Overvejelser / resume af publikationer
vedr. DOXYCYCLIN til behandling af
BORRELIOSE og EHRLICHIOSE.
Først generelt om tetracyclin/doxycyclin:
Lægemiddelkataloget online www.lk-online.dk
skriver:
"Ved infektioner med følgende
mikroorganismer kan tetracycliner [herunder doxycyclin] være indiceret: Rickettsia
(plettyfus, Q-fever, Rocky Mountain spotted fever m.fl.), Chlamydia
(ornitose, lymphogranuloma inguinale, trakom, pneumoni og
urethritis/cervicitis), Leptospira (Weils sygdom m.fl.), Mycoplasma
og Legionella (primær atypisk pneumoni), Listeria, Pasteurella,
Brucella (kalvekastningsfeber, Maltafeber), spirokæter, vibrioner og
Borrelia."
"Tetracyclin anvendes til behandling af malaria forårsaget af
chlorochinresistent P. falciparum, altid i forbindelse med et mere effektivt
skizontocidt middel, sædvanligvis chinin.
Doxycyclin anvendes profylaktisk mod malaria forårsaget af multiresistent P.
falciparum, særligt i grænseegnene mellem Thailand, Cambodia og Myanmar
(Burma). Doxycyclin anbefales i stigende grad som malariaprofylakse på lige fod
med meflochin og atovaquon/proguanil (EPI-NYT, WHO)."
Kontraindikationer: "Tetracyclin bør ikke anvendes til
gravide, fordi det indbygges i fosterets tand- og knoglevæv og derved giver
anledning til misfarvning af barnets tænder og dysplasi af tænder og knogler
med nedsat længdevækst. Hos barnet kan der desuden udvikles katarakt." .. "Tetracyclinallergi.
Leverinsufficiens. Tetracycliner bør kun på tvingende indikation anvendes til børn under 12 år."
En nyere artikel, der grundigt beskriver doxycyclin's virkemåde og
farmakokinetik m.v.
Joshi
N, Miller DQ
Doxycycline revisited.
Arch Intern Med 1997 Jul 14;157(13):1421-8
Although several new antibiotics have recently become
available, in several clinical instances conventional antibiotics may be
equally efficacious at a considerably lower cost. In today's era of cost
containment, it is particularly relevant to revisit older, inexpensive
antibiotics to reexplore their role in the face of the emergence of resistant
microorganisms and competition from newer agents. Doxycycline is one such
antibiotic. It is an inexpensive, broad-spectrum antimicrobial agent that
remains the drug of first choice for several infections. In addition, it can be
used for a variety of other indications. Adverse effects are infrequent and
relatively minor. While interactions occur with several medications, none of
these interactions has significant adverse consequences.
"Comment in:
Arch Intern Med. 1998 Apr 27;158(8):928-9
Arch Intern Med. 1998 Jan 26;158(2):191
Arch Intern Med. 1998 Jan 26;158(2):192-3
Arch Intern Med. 1998 Jul 13;158(13):1469-70
[Mit resume]:
Virkning:
hæmmer proteinsyntesen ved at binde til 30S ribosomal mRNA og blokere for aminosyre
produktion, hæmmer også pattedyrceller i høje koncentrationer, hvilket kan
medføre forsinket sårheling.
Bevirker ændringer i den cytoplasmatiske membran, som medfører lækage (kan
dermed virke baktericidt, men i højere koncentrationer end det er muligt at
opnå med tolerable doser).
To resistensmekanismer kendes:
1. Mikroorganismerne har nedsat evne til at akkumulere stoffet pga. nedsat
optag eller øget efflux -
2. Ved mekanismer der øger beskyttelsen af ribosomerne mod stoffet.
Absorberes næsten fuldstændig (95%) og hurtigt (kan spores allerede efter 15
min) via mave-tarm-kanalen.
Top-koncentrationen opnås efter 2- 3 1/2 time. Proteinbinding 80-90% og
lidpidopløselig. Disse faktorer forklarer en stabil koncentration og lang
halveringstid, som tillader 1-2 dosis per døgn administration.
Absorptionen hæmmes af antacida /som indeholder divalente ioner,
Ca (mælk), Mg el. Al, vismutsalte
{Zn og andre mineraler] hvorfor disse ting må indtages 1-2 timer forskudt for
medicinen, mens anden føde ikke influerer nævneværdigt på opt.
Stoffet krydser let placentabarrieren og udskilles i modermælk i målelige
koncentrationer, men er ikke kontraindiceret ved amning (trods risiko for
misfarvning af barnets tænder !?).
Den høje lipidopløselighed forklarer god
vævspenetration [MK: men det betyder også at der er et stort
fordelingsvolumen, som kan influere meget på serum- og vævskoncentration, hvis
man ikke tager højde for pt's størrelse og fedtprocent når man doserer
!].
Koncentrationen i væv sædvanligvis højere end i blod, f.eks. nyre = 2x blod
conc. I lunger og brokialsekret opnås 18-23% af blod konc. Galde = 8x lever
konc., synovia (ledhinde) 11-75%.
I CSF opnås 11-56% af serumkonc., niveau
over 1 mikrog/ml kan sjældent opnås, hvilkes anses for den lavest ønskelige konc.
Stoffet er effektivt mod mange grampos, gramneg. Aerobe og anaerobe bacterier,
mycoplasma, chlamydia, rickettsia, spirocheter og udvalgte mykobakterier.
Bivirkninger: kvalme, epigastriske smerter, opkastning og diarre,
oesophagal ulceration (forebygges ved at drikke rigelig væske til tabletten
min. 100ml). Ophobes i tænder og knogler, medførende misfarvning og
væksthæmning, derfor kontraindiceret til børn
under 8 år og gravide. Fototoksicitet. [MK: aldersgrænsen angives
forskelligt fra land til land, nogle siger doxycyclin er kontraindiceret under
10 år, i DK altså 12 år !]
[MK: På trods af at artiklen er ret ny og
ehrlichia er følsom, nævnes denne mikroorganisme end ikke i artiklen !]
Dr. Joe Burrascano (se hans guidelines på www.ilads.org) fortæller i sit video-foredrag
i York 2003 (jeg har den på DVD og har skrevet flg. af derfra), at han har
gennemført måling af serumkoncentration af forskellige antibiotika:
"I reported on a study in 1996, in which I
measured blood levels of the antibiotic in my Lyme patients, and I found a
remarkable thing. In using a variety of oral antibiotics, there is an as
much as 10 fold variability in peak and base blood levels, when you compare patients
who are otherwise matched for age, height, weight – for
example with doxycycline orally the range was a 3-fold variability,
with amoxicillin there was a 10-fold variability. When this study was done I uncovered many many cases of inadequate
blood-levels. This study also
demonstrated very clearly the advantage of intravenous therapy over
oral, specifically with doxycycline. It has been quoted
many times that oral doxycycline is equivalent to intravenous, that has been
shown to be false by my study, where there was at least a 2-fold if not a
3-fold difference in blood-levels when intravenous compared to oral therapy was
given in equivalent doses.”
Resume:
Burrascano fandt en variation på 3 gange (!) i
serumkoncentrationen af doxycyclin, blandt patienter matchet mht. samme
alder, højde, vægt og givet samme dosis doxycyclin som tablet !
- og selvom
optageligheden via mave-tarm-kanalen normalt angives at være næsten fuldstændig
(95%, se ovenfor), så var serumkoncentrationen 2-3
gange højere når samme dosis blev indgivet intravenøst i forhold til
indgivet som tablet !
Hvad / hvorhen skal vi nå med medicinen og hvordan
arter medicinen sig i kroppen ?
VIGTIGT: Både borrelia
og ehrlichia kan infiltrere centralnervesystemet - derfor et det meget vigtigt at medicinen
gives i en tilstrækkelig dosis til at bekæmpe infektion også derinde !
Det er vist at Borrelia kan åbne/krydse blod-hjerne barrieren indenfor
ret kort tid efter erythema migrans / bakterien er indsprøjtet i blodbanen. Neuro-BORRELIOSE er der
publiceret hundredevis af referencer om, så det bør være velkendt for de fleste
...
- men at EHRLICHIA også kan påvises i spinalvæsken, inficere
nervesystemet og fremkalde ansigtslammelse? - er sikkert mindre kendt, derfor
vil jeg referere en enkelt artikel om det:
Lee
FS, Chu FK, Tackley M, Wu AD, Atri A, Wessels MR
Human Granulocytic Ehrlichiosis Presenting as Facial Diplegia in a 42-Year-Old
Woman.
Clin Infect Dis 2000 Nov;31(5):1288-1291.
http://www.journals.uchicago.edu/CID/journal/issues/v31n5/994405/994405.html
Neurologic manifestations of human
ehrlichiosis are unusual and have been described almost exclusively in human monocytic
ehrlichiosis associated with Ehrlichia chaffeensis. We report here a case of a
previously healthy 42-year-old woman who developed bilateral facial
nerve palsies in association with infection by the agent of human
granulocytic ehrlichiosis (aoHGE). The diagnosis was made by specific
polymerase chain reaction amplification of aoHGE sequences from samples of the
patient's blood and cerebrospinal fluid (CSF), as well as propagation of
aoHGE in culture of HL60 cells inoculated with the patient's CSF. To our
knowledge, this is the first report directly demonstrating the presence of
aoHGE in CSF, and it underscores the importance of considering HGE in patients
presenting with a nonspecific febrile illness and unexplained neurologic
manifestations. HGE should also be considered in the differential diagnosis of
bilateral facial palsy-a rare occurrence.
Hvordan opnås – og hvad er en tilstrækkelig
koncentration af doxycyclin i ”hjernekisten” ?
= over den mindste hæmmende
koncentration (MIC=minimal inhibitory concentration)?
Hvad ved vi egentlig om hvor meget
doxycyclin, der når hjernen / spinalvæsken (i hvilken koncentration) ved
indgift af forskellige doser ?
- her fandt jeg følgende artikler:
Andersson
H, Alestig K
The penetration of doxycycline into CSF.
Scand J Infect Dis Suppl 1976;(9):17-9
After single oral or intravenous doses of
doxycycline the concentrations found in the spinal fluid did not exceed 0.1
mcg/ml.
Daily oral administration for 2-10 days gave a
level in the spinal fluid of 0.1-0.76 mcg/ml. The mean value,
0.37 mcg/ml, corresponded to 14% of the concentrations found in serum. Further
studies of the penetration of doxycycline in patients with a damaged
blood-brain barrier should be performed before doxycycline can be recommended
for the treatment of CNS-infections.
Dotevall
L, Hagberg L
Penetration of doxycycline into cerebrospinal fluid in patients treated for
suspected Lyme neuroborreliosis.
Antimicrob Agents Chemother 1989 Jul; 33(7): 1078-80
Twelve patients were treated orally with 100 mg of
doxycycline twice a day (b.i.d.) and 10 patients were treated
with 200 mg b.i.d. for suspected tick-borne neuroborreliosis (Lyme
borreliosis). At 5 to 8 days after the start of therapy, the mean
concentrations in serum were 4.7 micrograms/ml for the doxycycline dose of 100
mg b.i.d. and 7.5 micrograms/ml for 200 mg b.i.d., 2 to 3 h after the last drug
administration. The corresponding levels for
cerebrospinal fluid were 0.6 and 1.1 micrograms/ml. Since a
doxycycline concentration in cerebrospinal fluid above the estimated MIC for
Borrelia burgdorferi (0.6 to 0.7 microgram/ml) is wanted in patients
treated for severe neuroborreliosis, the higher dose is preferable.
Karlsson
M, Hammers S, Nilsson Ehle I, Malmborg AS, Wretlind B
Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid
of patients treated for neuroborreliosis.
Antimicrob Agents Chemother 1996 May; 40(5): 1104-7.
http://aac.asm.org/cgi/reprint/40/5/1104.pdf
Concentrations of doxycycline and penicillin G in serum and cerebrospinal
fluid (CSF) were analyzed in 46 patients during treatment for neuroborreliosis.
Twenty patients were treated intravenously with penicillin G at 3 g every 6 h
(q6h), and 26 patients were treated orally with doxycycline at 200 mg q24h. All
samples were collected on day 13 of treatment. The median concentrations of
penicillin G in serum were 0.5, 37, and 5.6 micrograms/ml before and 1 and 3 h
after drug administration, and that in CSF was 0.5 (range, 0.3 to 1.6)
microgram/ml after 2 to 3 h. The median
concentrations of doxycycline in serum were 2.1, 6.1, and 4.7 micrograms/ml
before and 2 and 6 h after drug administration, and that in CSF was 0.6 (range,
0.4 to 2.5) microgram/ml after 4 h. All patients had
concentrations of penicillin G or doxycycline in CSF above the lowest reported MICs of penicillin G (0.003
microgram/ml) and doxycycline (0.12
microgram/ml) for Borrelia burgdorferi. However, no patients
had a drug concentration in CSF above the highest reported MIC of penicillin G
(8 micrograms/ml), and only one had a drug concentration in CSF above the
highest reported MIC of doxycycline (2 micrograms/ml), despite good clinical
response to treatment. No treatment failure or relapse was observed during a
1-year follow-up, although one patient treated with penicillin G and one
treated with doxycycline were retreated because of residual pain. The chosen
dosages of penicillin G and doxycycline seem to give sufficient concentrations
in serum and CSF for the treatment of neuroborreliosis.
To arbejder nævner en tilstræbt
koncentration i spinalvasken (>MIC) på henholdvis:
...... niveau over 1
mikrog/ml kan sjældent opnås, hvilkes anses for den lavest ønskelige
konc.
..... the estimated MIC for Borrelia burgdorferi
(0.6 to 0.7 microgram/ml)
..... above the lowest reported MICs ...
doxycycline (0.12 microgram/ml) for Borrelia
burgdorferi.
En faktor på 5-6 forskel i opgivet MIC af doxycyclin
for Borrelia burgdorferi TYDER SIMPELTHEN PÅ MANGLENDE REEL VIDEN om hvilken
koncentration, der i virkeligheden er nødvendig at opnå for at kunne hæmme
Borrelia's vækst effektivt! - usikkerheden antydes også af udtrykkene
'estimeret', 'lavest rapporterede' ...
Underbehandling er værre end INGEN
behandling, fordi det medvirker til selektion af de mest resistente bakterier
!
Vil man behandle neuro-infektion med
doxycyclin som tablet, bør man derfor, for at være nogenlunde på den sikre side
tilstræbe at opnå i hvert fald den i det nyeste arbejde anbefalede
minimale MIC på 1 mikrogram/ml!
- hvilket som det fremgår sjældent eller ikke på nås med en
doxycyclin dosis på 100mg x 2 - der er den vanligt anbefaldede dosis til
behandling af BORRELIOSE og EHRLICHIOSE hos mennesker !
Selv den dobbelte dosis - 200mg x 2 per
døgn - gav kun lige akkurat en konc. i spinalvæsken på 1,1 mikrogram/ml, dvs.
lige over det minimalt ønskede ! - og her er der IKKE taget hensyn til
hverken individuelle forskelle i optageligheden via mave-tarm-kanalen eller
evt. forskel i fordelingsvolumen på henh. tynde og tykke mennesker
!
EHRLICHIA er - som alle andre
flåtbårne infektioner - primært en dyreinfektion, hvorfor det er naturligt at
skele til erfaringer med behandling af ehrlichiose hos dyr.
Selvom
dyr - f.eks. pga. kortere tarm / hurtigere tarmpassage - nok kan have lidt
anderledes optagelse af doxycyclin end mennesker, så ledte jeg altså efter
artikler, som omtalte rekommanderede doser og behandlings-varighed af
doxycyclin til behandling af ehrlichiose henholdsvis hos dyr og mennesker.
Ehrlichia er INTRACELLULÆRE
bakterier som inficeret immun-celler direkte og det er fundet at ehrlichia kan
overleve i selv de mest aktive 'dræber-immun-celler' vi har ved f.eks. at
nedregulere 'det oxidative burst' – se nedenfor - og den vigtigste effekt af
ehrlichia infektion er immunhæmning, visende sig at patienten får øget tendens
til ANDRE INFEKTIONER, et andet tegn kan f.eks. være cyklisk
leukopeni.
Banerjee
R, Anguita J, Roos D, Fikrig E
Cutting edge: infection by the agent of human granulocytic ehrlichiosis prevents
the respiratory burst by down-regulating gp91phox.
J Immunol 2000 Apr 15;164(8):3946-9
Citation:
"Diverse pathogens, including Legionella pneumophila, Toxoplasma gondii,
Chlamydia, Ehrlichia risticii (which infects macrophages), Entamoeba
histolytica, and Leishmania, have been shown to inhibit the respiratory burst;
however, the mechanism(s) is (are) not known (23-28). Suppression of
NADPH oxidase activity by down-regulating expression of a critical subunit of
the enzyme complex by HGE bacteria represents a new mechanism by which microbes
circumvent the oxidant-generating respiratory burst. It is intriguing that
Ehrlichia targets the gene, gp91phox, which is associated with chronic
granulomatous disease (12), and suggests that HGE bacteria induces a transient
state in which the host may be more susceptible to secondary infections. Understanding
the biological basis of respiratory burst arrest by pathogens should facilitate
the development of new strategies to prevent infectious diseases and modify
inflammatory responses."
.... derfor er det ikke spor
overraskende, hvis ehrlichia kan være meget svær at behandle til bunds, hvilket
følgende artikler da også viser:
Medline search: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=(ehrlichia+doxy*)
udpluk:
Breitschwerdt
EB, Hegarty BC, Hancock SI.
Sequential evaluation of dogs naturally infected with Ehrlichia canis,
Ehrlichia chaffeensis, Ehrlichia equi, Ehrlichia ewingii, or Bartonella
vinsonii.
J Clin Microbiol 1998 Sep;36(9):2645-51.
http://jcm.asm.org/cgi/pmidlookup?view=full&pmid=9705408
"Eleven of 12 dogs were treated with doxycycline
hydrochloride at an approximate dosage of 5 mg/kg of body weight
(range, 4.3 to 10.6 mg/kg; mean, 6.9 mg/kg) every 12 h for 14 to 28 days.
Due to concurrent endocarditis, dog 9 was treated with a combination of
amoxicillin and enrofloxacin. " ...
From abstract: "In addition, our findings support the efficacy of
doxycycline for treatment of E. canis, E. equi, and E. ewingii infections but
indicate that, based upon the persistence of E.
chaffeensis DNA for 1 year following treatment, E. chaffeensis infection in
dogs may be more refractory to doxycycline treatment."
Harrus
S, Waner T, Aizenberg I, Bark H.
Therapeutic effect of doxycycline in experimental subclinical canine monocytic
ehrlichiosis: evaluation of a 6-week course.
J Clin Microbiol. 1998 Jul;36(7):2140-2.
http://jcm.asm.org/cgi/pmidlookup?view=full&pmid=9650986
The efficacy of doxycycline treatment (10 mg/kg of
body weight every 24 h for 42 days) in eliminating Ehrlichia canis
from four subclinically infected dogs was evaluated. One dog remained PCR positive, suggesting that 6 weeks of
doxycycline treatment may not be sufficient to clear E. canis parasites from
all subclinically infected dogs. ...
Iqbal
Z, Rikihisa Y.
Reisolation of Ehrlichia canis from blood and tissues of dogs after doxycycline
treatment.
J Clin Microbiol 1994 Jul;32(7):1644-9
We present evidence that supports the carrier status of dogs
experimentally infected with Ehrlichia canis after treatment with doxycycline.
Canine ehrlichiosis was induced in five dogs by intravenous inoculation with E.
canis-infected DH82 cells. All animals developed mild clinical signs of
transient fever, body weight loss, thrombocytopenia, and increased gamma
globulin levels in plasma. An indirect fluorescent-antibody test (IFA) revealed
that all dogs had seroconverted (titer, 5,120) by day 10 postinoculation (p.i.).
E. canis was reisolated from blood samples collected at intervals throughout
the 2-month period p.i. Doxycycline was administered orally once daily
at 10 mg/kg of body weight per day for 1 week starting at 2 months p.i. Following
treatment, gamma globulin levels in plasma were decreased. At necropsy on days 54 to 59 after the start of treatment,
spleen, liver, kidney, and lymph nodes were collected for E. canis culture and
histopathologic examination. Although the dogs did not show significant
clinical signs during or after treatment with the antibiotic, E. canis was
reisolated from the blood and tissue samples of three of five dogs. A
16-fold reduction in IFA titer was noted in two dogs which were negative for E.
canis reisolation at day 49 after the start of treatment, whereas a zero- to
fourfold reduction in IFA titer was seen in the remaining three dogs.(ABSTRACT
TRUNCATED AT 250 WORDS)
Peavy
GM, Holland CJ, Dutta SK, Smith G, Moore A, Rich LJ, Lappin MR, Richter K.
Suspected ehrlichial infection in five cats from a household.
J Am Vet Med Assoc 1997 Jan 15;210(2):231-4.
Ehrlichiosis is a poorly recognized condition of cats that
may be associated with anemia, leukopenia, thrombocytopenia, or dysproteinemia.
Affected cats may have indirect fluorescent antibody titers to Ehrlichia canis
and E risticii. We reviewed the clinical evaluation and response to treatment
of 5 cats in a household where ehrlichial disease was suspected as the cause of
recurrent leukopenias and thrombocytopenias. All of the cats had E risticii
indirect fluorescent antibody titers and western blot confirmation of
antibodies to 4 of the 9 major antigens of E risticii. Response to
doxycycline was monitored serologically and hematologically in each cat, and
indicated that administration of doxycycline at a dosage of 10 mg/kg of body
weight, PO, every 12 hours, for a minimum of 21 days is necessary for
treatment of this condition.
Schutze
GE, Jacobs RF.
Human monocytic ehrlichiosis in children.
Pediatrics 1997 Jul;100(1):E10
http://www.pediatrics.org/cgi/content/full/100/1/e10
BACKGROUND: Much of what is known about human
monocytic ehrlichiosis (HME) is based upon studies with adult patients.
PURPOSE: To review our experience with HME to better understand the
epidemiology, clinical manifestations, and outcome of this disease in children.
METHODS: Demographic, clinical, and laboratory data were gathered after review
of the medical records of patients identified with HME. RESULTS: Twelve
patients with an median age of 7.4 years (range, 7 months to 13.7 years) were
identified with HME; 10 were white, 7 were male, and 10 were from hometowns of
<800 people. Eight patients presented from May through July, and 8 had a
history of tick bites. Symptoms demonstrated by the patients during their
illness included fever (100%), rash (67%), myalgias (58%), and vomiting,
diarrhea, and headache (25%). On presentation, patients demonstrated
thrombocytopenia (92%), elevated liver function tests (91%), lymphopenia (75%),
hyponatremia (67%), leukopenia (58%), and anemia (42%) on the initial
laboratory examination. Four patients presented in shock and 3 required blood
pressure support and mechanical ventilation for a median of 10 days (8 to 37
days). These complicated patients required longer hospitalization (19.5 days vs
5. 5 days) and attained higher blood urea nitrogen levels (42.5 mg/dL vs 10
mg/dL) than the patients not presenting with shock. Morbidity associated with
HME patients included a decrease in cognitive and neurologic performance.
CONCLUSIONS: More information and long-term follow-up is required to understand
the full spectrum of disease and morbidity associated with HME in children.
Citation:
"All patients [Children] were treated with doxycycline (4mg/kg/day
given twice daily either intravenously or orally for 10 to 14 days) ..."
Dumler
JS, Sutker WL, Walker DH.
Persistent infection with Ehrlichia chaffeensis.
Clin Infect Dis 1993 Nov;17(5):903-5
Excerpt:
"Therapy with doxycycline (200mg/d) was started on hospital day 7
and continued for 9 days. His condition improved slightly, but in the ensuring
weeks imipenem, acyclovir, ceftazidime, tobramycin, piperacillin, amphoterician
B. and vancomycin were added to the therapeutic regimen for controlling a
variety of nosokomial infections (intravenous catheder-associated sepsis,
Pseudomonas cepacia penumonia, and Candida albicans and Aspergillus flavus
revealed by cultures of sputum) …. A fourfold rise in the Ehrlichia
canis titer (640 to 2.560) was demonstrated within the first months of illness.
Despite vigorous therapy over 2 months, the patient's condition remained
grave: he had gastrointestinal hemorrhage, pancreatitis, and
hyperbilirubinaemia and was dependent on a ventilator. The patient's illness
lasted 68 days from the onset of symptoms until death.
Pertinent findings in the final autopsy report included pulmonary
aspergillosis; active cytomegalovirus infection in the lungs, stomach, and
pancreas; multiple nonperforating gastric ulcers, marked hepatic cholestasis;
acute and chronic pancreatitis; a small focal intestinal infarct; and congestive
splenomegaly. Paraffin-embedded bone marrow obtained on hospital day 5
and liver tissue sections obtained post-mortem were prepared and stained by an
immunohistologic method; in this method for detecting the presence of
E. chaffeensis [6], a biotinylated human antibody to E. chaffeensis [6] and a
monoclonal antibody (kondly provided by Dr. Xuejie Yu, Unité des Richettsies,
Marseille, France) reactive with only E. chaffeensis were used. Morulae of E. chaffeensis
were detected with both antibodies in mononuclear cells and histiocytes in the
acute-phase bone marrow specimen (firgure 1A) and in hepatic sinusoidal
mononuclear cells (presumably Kupffer's cells; figure 1B) and foamy histiocytes
in the post-mortem liver tissue section.
Persistent
infection by obligate intracellular bacterial species in the genera Rickettsis
[7-9], Coxiella [10], and Ehrlichia [1,2] is well documented. Both chronic human Q fever
[10] and chronic canine ehrlichiosis are refractory to antimicrobial therapy
[3,11].
Most dogs die from hemorrhage or bacterial infections presumed to be secondary
to pancytopenia [11,12]. ……. The findings of the case described in this
report demonstrate for the first time that E. chaffeensis is capable of
persistent infection of human tissues. Moreover the course of illness for this
patient is consistent with that for canine ehrlichiosis. The initial
acute disease was characterized by leukopenia, thrombocytopenia, and elevated
levels of hepatic transaminases and occurred - during the expected season - in
a patient who lived in an area with know tick activity. This stage was followed
by a brief quescent phase that rapidly proceeded into the terminal phase, which
was characterized by secondary infections and hemorrhagic complications similar
to those seen for chronic canine ehrlichiosis. The continued presence of E.
chaffeensis in tissues is stiking given that the patient received antimicrobial
therapy with doxycycline, which is thought to be effective against ehrlichia
[4,14]. The complicated and prolonged clinical course that was observed for the
patient described herein has been observed for other cases of documented
ehrlichiosis [4,15] and may result form accrued tissue injury after delayed
therapy, secondary infections after broad-spectrum antimicrobial therapy, or
persistent infection by E. chaffeensis.
The following unresolved issues reguire investigation: the prevalence of
persistent ehrlichial infection; the clinical sequelae of untreated acute
ehrlichiosis; the mechanisms of ehrlichial persistence, the effect of
ehrlichial infection on the host's immune system; the functional status of
macrophages in persistent ehrlichiosis; the potential of latent ehrlichiosis to
reactivate, particularly in immune-compromised patients; and the ability of
Ehrlichia species to avoid the effects of antimicrobial agents."
Walker
DH, Dumler JS
Emergence of the ehrlichioses as human health problems.
Emerg Infect Dis 1996 Jan-Mar;2(1):18-29
http://www.cdc.gov/ncidod/eid/vol2no1/walker1.htm
Ehrlichiae are small, gram-negative,
obligately intracellular bacteria that reside within a phagosome. The first human
ehrlichial infection was recognized in the United States in 1987. It
was later shown to be caused by a new species, Ehrlichia chaffeensis. In
1994, an ehrlichial pathogen within neutrophils that is closely related to the
known veterinary pathogens E. equi and E. phagocytophila was found to infect
humans. Molecular methods were required to detect, characterize, and
identify these fastidious and uncultivated bacteria. Subsequently, E.
chaffeensis infection was documented in more than 400 patients in 30 states,
Europe, and Africa. Likewise, approximately 170 cases of human granulocytic
ehrlichiosis have been diagnosed, most since 1994, predominantly in the upper
midwestern and northeastern states, but also in northern California. The
disease caused by ehrlichiae is generally undifferentiated but is often
associated with leukopenia, thrombocytopenia, and elevated serum hepatic
transaminase levels in tick-exposed patients. Infection ranges from
subclinical to fatal; tetracycline appears to be an effective therapy. The emergence of
these two newly recognized tickborne infections as threats to human health is
probably due to increased clinical cognizance, but as in other emerging
tickborne infections, it is likely that the rapid increase in identified cases
signals a true emergence of disease associated with a changing vector-host
ecology.
Excepts:
"Some patients have a life-threatening illness resembling toxic shock
syndrome (24). Deaths have occurred in approximately 2% to 3% of patients, including
previously healthy children (13,23-28). "
"However, the fact that two-thirds of the seroconverters remained
asymptomatic emphasizes that the relationship between severity of illness and
either host factors or ehrlichial strain differences in virulence remains
unknown. "
"Human monocytic ehrlichiosis occurs not only as an acute illness
of apparently immunocompetent persons but also as an opportunistic infection of
patients with compromised host defenses, including acquired
immunodeficiency syndrome (AIDS) patients (24,26). The
report of a fatal E. chaffeensis infection in an AIDS patient, in whom a
diagnostic antibody response to E. chaffeensis never developed, suggests that
such cases would not usually be diagnosed correctly. "
"Furthermore, antibodies to E.
chaffeensis did not develop in six PCR-confirmed patients during convalescence,
suggesting that serologic testing may be less sensitive than generally assumed
(31,45). The sensitivity of PCR seems to be 80% to 87%; the
specificity depends critically upon avoiding contamination with ehrlichial DNA.
Search for morulae of E. chaffeensis in leukocytes is unrewarding. Even
an exhaustive search of buffy coat smears seldom yields a diagnostic result.
"
[MK: ikke desto mindre viser resultaterne fra Bowen RTI og undertegnede at
det altså muligt at finde Ehrlichia lignende mikrober i blodudstryg, bare man
leder grundigt nok !!!]
"E. chaffeensis is killed in cell culture in the presence of doxycycline
or rifampin but is resistant to chloramphenicol, ciprofloxacin,
erythromycin, cotrimoxazole gentamicin, and penicillin (47). E. chaffeensis can establish persistent infection even after
treatment with tetracycline and chloramphenicol (25). Persistent
ehrlichial infection, in some instances even after treatment, is a
well-documented aspect of the veterinary ehrlichioses, e.g., canine monocytic
ehrlichiosis (E. canis) and tick-borne fever (E. phagocytophila). The
long-term implications of persistent ehrlichiosis in humans are unclear but
might include subsequent reactivation of infection or altered host defenses.
"
Patel
RG, Byrd MA
Near fatal acute respiratory distress syndrome in a patient with human
ehrlichiosis.
South Med J 1999 Mar;92(3):333-5
Human ehrlichiosis is not a common cause of acute
respiratory distress syndrome (ARDS). Physicians should be aware of this
life-threatening but treatable entity. Progression to ARDS may be related to
delay in diagnosis and treatment. Fever, leukopenia, thrombocytopenia, and a
history of tick exposure in an endemic area during the spring and summer months
should alert the physician to the possibility of human ehrlichiosis, since a
definitive diagnosis requires serologic testing that may take weeks to confirm.
We describe a case of ARDS resulting from human ehrlichiosis. A unique
feature in our case was that despite the early use of doxycycline, the patient
had near fatal ARDS that responded dramatically to high doses of steroids.
Bakken
JS, Krueth J, Wilson-Nordskog C, Tilden RL, Asanovich K, Dumler JS
Clinical and laboratory characteristics of human granulocytic ehrlichiosis
JAMA 1996 Jan 17;275(3):199-205
OBJECTIVE--To characterize the clinical and laboratory
features observed in patients with human granulocytic ehrlichiosis (HGE) and
evaluate the utility of the diagnostic tools used to confirm the diagnosis.
DESIGN--Retrospective case study of 41 patients with laboratory-diagnosed HGE.
SETTING--A total of 228 patients from Minnesota and Wisconsin were evaluated
between June 1990 and May 1995.
METHODS--Cases were presumptively identified by a history of an influenzalike
illness acquired in an area known to be endemic for ticks. Diagnostic
laboratory testing included microscopic examination of Wright-stained
peripheral blood smears for presence of neutrophilic morulae, polymerase chain
reaction (PCR) analysis of acute-phase blood samples for the Ehrlichia
phagocytophila/Ehrlichia equi group DNA, and evaluation of serological
responses by indirect immunofluorescent antibody assay (IFA), using E equi as
antigen.
RESULTS--All patients presented with a temperature of at least 37.6 degrees C,
and most had headache, myalgias, chills, and varying combinations of
leukopenia, anemia, and thrombocytopenia. Eighty percent of the
patients tested demonstrated morulae in the cytoplasm of peripheral blood
neutrophils. Only 16 of 37 patients tested by PCR were positive for HGE,
whereas serum IFA assays of acute or convalescent blood samples detected
antibodies against E equi in 38 of 40 patients tested. Two patients
died, and the calculated case fatality rate was 4.9%.
CONCLUSIONS--Human granulocytic ehrlichiosis is being increasingly recognized
in Wisconsin and Minnesota. A more severe illness is associated with increased
age, anemia, increased percentage of neutrophils and decreased percentage of
lymphocytes in peripheral blood, and presence of morulae in neutrophils. The
differential diagnosis for patients who develop an influenzalike illness
following a tick bite should include HGE. Microscopic examination of
the acute-phase blood smear to detect neutrophilic morulae is currently the
quickest and most practical screening method for diagnosing HGE in the upper
Midwest.
Paddock
CD, Sumner JW, Shore GM, Bartley DC, Elie RC, McQuade JG, Martin CR, Goldsmith
CS, Childs JE.
Isolation and characterization of Ehrlichia chaffeensis strains from patients
with fatal ehrlichiosis.
J Clin Microbiol 1997 Oct;35(10):2496-502
http://jcm.asm.org/cgi/reprint/35/10/2496?view=reprint&pmid=9316896
Two new isolates of Ehrlichia
chaffeensis (designated Jax and St. Vincent) were obtained from patients with
fatal ehrlichial infections. Patients developed characteristic manifestations of severe
disease due to E. chaffeensis, including marked thrombocytopenia, pulmonary
insufficiency, and encephalopathy. ....
Jahangir
A, Kolbert C, Edwards W, Mitchell P, Dumler JS, Persing DH
Fatal pancarditis associated with human granulocytic Ehrlichiosis in a
44-year-old man.
Clin Infect Dis 1998 Dec;27(6):1424-7
Human cases of infection with a granulocytotropic Ehrlichia
species closely related to Ehrlichia equi are now being described with
increasing frequency in the United States, especially in areas where Lyme
disease is already endemic. We describe a case of fatal pancarditis during the
course of human granulocytic ehrlichiosis (HGE) in a 44-year-old outdoor worker
who was previously treated for presumptive Lyme disease. Serological and
molecular diagnostic tests for Borrelia burgdorferi and Babesia microti infections
were negative. Postmortem serum specimens were seroreactive for HGE, and
molecular evidence of infection with the HGE agent was obtained. These findings
suggest that carditis may be a manifestation of HGE, further complicating the
differential diagnosis of tick-borne illness.
CDC recommends for treatment of HUMAN ehrlichiosis:
http://www.cdc.gov/ncidod/dvrd/ehrlichia/Treatment/Treatment.htm
"Doxycycline (100 mg twice daily for adults or 4.4 mg/kg body weight per day in two divided doses for
children under 45.4 kgs (100 lbs)) is the drug of choice for patients
with ehrlichiosis. The optimal duration of therapy has not been established, but current
regimens recommend continuation of treatment for at least 3 days after the
fever subsides and until evidence of clinical improvement, for a minimum total
course of 5 to 7 days. Severe or complicated disease may require longer
treatment courses. Because tetracyclines are contraindicated in pregnancy,
rifampin has been used successfully in a limited number of pregnant women with
documented HGE.
Det fremgår altså at anbefalet
doxycyclin-dosis til behandling af EHRLICHIOSE i litteraturen er:
DYR (hund og
kat): 5-10 mg/kg/døgn
BØRN: 4.4 mg/kg/døgn
VOKSNE MENNESKER: 100 mg x 2 ! - uden hensyntagen til ovenstående VIDEN om
ønsket CSF koncentration og evt. forskelle i opnået koncentration som følge af
individuelle forskelle i fordelingsvolumen!)
Gennemgår man litteraturen med henblik på
”persisterende Borreliose efter behandling med doxycyclin f.eks. for erythema
migrans i vanlig dosis 100 mg x 2” forekommer der faktisk temmelig MANGE
rapporterede behandlingssvigt …
– kan grunden til det være at doxycyclin dosis simpelthen har været for
lille til at gøre noget effektivt ved infektionen ?
Jeg har ikke fundet et eneste studie
der sammenlignede opnået serumkoncentration af doxycyclin hos forskellige dyr
og mennesker ved forskellige doser i mg/kg/dg ! - den valgte anbefalede
menneske-dosis synes således at bygge alene på tradition - ikke på reel
VIDEN ?
Trods meget grundig
litteratur-søgning efter dette, er det endnu IKKE lykkedes mig at finde nogen
logisk begrundelse (læs EVIDENS) for IKKE at variere dosis i forhold til vægten
også til voksne mennesker, sådan som det er reglen at gøre for børn og dyr –
eller hvorfor mennesker skal have så meget lavere dosis/kg/dg af doxycyclin til
behandling af ehrlichiose end dyr !!!
For en læge, der som jeg har arbejdet
meget af min lægetid med børn og har været vant til ALTID at dosere AL MEDICIN
under hensyntagen til størrelse og vægt / overfladeberegning, virker det meget,
meget ULOGISK at voksen-medicinere som regel doserer medicin efter en
'normalvægt' = 70 kg mand, og kun MEGET SJÆLDENT tager hensyn til forskelle i
folks størrelse og fedt%!
Jf. "den høje lipid-opløselighed [af doxycyclin] forklarer god
vævspenetration", så må der logisk set være tale om et betydeligt
meget større fordelings-volumen og heraf følgende lavere vævskoncentration på
samme mg doxycyclin-dosis, i henholdvis en fed person på 150 kg og en mager
person på 50 kg?
Følgende beregning viser tydeligt forskellen i totaldosis, hvis der gives
’børnedosis’ 4 mg/kg/døgn. Personen på 50 kg skal have 200 mg, mens personen på
150 kg skal have 600 mg = 3 gange så stor dosis ! - og så er der IKKE taget
hensyn til evt. individuelle forskelle i optagelighed via mave-kanalen etc.!
Tabel
over dosis udregnet i mg/kg/døgn ved forskellige døgndoser og vægte:
mg/dg 100
mg 200
mg 400
mg 600 mg 800 mg
kg
50 -
2
4
8
12 16
70
-
1,4
2,8
5,7
8,5 11,4
90
-
1,1
2,2
4,4
6,7 8,9
110 -
0,9
1,8
3,6
5,5 7,3
130 -
0,8
1,5
3,0
4,6 6,2
150 -
0,7
1,3
2,7
4,0 5,3
HVAD ER SÅ EN RATIONEL DOSIS AF DOXYCYCLIN, givet som tablet, når man
ønsker at opnå tilstrækkelig koncentration i spinalvæsken til at bekæmpe såvel
Borrelia som Ehrlichia effektivt derinde?
- ja DET må patienten og
lægen afgøre i fællesskab efter at have sat sig ind i alt ovenstående og tænkt
lidt over fakta !
Hvis ønskværdig dosis giver toksiske
bivirkninger må dosis naturligvis reduceres. Varigheden af behandling må rette sig
efter den individuelle patients kliniske repons og som minimum vare til blodet
er uden tegn på infektion / inklusioner i de hvide blodlegemer på buffy-coat
udstryg, hvor min 500-1000 hvide blodceller bør ses igennem med negativt
resultat !
Hvordan tolereres ”høje doser” af
DOXYCYCLIN ? - erfaringen er at
det tolereres faktisk generelt godt !
Personligt vejer jeg cirka 95 kg og
har IKKE haft nogen problemer - udover det forventelige fototoksisk udslet ved
udsættelse for sollys ud over 15 min per dag om højsommeren, som var lige så
slem på en lavere dosis ! - med at tolerere en dosis af doxycyclin på 600 mg
per døgn (cirka 6 mg/kg/døgn), når blot jeg tog medicinen sammen med
mad/rigeligt at drikke og jeg følte faktisk først rigtig god effekt på mine NEURO-symptomer
ved denne ”høje dosis” !
De fleste patienter der har været i doxycyclin i dosis 5-6 mg/kg/dg angiver
IKKE problemer med at tåle dette, undtagen hvis de tager medicinen på tom mave
– så gør det ondt i nogle timer og kan fremkalde opkastninger. Jarisch-Herxheimer
er som regel mild hvis man starter med én 100 mg tablet og gradvis øgning til ønsket dosis under hensyntagen
til reaktionen.
Forstyrret mave-tarm flora synes mindre ved doxycyclin end andre antibiotika og
kan som regel forebygges ved tilførsel af probiotiske bakterier f.eks. i form
af Cultura yoghurt (bifido-bakterier synes særlig vigtige, acidophilus alene er
ikke nok !) – naturligvis indtaget nogle timer forskudt, så Ca i mælkeproduktet
det ikke forstyrrer optagelsen af doxycyclin – alternativt anvendes probiotiske
bakterier i kapselform.
ALTERNATIVER til
doxycycline til behandling af Ehrlichiose, f.eks. til gravide og børn og folk
som ikke tåler doxycyclin:
Fra http://aac.asm.org/cgi/reprint/41/1/76.pdf
"No clear treatment
alternatives exist for young children, pregnant women, or allergic individuals,
in whom tetracyclines are contraindicated. We performed in vitro antibiotic susceptibility
tests with this recently isolated agent grown in the human promyelocytic
leukemia cell line HL-60. Doxycycline (MIC, 0.25 mg/ml), rifampin (MIC, 0.5
mg/ml), rifabutin (MIC, <0.125 mg/ml), ciprofloxacin and ofloxacin (both
with MICs of 2 mg/ml), and trovafloxacin (MIC, <0.125 mg/ml) demonstrated
significant activity against the HGE agent. These agents were also
bactericidal.
The HGE agent was resistant to clindamycin, trimethoprim-sulfamethoxazole, and
imipenem-cilastatin, as well as to ampicillin, ceftriaxone, erythromycin, and
azithromycin, antibiotics commonly used to treat Lyme disease.
Both chloramphenicol and gentamicin had weak inhibitory activities but were not
bactericidal. Our findings confirm the observed clinical efficacy of doxycycline
and further suggest that the rifamycins and quinolones, particularly
trovafloxacin, hold promise as alternative agents for treating this new
infection."
Brouqui
P, Raoult D.
In vitro antibiotic susceptibility of the newly recognized agent of
ehrlichiosis in humans, Ehrlichia chaffeensis.
Antimicrob Agents Chemother 1992 Dec;36(12):2799-803
..."Further clinical
investigations are necessary to evaluate the role of rifampin in the treatment
of human ehrlichiosis, especially in children."
Raoult sagde iøvrigt - på Rickettsia-mødet 07/09/2000 i København - at han ikke
ville betænke sig på at behandle børn med rickettsiose med tetracycliner, fordi
det er en meget alvorlig infektion, men han giver kun dette i relativ kort tid.
Ovenstående er sandsynligvis ikke en fuldstændig oversigt over emnet ? -
og kender læseren til supplerende information – så send mig venligst en note om
det per email, så listen kan blive opdateret, tak J
Marie Kroun, læge
kroun@ulmar.dk
Rev. Sep. 2003