. It's the microbiologists that are more familiar with the cryptic formi. Neither group appears aware of the differential response of the different Cpn phases to the different antibiotic agents. 

CAPi for Cpn 11/04. Dxi: 25yrs CFSi & FMSi. Protocol: 200mg Doxyi, 500mg MWF Azith, Tinii 1000mg/day pulses; Vit D1000 units, INHi 150mg, Magnascent Iodine 20 drps/day, T4 & T3

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

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