Rickettsia species DU de thérapeutiques anti-infectieuses Pierre-Edouard Fournier - Infectiologie
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DU de thérapeutiques anti-infectieuses
Rickettsia species
Pierre-Edouard Fournier
Grenoble, 19 janvier 2018
Puzzling bacteria
➢ 1970s
➢ Few culture systems
➢ Few phenotypic characteristics
➢ => any intracellular bacterium, including chlamydiae,
was classified as a “rickettsia”
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R
R. rickettsii Rickettsia rickettsii
R. prowazekii R. prowazekii
Orientia tsutsugamushi
R. tsutsugamushi Ehrlichia chaffeensis
R. quintana E. ewingii
C. burnetii E. canis
E. ruminantium
Rickettsiales
Anaplasma phagocytophilum
E. canis A. marginale
E. phagocytophila Wolbachia pipientis
E. sennetsu
C. ruminantium Changing Neorickettsia sennetsu
N.helminthoeca
N. helminthoeca Bartonella quintana
W. pipientis
Taxonomy B. henselae
B. talpae a
B. bacilliformis
W. persica Brucella melitensis
R. grylli Coxiella burnetii
Rickettsiella grylli
B. bacilliformis Legionella pneumophila g
G. talpae «Wolbachia persica»
Francisella tularensis
A. marginale Eperythrozoon ovis
E. ovis Hemobartonella felis
Gram +
H. felis Mycoplasma pneumoniae
Ureaplasma urealyticum
What is a Rickettsia spp. in 2018?
➢ a-Proteobacteria
➢ Gram-negative rod
➢ Size 0.8 – 2 x 0.3 µ
➢ Stained by the Gimenez
method
➢ Strictly intracellular
➢ Associated to endothelial cells
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Rickettsia spp.
➢ Associated to arthropods: ticks, fleas, lice, mites
➢ 30 validated species, incl. 17 pathogens
➢ > 100 unclassified rickettsial isolates
➢ Major human pathogens
➢ B list of potential bioterrorism agents
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Rickettsioses ➢ Zoonotic diseases ➢ Short incubation (6-7 jours) ➢ Clinical triad: fever, eschar, maculo-papular rash
Worldwide diseases
Parola et al. 2014
Rickettsioses
➢ Severity varies greatly from mild, self-limiting,
to life-threatening diseases
Mortality
0 % (R. slovaca, R. africae, R. felis)
1% (R. typhi)
2 - 5 % (R. conorii, R. rickettsii)
30% (R. prowazekii)
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Differences in pathogenicity
➢ No virulence factor differentially present
➢ Role of genome decay in virulence?
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R
Virulence linked to genome reduction
➢ R. africae genome
➢ 1,27 Mb chromosome
➢ 1 unstable plasmid
➢ Highly clonal
➢ The most virulent species has the smallest genome
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➢ Loss of regulatory genes RAn isolated phenomenon?
Species genome size (bp) GC (%) coding % ORFs pseudogenes phylum order/family
M. leprae 3, 268, 203 57% 49% 1605 1115 Actinobacteria Mycobacteria
M. avium 5, 475, 491 68% 88% 5120 1143 Actinobacteria Mycobacteria
M. tuberculosis 4, 411, 532 65% 90% 3988 8 Actinobacteria Mycobacteria
M. smegmatis 6, 988, 209 67% 90% 6716 168 Actinobacteria Mycobacteria
R. prowazekii 1, 111, 523 29% 75% 835 0 Proteobacteria Rickettsiae
R. africae 1, 278, 540 32% 72% 1030 87 Proteobacteria Rickettsiae
C. diphtheriae 2, 488, 635 53% 87% 2272 48 Actinobacteria Corynebacteria
C. glutamicum 3, 314, 179 54% 86% 3052 0 Actinobacteria Corynebacteria
T. pallidum 1, 139, 457 52% 93% 1028 9 Spirochetes Spirochaetaceae
T. denticola 2, 843, 201 37% 91% 2767 19 Spirochetes Spirochaetaceae
Y. pestis 4, 600, 755 47% 82% 4048 54 Proteobacteria γ-enterobacteria
Y. pseudotuberculosis 4, 744, 671 47% 82% 3901 73 Proteobacteria γ-enterobacteria
B. pertussis 4, 086, 189 67% 82% 3436 358 Proteobacteria β-enterobacteria
B. bronchiseptica 5, 339, 179 68% 91% 4994 12 Proteobacteria β-enterobacteria
S. pneumoniae 2, 078, 953 39% 85% 2115 0 Firmicutes Lactobacillales
S. agalactiae 2, 160, 267 35% 86% 2124 0 Firmicutes Lactobacillales
S. pyogenes 1, 852, 442 38% 83% 1696 35 Firmicutes Lactobacillales
S. suis 2, 096, 309 41% 86% 2186 0 Firmicutes Lactobacillales
S. Typhi 4, 809, 037 52% 83% 4391 205 Proteobacteria γ-enterobacteria
S. Schwarzengrund 4, 709, 075 52% 85% 4502 152 Proteobacteria γ-enterobacteria
S. dysenteriae 4, 369, 232 51% 76% 4270 284 Proteobacteria γ-enterobacteria
E. coli HS 4, 643, 538 50% 86% 4378 95 Proteobacteria γ-enterobacteria
V. cholerae chr1: 1, 108, 250 46% 86% 1133 0 Proteobacteria γ-enterobacteria
chr2: 3, 024, 069 47% 88% 2742 1 Proteobacteria γ-enterobacteria
V .parahaemolyticus chr1: 3, 288, 558 45% 86% 3080 0 Proteobacteria γ-enterobacteria
chr2: 1, 877, 212 45% 86% 1752 0 Proteobacteria γ-enterobacteria
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RPathogenesis of rickettsial infections
Host-associated factors
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RWorse outcome
➢ Age > 40 years (RMSF), > 60 years (MSF)
➢ Male sex ( occupational bias)
➢ Ethnical factors: Native Americans (reduced access to healthcare
facilities)
➢ Comorbidities: Chronic alcoholism, diabetes
➢ Genetic background: deficit in G6PD
mutated TLR-4
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RTick-borne rickettsioses
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RTick hypostoma inserted
in the skin of a patient
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REurope
and Mediterranean area
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REurope: emerging pathogens
R. conorii conorii
R. conorii israelensis
R. conorii caspia
R. conorii indica
R. sibirica mongolitimonae
R. aeschlimannii
R. slovaca
R. raoultii
R. massiliaa
R. rioja
R. monacensis
R. hoogstraalii
R. helvetica
R. rhipicephali
Rickettsia sp. « DmS1 »
‘Candidatus R. barbariae
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Rickettsia sp. AvBat RMEDITERRANEAN SPOTTED FEVER
Rickettsia conorii subsp. conorii
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RGlobal distribution of MSF/ Rh. sanguineus
http://jfbradu.free.fr/cartesvect/fdcmonde.htm
Many gaps in the Ecology of MSF: Rh. sanguineus has a worldwide distribution but
MSF is known to be only endemic in Mediterranean areaRickettsia conorii – animal reservoir?
Which host for Rh. sanguineus ?
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RMediterranean spotted fever :
clinical
➢ Urban disease 2/3 - rural 1/3
aspects
Peak
➢ Tick-bite is often unnoticed (larva, nymphs++) in August
➢ Seasonal zoonosis: warmest period
➢ Males
➢ Incidence 50/100 000 hbts
➢ Incubation 6 – 7 days
➢ Fever 100%, flu-like symptoms
➢ Inoculation eschar (single ?) 72 %
➢ Conjunctivitis
➢ Skin rash 97% U
RMSF rash
involves palms-soles, not face
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RMay occur at any age
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REvolution
➢ Most often mild
➢ 6% => malignant
forms
➢ Diabetes,
immunodeficiency,
G6PD deficiency,
elderly, alcoholism,
delayed antibiotics
➢ Mortality 2-3%
Mouffok et al. Int J Infect Dis 2009; 13: 225-37Changing epidemiology of MSF
!!! Global warming => effect on tick
behavior
➢↑ period of activity of Rh. Sanguineus
➢↑ aggressiveness
➢ ↑ biting of unusual hosts (humans)
Fatal MSF French in
=> Multiple eschars, severe forms 2003 heat wave:
=> ↑ incidence of Rh. sanguineus-transmitted 22 attached ticks
on a man
diseases
Fatal cases 2 – 6%, and reach 30% in hospitalized patients
Socolovschi et al. 2009. Parola et al. 2008 Multiple escharsOther Rickettsia conorii subspecies
Rickettsia conorii subsp. israelensis
Rickettsia conorii subsp. caspiensis
Rickettsia conorii subsp. indica
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ROther Rickettsia conorii subspecies
• R. conorii subsp. israelensis
• Israeli spotted fever
• Sicily, Portugal:
• Rh. sanguineus ticks,
• Human cases: Inoculation eschar 4%
• Imported fatal cases: UK (from Portugal),
Switzerland (from Lybia)
• R. conorii subsp. caspia
• Astrakhan fever
• Kosovo, France: Rh. sanguineus ticks (cluster of spotted fever)
• No human cases in Europe
• Imported cases: France (from Chad)
• R. conorii subsp. indica
• Indian tick typhus
• Sicily : one human case
• Imported cases: French traveler (from India)
Chai JT JTM 2008; Boillat et al. 2008; Levin et al. 2012; Alexandre N et al.2011; Tarasevich 1991; Parola et al. 2001; Renvoisé et al. 2012 U
RSENLAT
(SCALP ESCHAR AND NECK LYMPHADENOPATHY)
Rickettsia slovaca, Rickettsia raoultii, Rickettsia « rioja »
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RSENLAT
➢ Endemic: Europe
➢ Vecteur: Dermacentor marginatus and
D. reticulatus
➢ The peak incidence:
March-May & September-November
Parola et al. 2009R. slovaca and R. raoultii infection
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(Parola et al. 2009) RUnusual agents of SENLAT
➢ Bartonella henselae : 3 patients, France
➢ Francisella tularensis : 1 patient, France
➢ Rickettsia “rioja”: 1 patient, Spain
➢ Co-infections:
➢ R. slovaca-Coxiella burnetii: 1 patient, France
➢ R. slovaca-Borrelia burgdorferi : 8 patients, Spain
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Lakos et al. 2002; , Parola et al. 2009; Angelakis et al. 2010; Edouard et al. 2012; Perez-Perez et al. 2009 RLAR
(Lymphangitis-associated rickettsiosis)
Rickettsia sibirica mongolitimonae
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RR. sibirica mongolitimonae
1996:
1st human case, France,
tick vector?
>20 cases to date
1991:
Detection in Hyalomma
2005: first case
asiaticum, Mongolia
in Algeria
Detection in H. truncatum 2004:
Niger First case in
South Africa
Migratory birds?
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Raoult et al. 1996; Pretorius et al. 2004 RR. sibirica mongolitimonae
➢ Mediterranean area (France, Greece,
Portugal, Spain)
➢ Potential vector in Europe:
➢ Hyalomma anatolicum excavatum
(Greece, Cyprus)
➢ Rh. pusillus (France, Portugal) R. sibirica mongolitimonae in ticks
8
6
4
2
Human infection
0
Imported case: French
traveler (from Egypt)
France Greece Portugal Spain
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Psaroulaki et al. 2005; Chochlakis D. et al. 2012; de Sousa et al; 2006; Edouard et al. 2012 RLAR (Lymphangitis-associated rickettsiosis)
➢ Men 70%
➢ Fever 100%
➢ Headache and myalgia: 87%
➢ Skin rash 90%
➢ Inoculation eschar: 87%, including multiple eschars
15%
➢ Lymphangitis expanding from
➢ eschar 32%
➢ Painful enlarged lymph nodes 65%
Fournier et al. 2000 EID; Socolovschi et al. 2010Africa
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RR. africae
(Raoult et al. N.Engl.J.Med. 2001;344:1504-10)
➢Distribution of R. africae similar to that of Amblyomma
➢Sub-saharan Africa (Parola et al. N.Engl.J.Med.1998;338:1391;
Parola et al. Am.J.Trop.Med.Hyg.1999;60:888-93; Kelly et al. 2003;unpublished data)
➢Prevalence = 1,7 - 72% (Tissot-Dupont et al. Am.J.Trop.Med.Hyg. 1994;50:373-80; Beati et al.
J.Med.Entomol. 1995;32: 787-92; Clin.Infect.Dis.1995;21:1126-33 Parola et al. Emerg.Infect.Dis. 2001;7:1014-17)
➢Seroprevalence = 27 – 52% (Tissot-Dupont et al. Clin.Infect.Dis.1995;21:1126-33)
➢Most frequent SF rickettsiosis
➢Importation of Amblyomma
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REpidemiology
(Raoult et al. N.Engl.J.Med. 2001;344:1504-10)
Amblyomma : attack strategy (CO2)
grouped cases (74%)
multiple eschars U
attack rate 4-14% RClinical manifestations
Raoult et al. N.Engl.J.Med. 2001;344:1504-10)
➢ Sex-ratio H/F 1.6, mean age 45 years
➢ Silent incubation, 6-7 days
➢ Sudden onset, fever 88%
➢ Rash 46% = MP 51%,
vesicular 45%, purpuric 4%
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RClinical manifestations
Raoult et al. N.Engl.J.Med. 2001;344:1504-10)
➢ Inoculation eschar 95%, multiple 54%, limbs 73%
➢ Satellite enlarged lymph nodes 43%
➢ Mild disease (recovery 100%, no sequellae) U
RDistribution of R. Africae in West Indies
Parola P, et al. N Engl J Med. 1998
+ Reunion island, New Caledonia
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RAmerica
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RRocky Mountain Spotted Fever
➢ Rickettsia rickettsii
➢ Vector = Dermacentor
andersoni
➢ summer
➢ USA : 500 cases/year
(south-east)
➢ central America, Brazil,
Argentina, Colombia
1 - 2.5 p. 106
➢ Fever, rash, no eschar 2.6 - 5 p. 106
➢ Mortality 5 - 80 % without > 5 p. 106
treatment U
RFlea-transmitted rickettsioses
Worldwide diseases
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RFlea-transmitted diseases
➢ R. felis
➢ R. typhi
➢ B. henselae
➢ B. quintana?
➢ Y. pestis
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RFleas
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RFleas
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RMurine typhus
➢ Rickettsia typhi (R. mooseri)
➢ Vector : rat fleas (X. cheopis), cat fleas, mouse fleas
➢ Reservoir: rats, cats, opossums
➢ Infection by flea feces
➢ Prevalent in southern USA, Hawai,
central and south America, Africa, Asia
(Indonesia), Mediterranean area (Greece, Cyprus,
Spain, North Africa)
➢ Fever, headache, arthro-myalgias,
➢ MP rash (40 - 50 %)
➢ Neurological signs such as confusion, stupor, seizures or imbalance (up to
45%)
➢ Mostly mild. Deadly in elderly and immunocompromised patients without
treatment U
RFlea spotted fever
➢ Triad fever + eschar + rash = “Yaaf” in Africa (febrile vesicular rash
with eschar) Mediannikov et al. J Infect . 2013;66:536-40
➢ Photophobia, hearing loss, and signs of meningitis (rare)
➢ Mostly mild
➢ USA, Brazil, Mexico, Germany, France,
Australia, Algeria, Senegal
➢ High seroprevalence in Senegal
and Kenya (51 and 57% of febrile patients,
respectively) Maina et al. Emerg Infect Dis. 2012;18:328-31
➢ Role of Anopheles and Aedes mosquitoes in Africa (similar
epidemiology to malaria) Socolovschi et al. PLOS One. 2012;7:e48254 U
RLouse-transmitted
rickettsioses
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RLouse transmitted
bacteria
➢ Rickettsia prowazekii
➢ Borrelia recurrentis
➢ Bartonella quintana
➢ Acinetobacter baumanii?Human lice
Pediculus humanus capitis Pediculus humanus humanus Phtirus pubis
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RPediculus humanus humanus-
transmitted bacteria
France Russia
R. prowazekii
B. quintana
B. quintana
Algeria
R. prowazekii
USA
B. quintana
Sudan
Peru B. recurrentis
R. prowazekii Burundi
B. quintana B. quintana Zimbabwe
R. prowazekii B. quintana
(Fournier et al. Emerg Infect Dis 2002)Pediculus humanus humanus
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RBlood meal on a healthy volunteer
➢ P.h.humanus only bites
humans (except Culpepper)
➢ Only blood meal
➢ 5 meals/day
➢ Highly sensitive to heat and dessication
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RP.h. humanus lives
In clothes
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REpidemic typhus,
Reemerging disease
➢ 1990-1992: Isolated cases in Ethiopia and Nigeria
(Perine et al. Clin. Infect. Dis. 1992)
➢ 1990-1993: Isolated cases in Peru (WHO memorandum. Bull. World Health Organ. 1993)
➢ 1993 : Civil war in Burundi and Rwanda
➢ 1994 : 800,000 Rwandan refugees in Goma, Zaïre: louse
outbreak but no typhus
➢ 1995: outbreak in a jail in Burundi: 9 cases (Raoult et al. Emerg. Infect. Dis. 1997)
➢ 1996-1997: Outbreak in refugee camps in Burundi
> 45,000 cas (Raoult et al. Lancet. 1998)
➢ 2004: Isolated case in Algeria (Mokrani et al. J. Clin. Microbiol. 2004) U
REpidemic typhus
(Jail fever, Red louse fever)
✓ Rickettsia prowazekii
(Houhamidi et al. J. Infect. Dis. 2002)
✓ Vector : only P. h. humanus (not capitis)
✓ Fever - rash : 30 - 60 %
✓ Myalgia ++ (“sutama”)
✓ Headache, obnubilation (“tuphos”)
✓ 10-30% mortality without treatment
✓ Treatment : unique dose of 200 mg doxycycline U
REpidemic typhus in USA
Role of flying squirrels (1975)
➢ R. prowazekii associated to
squirrel lice
➢ East and West USA
➢ Less severe
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RDetection of R. prowazekii
in ticks
1966: Amblyomma in Africa
Reiss-Gutfreund RJ. 1966. Am J Trop Med Hyg; 15: 943-49.
2005: Amblyomma in Mexico in 2005
Medina-Sanchez A., et al. 2005. Ann N Y Acad Sci; 1063:327-32.
Role in epidemiology?
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RMite-transmitted
rickettsioses
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RRickettsialpox
➢ Rickettsia akari
➢ Vector = Allodermanyssus sanguineus
(mouse mite)
➢ Prevalent in USA, Ukraine,
➢ Slovenia, Korea
➢ Fever, rash (vesicular)
➢ Eschar, regional lymph nodes
➢ Mild
➢ New York +++
➢ High seroprevalence in
Baltimore drug addicts
➢ Under high surveillance since 9-11, 2001
(eschar ~ smallpox)
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(Paddock et al. Ann N Y Acad Sci. 2003) RRickettsia spp. and antibiotics
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RNatural antibiotic resistance
Erythromycin
Erythromycin Rifampin Rifampin
R S R. sibirica
R S R. africae
R S R. conorii
Not other macrolides R S R. slovaca
R S R. honei
R S R. rickettsii
R S R. japonica
R R Bar 29
R R R. massiliae
R R R. rhipicephali
R R R. aeschlimanii
R R R. montanensis
R S R. helvetica
R S R. australis
R S R. akari
S S R. typhi
S S R. prowazekii
R S R. canadensis
R S R. bellii U
R
Rolain et al. AAC 1998;42:1537-41In vivo efficiency of antibiotics
➢ Reference TRT : doxycycline 200 mg/day, 7-10 d or until
3d after apyrexia (per os ou I.V. if severe)
➢ Adults and children (Purvis et al. Pediatr Infect Dis J. 2000)
Alternatives :
➢ Doxycycline, 200mg x 2 once for MSF
and typhus (Bella-Cueto F. et al J.Infect.Dis. 1987)
➢ Chloramphenicol, 25-50 mg/kg/d, 7-10 days
but hematologic toxicity
➢ Relapses in MSF (Shaked Y., et al J Infect., 1989)
➢ Less efficient in RMSF (Holman RC., et al. J Infect Dis., 2001)
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Rin vivo efficiency of antibiotics
➢ Other efficient ATB:
➢ Fluoroquinolones
➢ Josamycin
➢ Roxithromycin
➢ Clarithromycin
➢ Telithromycin
➢ Rifampin (except R. massiliae group)
➢ No acquisition of resistance U
RWorse outcome if
➢ Delayed diagnosis and treatment
➢ Cotrimoxazole, chloramphenicol in MSF and ET
➢ Fluoroquinolones in ET, MT, MSF
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REasy to treat…
If you can obtain the antibiotics
« Bonjour à tous,
Ce message pour vous annoncer l’arrêt de fabrication de la MINOCYCLINE 100MG
Il ne restait plus qu’un seul fournisseur qui nous explique la chose suivante :
« l’unique fabricant de ce produit ne peut approvisionner en raison d’une suspension unilatérale des fabrications d’un excipient dont le
fabricant est lié au dossier d’AMM »
Cette arrêt de fabrication nous est annoncé comme provisoire mais la variation du dossier d’AMM pourra prendre du temps pour un
produit qui reste peu utilisé ce qui ne présage rien de bon…
Il n’y a donc plus d’alternative en 50mg et en 100mg.
Ci-dessous les sorties par UF depuis le début de l’année 2017 (800 unités en 2017 soit 67/mois) - si les stocks sont justes il en reste 204
en stock »
UF QTITES 2017
8181 SURV.CONTINUE MAL.INFECTIEUSES-IHU 84
8180 HOSPIT.CONTAGIEUX-IHU 183
8170 HOSPIT.POST-URGENCE ET M.I.A.-IHU 7
8161 HOSPIT.MAL.INFECT.CHRONIQUES-IHU 43
5921 SURV.CONTINU.DET.RESP.INF.SEVERE-HN 14
5920 REA DETRESSE RESPI-INF.SEVERE-HN 30
5890 HOSPIT.CHIRURGIE THORACIQUE-HN 27
5783 HOSPIT.2 HEPATO-GASTRO-ENTERO-TA 14
5580 HOSPIT.PNEUMO.MAL.RESP.RARES-HN 334
3540 HOSPIT.CHIR.VASCULAIRE PIQUET-2TA 14
2952 REANIMATION BRULES-CO 17 U
R
2579 HOSPIT.TRANSPLANTATION RENALE-CO 7Easy to treat…
If you can obtain the antibiotics
➢ La VIBRAMYCINE N 100 mg cp à nouveau disponible après une
rupture de stock de presque 2 ans
La distribution de cette spécialité était interrompue en raison d'un
problème d'approvisionnement en matière
première. VIBRAMYCINE N 100 mg comprimé (doxycycline), boîtes de
5 (CIP 3400932499700) et de 30 (CIP 3400935599438) - Laboratoire
Sinclair Pharma : rupture de stock suite à un changement de fournisseur
de matières premières
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REasy to treat…
If you can obtain the antibiotics
➢ Pénurie d’ampoules Vibraveineuse® (doxycycline i.v.), rupture de
stock effective
Le laboratoire SERB, en accord avec l'Afssaps (Agence française de
sécurité sanitaire des produits de santé), signale la rupture de stock
effective de VIBRAVEINEUSE solution injectable pour voie intraveineuse
et perfusion (boîte de 1 ampoule de 5 ml).
Cette rupture de stock était envisagée depuis avril, en raison des
difficultés de production rencontrées.
Aucune date de remise à disposition normale n'est annoncée…
U
RThank you
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