nemoci-sympt/BAKTERIALNI-INFEKCE/chlamydie/antibiotika
Terapie
- Vhodné atb
- Ev. kombinace
- Dost dlouho
- V dostatečné dávce
- Podpora buněčné imunity
- Ki kortikoidy
Časté relapsy
- It may seem unlikely that doxycycline, roxithromycin and rifampicin can kill chlamydiae
- Considered to be bacteriostatic agents
- Normally they inhibit rather than kill bacteria
- Intracellular Chlamydia pneumoniae must continuously elaborate proteins to ensure its own survival within the host-cell [27]
- C. pneumoniae infection frequently recur after short or conventional courses of appropriate antibiotics
- Persistent infection has been documented by culture after treatment [25]
- Consequently, a relatively intensive long-term course of treatment is recommended. [25]
- If symptoms such as cough or malaise persist after one course of antibiotics, a second course may be useful. [25]
- Tetracycline or doxycycline is recommended for the second course [25]
- Infections may be prolonged
- Serious sequelae are rare
- Most patients are expected to completely recover from their infection [25]
- Eradication of C. pneumoniae during first infection is difficult
- Even with prolonged (up to 3–4 weeks) use of macrolides
- Length of treatment
- May be associated with the long life cycle of Chlamydia
- With the possibility of a quiescent phase in the replication of the bacterium [26]
- New macrolides and fluoroquinolones
- Clinical cure can be obtained with a shorter course of therapy
- Much more complex is the eradication of chronic infection
- Prolonged macrolide treatment of 6 weeks or more has been suggested
- Definitive proof of its efficacy is lacking
- To overcome the problem of the quiescent phase
- Multiple-injection therapy
- Multiple-drug regimens have been employed
- Macrolides or ketolides combined with fluoroquinolones [26]
Antibiotika citlivost
MIC determination
- Most investigators - MIC for second passage
- Harvesting the cells from duplicate plates run in parallel
- Disrupting and passing the cells onto new monolayers
- These cells are cultured in antimicrobial agent free media and stained with fluorescent antibody for inclusion counts
- The MIC for second passage is defined
- Lowest antibiotic concentration that results in no inclusions after passage [25]
- Synonyms:
- MCC (minimum chlamydicidal concentration)
- MLC (minimal lethal concentration)
- Methods for in vitro susceptibility testing of C. pneumoniae not yet standardized and vary:
- Type of tissue culture system
- Treatment of cells prior to testing
- Inoculum size
- Method for detection of inclusions [25]
Effective in the treatment of uncomplicated chlamydial infections
- Tetracyclines (TETs) [25]
- Macrolides
- Azithromycin (AZM) [1] [25]
- Azalides [25]
- 50% of genital C. trachomatis infections
- Resolve spontaneously within 1 year of testing [1]
C. pneumoniae isolates from vascular tissue in patients with atherosclerotic CAD
- Strains were no different than respiratory strains
- Susceptible to azithromycin, erythromycin, ofloxacin, doxycycline, and rifampin [24]
Perzistence k ATB
- Break in the normal chlamydial developmental cycle can result in
- Persistence
- Long-term infection that is refractory to antibiotic therapy [1]
- Remain in a viable but culture-negative state [22]
- “chronic” and “latent” are widely used as synonyms for persistent [22]
- Macrolides, tetracyclines, rifampin, and quinolones, are shown to induce persistence (Gieffers et al., 2004)
Persistent chlamydiae
- Characteristic gene and protein expression profiles
- Reduced levels of outer membrane proteins like Omp1 or OmcB [37]
- Blocked in the final RB-to-EB transition [37]
- Vznik perzistence
- Without additional support from the host immune system persistent and static bacteria remain viable and may resume normal growth [37]
- Treatment that target DNA or peptidoglycan synthesis
- Specifically inhibit RB-to-EB differentiation [38]
- Early addition of 200 U of penicillin/ml
- Targets peptidoglycan cross-linking
- Up to 12 h PI
- no effect on C. psittaci MN/Cal-10 development in L cells
- From that time onwards
- RB became enlarged and progressively more aberrant
- Transfer to penicillin-free medium
- Productive developmental cycle resumed and normal RB were produced [38]
Peristence chlamydií routinely induced in the lab (bakteriostatický efekt)
- Infected cells are exposed to
- ß-lactam antibiotics
- IFN-gamma
- Deprived of iron supplements [1] [38]
- Deprived of amino acids [1]
- Especially tryptophan deficiency [22] [38]
Chtěla jsem posílit, více sportovat a začala sem si dávat větší porce bílkovin a proteinové nápoje a krátce na to se mi silně zhoršily bolesti kloubů, pocit blokády a zánětu. Vysvětleních by mohlo být samozřejmě milion. Prostě najednou bylo dost materiálu pro bakterie i pro zánětlivou reakci na ně a místo divokého sportu se konalo jen divoké oblejzání rehabilitace a hledání pomoci.
- Monocyte infection [52]
- Phage infection [52]
- Continuous culture [52]
- Macrolides [54]
- Selective cycloxygenase inhibitors [54]
- Rottlerin [54]
- Pan-specific inhibitor of eukaryotic protein kinases
- Inhibit the growth of C. pneumoniae in HeLa cells
- May interfere with activation of the host MEK/ERK pathway
- Necessary for chlamydial cell invasion [54]
- Inhibitors of type III secretion [54]
- Prevent completion of the normal developmental cycle
- Resulting in aberrant, noninfectious forms of Chlamydia [22]
Persistent or ‘aberrant’ RBs - PB
- Continue to synthesize proteins and replicate DNA
- Halt cell division
- Inclusions contain small numbers of very large aberrant RBs
- Prolonged infection by viable but nonculturable chlamydia
- PB is an abnormally large form of chlamydia
- Inability to segregate into daughter cells after genomic DNA replication
- Arrest of the developmental cycle at the PB stage can be reversed
Snížená exprese
- Selective down-regulation of late-stage-specific genes
- Type III secretion genes
- 60-kDa cysteine-rich protein (CRP)
- Abundant in EB envelopes
- Completely absent in C. trachomatis strains exposed to
- ß-lactam ATB
- IFN-?
- Heat shock
- Hc-1 and Hc-2 DNA-binding proteins (TR)
- Involved in chromosomal condensation
- IFN-?-exposed [39]
- HctB/Hc-2 down-regulation
- Currently appears to be a more reliable marker of persistence (TR) [39]
- Genes involved in :
- RB to EB differentiation
- Late genes such as hctAB and omcAB [52]
- Proteolysis
- Peptide transport
- Cell division [52]
- Aberrant RBs in that cells were blocked in cytokinesis
- Developmental cycle was arrested at a point preceding late gene expression [52]
Removal of IFN-? and supplementation with added tryptophan
- Rapid reactivation from persistent growth [52]
- Expression differences rapidly returned to control levels
Možnost obnovy vyšší citlivosti k dalším ATB ???
Up-regulace
- Up-regulation of ompA/MOMP (PN) [39]
- tryptophan utilization [52]
- DNA repair and recombination [52]
- Phospholipid biosynthesis and translation [52]
- Up-regulation of the repressible trp BA operon [52]
- IFN-? treatment reduces intracellular concentrations of tryptophan [52]
- Euo gene (30-fold increase)
- Encodes a DNA-binding protein
- Bind to a late gene promoter region (i.e. omcAB ) [52]
Removal of the stressor
- Septum formation
- RB division
- Differentiation to EBs
ß-lactamová antibiotika indukují perzistenci chlamydií
- Ampicillin and penicillin
- Have high MICs on first passage
- Relatively low MICs on second passage
- Beta-lactams inhibit the production of infectious particles
- Inhibition of the maturation of RB to EB
- Do not completely inhibit the replication of RB [25]
- High concentrations of antibiotic are required to produce the complete absence of inclusions for the MIC on first passage [25]
- no effect on Chlamydia viability
- Can inhibit infectivity [26]
- The ß-lactam target is the bacterial cell wall, a structure absent in chlamydiae [26]
- Inhibit the synthesis of peptidoglycan
- Interrupt the developmental cycle
- By preventing the maturation of reticulate bodies into elementary bodies
- If these antibiotics are removed, development proceeds normally (Bergey et al. 2011) [148]
Peniciliny
- Historically recommended for T. pallidum and N. gonorrheae
- But treatment of chlamydial infections with these antibiotics induces chlamydia to become persistent [1]
- May exacerbate disease in the genital tract
- Lead to treatment failure and long-term complications
- Carefully evaluated broad spectrum antibiotic therapies for bacterial genital tract infections are recommended [1]
- Penicillin treatment
- Dramatic change in the bacterial cell structure
- Can suspend the developmental lifecycle and trigger a persistent state [1]
- Persistent chlamydia
- Became phenotypically resistant to AZM clearance after initial exposure to penicillin [1]
- Inhibition of the cross binding of PG chains
- Do not have a remarkable effect on Chlamydias
- Lacking peptidoglycan (PG) in their cell walls (Garrett et al., 1974; Newhall & Jones, 1983)
- Chlamydias have some susceptibility to anti-PG antibiotics
- Phenomenon known as “chlamydial anomaly”
- Has been shown that there is functional PG in the cell wall of Chlamydia trachomatis (Liechti et al., 2014)
- Chlamydias have penicillinbinding proteins
- Somewhat sensitive to drugs that inhibit PG synthesis (Barbour et al., 1982)
Erythromycin macrolide
- Added prior to infection
- Blocked EB to RB differentiation [1]
- Added 18 or 24 h postinoculation
- RBs to enlarge and blocked differentiation to EBs [1]
- 10 µg of erythromycin/ml - low dose
- Reduces ribosome activity
- Inhibited C. trachomatis serovar A EB-to-RB differentiation in McCoy cells when added within 12 h PI [38]
- Erythromycin applied at later times
- Enlarged RB that could not differentiate to EB [38]
Antibiotická rezistence
- The infection is often chronic, asymptomatic, and persistent
- Chlamydiae-infected patients may thus be exposed to intermittent, incomplete, or recurrent antimicrobial treatment episodes
- Promote resistance in C.p. and other chronic intracellular infections such as mycobacterial infections [23]
- In vitro resistance to antibiotic stressors
- Accumulation of point mutations circulated among strains via
- Horizontal gene transfer
- Homologous recombination [1]
- Stable antibiotic resistance remains undetected in human chlamydial isolates, despite significant selective pressures
- Relative resistance of Chlamydiae to alterations of genome structure
- Challenging in vivo to dif. dg. persistence x resistance [1]
- Uncomplicated infections quite responsive to antibiotics
- Genital, ocular and respiratory infections that fail to respond to antibiotic treatment extensively documented
- Poor therapeutic control of aberrant, persistent Chlamydiae in patients [1]
- Distinguish persistence from
- X treatment compliance
- Re-infection
- Antibiotic resistance [1]
Natural resistence
Sulfonamidy
- C. trachomatis, C. pneumoniae is resistant to sulfonamides
- Chlamydia suis are sensitive to sulphonamides, whereas other species are resistant (Bergey et al. 2011) [148]
Ostatní
- Chlamydial multiplication is not blocked by
- Aminoglycosides
- Bacitracin
- Vancomycin (Bergey et al. 2011) [148]
Částečná aktivita
Chinolony
- Older quinolones
- Oflaxacin
- Not highly active against C. pneumoniae [25]
- Newer quinolone agents
- Sparfloxacin, grepafloxacin, gatifloxacin, and gemifloxacin [25]
- Comparable to macrolide agents in MIC ranges [25]
Heterotypic resistance
- Form of phenotypic resistance
- Small proportion (<1–10%) of an infecting microbial species is capable of expressing resistance at any one time
- Also described in Staphylococcus spp.
- Drug indifference, persistence, tolerance, properties of biofilms etc. [1]
Tolerance
- Often specific to antibiotics that affect cell wall synthesis
- Shown in the penicillin persistence model of Chlamydiae [1]
Multistage development resistence
- Asynchronous differentiation of RBs to EBs
- Begins relatively early
- Continues throughout the developmental cycle
- Midstage inclusion
- Harbor actively dividing RBs
- As well as nondividing EBs
- Can ensure the survival of a subset of the population
- Regardless of the timing of antibiotic or metabolic stress [1]
- Inclusions of varying developmental stages will be present at any given time
- Standard MIC assay synchronizes the infection
- Applies antibiotics within 1–2 h post infection
- Long before EB differentiation can be observed
- Chlamydia are most vulnerable in the log-phase of growth prior to EB differentiation
- Capable of expressing phenotypic resistance when both replicating and nonreplicating forms are present
AZM, clarithromycin, levofloxacin and ofloxacin
- Approach 100% inhibition in synchronized assays
- In a continuous model of C. pneumoniae infection
- None of these antibiotics eliminated the organism
- Even in concentrations greater than four-times their minimum inhibitory concentrations (MICs) [1]
Ciprofloxacin and ofloxacin
- Failed to eradicate C. trachomatis in infected cells
- Induced persistence when applied to established infections (2–3 days post infection) [1]
Horziontální /laterální přenos genů pro rezistenci
- Co-infected and grown in the presence of RIF and OF
- ofloxacin (OF)-resistant C. trachomatis L1 strain - mutation in gyrA (T249->G)
- RIF-resistant C. trachomatis D/UW-3/CX strain - mutation in rpoB (C1400->T)
- A RIF- and OF-resistant C. trachomatis D strain isolated - carried both the gyrA (T249->G) and the rpoB (C1400->T) mutations [1]
- Lateral gene transfer
- Resistance was stable in recombinants [1]
- Routine transfer of TET resistance from C. suis to any of
- Several C. trachomatis strains
- Mouse-tropic C. muridarum [1]
Fusogenic inclusions when occupying the same cell
- C. suis, C. trachomatis and C. muridarum IncA+
- An important protein involved in homotypic inclusion fusion
- Nonfusogenic strains of C. trachomatis that lack IncA
- But still recombine in vitro when subjected to the same selection parameters !!! [1]
Nová atb
- All the new antichlamydial agents in early clinical development
- Only slight modifications to the existing antibiotics (Golparian et al., 2012; Gebremedhin, 2012; Georgopapadakou, 2014; Chotikhanatis et al., 2014; Kohlhoff et al., 2014; van Bambeke, 2015)
- Therefore susceptible to cross-resistance.
Autoimunitní aspekty chronické infekce
- Nedostatečný efekt terapie antibiotiky u chronických perzistujících infekcí může svědčit o již probíhajícím autoimunitním procesu
- K ovlivnění je nutno hledat jiné léčebné postupy než antibiotika, např. imunoterapii [121]
- Auto Ig proti lidskému Hsp60 !
- „IgA-itis“
- Stěhovavé myalgie, artralgie
- Nevýkonnost
- Oprese na hrudníku
- únavový syndrom
- Neurastenické ladění [121]
Aminoglycosides
- Interfere with translation initiation
- Interacting with the 30S ribosome
- Poor penetration into mammalian cells
- MIC values for Chlamydiae that are extremely high (~1 mg/ml)
- Kasugamycin (KSM) and spectinomycin (SPC)
- Used to generate aminoglycoside-resistant chlamydial strains in the lab
- Passage of infected cells in concentrations greater than the MIC led to selection for C. psittaci 6BC at a frequency of approximately 2.3 × 10-5
- Resistant strains carried mutations in the 16S rRNA gene at the KSM binding site
- Resistance was present against all tested aminoglycosides.
- Chlamydia trachomatis strains resistant to KSM
- Selected in sub-inhibitory concentrations
- Did not have a mutation in the 16S rRNA
- Carry a two-nucleotide insertion in ksgA
- Encodes a protein (KsgA)
- Responsible for post-transcriptional methylation of ribosomal adenosine residues in other bacteria
- Resistant C. psittaci strain
- Grew comparable to wild-type strains
- Mutant was severely impaired for growth
- Was sensitive to high concentrations of antibiotic [1]
- Subinhibitory concentrations of SPC
- Selected stable resistance in C. psittaci
- Some of these mutant genes conferred resistance to SPC in E. coli
- Spectinomycin-resistant C. trachomatis
- A single mutation in an organism encoding more than one rRNA operon is typically recessive [1]
Ansamycins
- Inhibit the bacterial DNA-dependent RNA polymerase [14]
Benzoxazinorifamycin (rifalazil)
- 10–1000-fold more active than azithromycin against C. pneumoniae [14]
- Long plasma and tissue half-life
- Permitting once-weekly treatment
- Does not interact with the cytochrome P450 system
- Currently undergoing clinical evaluation for treatment of C. pneumoniae in atherosclerosis
- PROVIDENCE-1 (Prospective Evaluation of Rifalazil Effect On Vascular Symptoms of Intermittent Claudication and Other Endpoint) trial
- Phase III multinational randomized double-blind placebo-controlled trial
- In C. pneumoniae-seropositive patients with PAD (peripheral artery disease)
- Preliminary negative results reported in abstract form at the American Heart Association Scientific Sessions, November 2007
- The RESTORE-IT (Randomized Evaluation of Short-Term Rifalazil Treatment on Carotid Atherosclerosis and Intima Media Thickness) trial
- Phase II multicentre randomized double-blind placebo-controlled trial
- Recruiting C. pneumoniae-seropositive patients with PVD, cerebrovascular disease or CAD
- Receive rifalazil or placebo once a week for 12 weeks
- Will be followed for 18 months with serial MRI (magnetic resonance imaging) and ultrasound
- Determine carotid artery intima-media thickness (at 6, 12 and 18 months)
- Results are expected in late 2008 [14]
- Inhibits bacterial DNA-dependent RNA polymerase [26]
- MIC values of benzoxazinorifamycins for chlamydiae are in the microgram per litre range [26]
Azalides
- Inhibited growth of Chlamydias in culture [148]
Fluoroquinolones
- Bactericidal antibiotics
- Target DNA gyrase and topoisomerase IV
- Essential enzymes for controlling the topological state of DNA replication and transcription
- DNA gyrase
- Composed of subunits A and B
- Encoded by the gyrA and gyrB genes
- Catalyzes ATP-dependent negative supercoiling of DNA [16]
- C. trachomatis, C. muridarum and C. suis
- Develop quinolone resistance in vitro
- When exposed to subinhibitory concentrations
- After only four passages in 0.5 µg/ml of ofloxacin
- C. trachomatis MIC increased from 1 to 64 µg/ml
- Similar result after four passages in the presence of 0.015 µg/ml of sparfloxacin
- Similar mutations associated with passage of C. trachomatis in the presence of quinolones
- Number of passages required to select for resistant mutants varied between four and 24
- Wide antimicrobial spectrum
- Potent activity against C. pneumoniae
- Expected to be useful in the treatment of infectious diseases caused by C. pneumoniae [16]
Quinolone-resistant strains
- Resistant to multiple derivatives
- Carried the same point mutation
- Quinolone-resistance determining region of gyrA
- Attempts to generate fluoroquinolone-resistant C. pneumoniae
- Unsuccessful for one group
- Cultivate moxifloxacin-resistant C. pneumoniae
- Amino acid substitution at the same nucleotide position of gyrA as other fluoroquinolone-resistant C. trachomatis isolates
- Natural quinolone resistance
- Mutations in the quinolone-resistance determining region of gyrA
- In C. muridarum, Parachlamydia acanthamoebae, Neochlamydia hartmannellae, Simkania negevensis and Waddlia chondrophila
- Associated with respiratory disease in humans [1]
Levofloxacin
- More active than ofloxacin and ciprofloxacin
Oxacilin
- Reported the clinical response of pneumonia and bronchitis caused by C. pneumoniae to ofloxacin [25]
- Four patients ofloxacin 400 mg 2xd for 10 days appeared to respond clinically [25]
Moxifloxacin
- Treatment of community-acquired pneumonia
- Shown persistence of C. pneumoniae in nasopharyngeal specimens in a minority of patients
- The MIC of moxifloxacin for three strains of C. pneumoniae was 0.6 mg/L
- Minimal chlamidiacidal concentration values ranged from 0.06 to 0.125 mg/L [27]
Garenoxacin (T-3811, BMS-284756) (Geninax(®) Tablets 200 mg)
- Garenoxacin had the most-potent inhibitory activity against DNA gyrase [16]
- Against atypical pneumonia
- October 2009 and July 2011 community-acquired pneumonia - 26 facilities in Japan
- Survey forms from 105 of these patients
- Confirmed diagnosis of atypical pneumonia were 94.8% (55/58 patients) and 92.3% (12/13 patients)
- Incidence of adverse drug reactions
- (including abnormal laboratory tests) was 4.8% (5/105 patients)
- Gastrointestinal disorders 2.9% of patients (3/105)
- Infection and infestation 1.0% (1/105)
- Nervous system disorder 1.0% (1/105)
- Skin and subcutaneous tissue disorder 1.0% (1/105) [103]
- Garenoxacin showed an efficacy rate of greater than 90% for suspected atypical pneumonia and confirmed atypical pneumonia [103]
Gatifloxacin
Nemonoxacin (TG873870)
- Novel broad spectrum non-fluorinated quinolone
- Antichlamydial activity
- Against the both species (Chotikanatis et al., 2014)
- Differs from fluoroquinolones
- Lacks fluorine atom in R6 position
- Over ten-fold increase to the DNA gyrase inhibiting effect
- Can decrease MIC-values 100-fold
- Against C. trachomatis was 2-fold lower than that of azithromycin
- Against C. pneumoniae it was comparable to azithromycin
Chloramphenicol
- Inhibited growth of Chlamydias in culture [148]
Fluoroquinolones
- Bactericidal antibiotics
- Inhibit DNA gyrase and DNA topoisomerase IV
- In turn inhibits duplication of bacterial DNA
- C. trachomatis, C. muridarum and C. suis
- Develop quinolone resistance in vitro
- When exposed to subinhibitory concentrations
- After only four passages in 0.5 µg/ml of ofloxacin
- C. trachomatis MIC increased from 1 to 64 µg/ml
- Similar result after four passages in the presence of 0.015 µg/ml of sparfloxacin
- Similar mutations associated with passage of C. trachomatis in the presence of quinolones
- Number of passages required to select for resistant mutants varied between four and 24
- Good ability of penetrating into tissues
- Interfering with the bacterial type II DNA topoisomerases:
- DNA gyrase encoded by gyrA and gyrB
- Topoisomerase IV encoded by parC and pare
- Topoisomerases function by
- Forming protein-bridged DNA double strand breaks (DSBs)
- Manipulating DNA strand topology
- Rejoining the ends of the DNA
- Reversibly bind to the protein-bridged DSB intermediates
- Inhibit the rejoining of the DNA ends
- Cell death results from
- Creation of free DSBs when the topoisomerase dissociates from the DNA without rejoining the DNA ends
- DNA replication is inhibited by covalent DNA-protein complexes
- Potentially by the induction of suicide proteins
Gatifloxacin
Levofloxacin
- More active than ofloxacin and ciprofloxacin
Moxifloxacin
- The MIC of moxifloxacin for three strains of C. pneumoniae was 0.6 mg/L
- Minimal chlamidiacidal concentration values ranged from 0.06 to 0.125 mg/L [27]
- Fourth-generation fluoroquinolone
- Effective against
- Gram-positive (Streptococcus pneumoniae)
- Gram-negative (Haemophilus influenzae, Moraxella catarrhalis)
- Atypical strains (Chlamydia pneumoniae, Mycoplasma pneumoniae)
- Multi-drug resistant S. pneumoniae
- Including strains resistant to penicillin, macrolides, tetracyclines, trimethoprim/sulfamethoxazole and some fluoroquinolones
- Highly concentrated in lung tissue
- Rapid eradication rates
- Bioavailability and half-life of moxifloxacin provides potent bactericidal effects at a dose of 400mg/day
- MIC of moxifloxacin is the highest among the fluoroquinolones against S. pneumoniae
- Faster resolution of symptoms in CAP (community acquired pneumonia) with first-line therapy
- Better eradication in exacerbations of CB (chronick bronchitis) compared with standard therapy, in particular the macrolides [166]
Oxacilin
- Reported the clinical response of pneumonia and bronchitis caused by C. pneumoniae to ofloxacin [25]
- Four patients ofloxacin 400 mg 2xd for 10 days appeared to respond clinically [25]
Moxifloxacin
- Treatment of community-acquired pneumonia
- Shown persistence of C. pneumoniae in nasopharyngeal specimens in a minority of patients
AZD0914
- Novel DNA gyrase inhibitior
- Developed by Astra Zeneca
- Promising activity against Chlamydia pneumoniae and Chlamydia trachomatis in vitro (Kohlhoff et al., 2014)
- Comparable to levofloxacin
- 16-fold less than the gold standard, azithromycin
- Based on MIC90 values
- Minimal chlamydiacidic value were remarkably lower than that of azithromycin
- Higher recovery rates of the isolates after the treatment
- Depends on the outcome of clinical studies assessing microbiological efficacy
Delafloxacin
- A novel fluoroquinolone
- Lacking a basic substituent in position 7
- Low MIC values against gram-positive and gram-negative bacteria
- Including atypical pathogens such as C. pneumoniae (van Bambeke, 2015)
- Recently evaluated in Phase III trials
- Qualified for the treatment of community-acquired bacterial pneumonia (CAP)
- High activity on pneumococci and atypical pathogens
Sitafloxacin (DU-6859a)
- A new-generation oral fluoroquinolone
- Broad range in vitro activity against gram-positive and -negative bacteria
- Approved in Japan in 2008 (Ghebremedhin, 2012)
- Caucasian population its use is currently limited
- Potential for ultraviolet A phototoxicity
Levofloxacin
- No viable C. pneumoniae were detected in infected HEp-2 cells when the monolayer was treated with levofloxacin immediately after infection (0 h) [147]
- Treated 24 h after infection, a gradual decline in the number of viable C. pneumoniae occurred; [147]
- By 96 h into the assay 98% of C. pneumoniae were killed [147]
Quinolone-resistant strains
- Resistant to multiple derivatives
- Carried the same point mutation
- Quinolone-resistance determining region of gyrA
- Attempts to generate fluoroquinolone-resistant C. pneumoniae
- Unsuccessful for one group
- Cultivate moxifloxacin-resistant C. pneumoniae
- Amino acid substitution at the same nucleotide position of gyrA as other fluoroquinolone-resistant C. trachomatis isolates
- Natural quinolone resistance
- Mutations in the quinolone-resistance determining region of gyrA
- In C. muridarum, Parachlamydia acanthamoebae, Neochlamydia hartmannellae, Simkania negevensis and Waddlia chondrophila
- Associated with respiratory disease in humans [1]
Ketolidy
- Ketolide class of antibacterial agents
- 14-membered ring macrolides
- Differ from erythromycin A
- Have a 3-keto group instead of the l-cladinose moiety in the lactone ring
Telithromycin
- First ketolide for clinical use [15]
- 800 mg once daily for 7–10 days good clinical efficacy against CAP due to C. pneumoniae
- Diagnosis of C. pneumoniae infection based entirely on serology, not culture [15]
- Attractive additions to antibacterial tool kit for mild-to-moderate CAP (Georgopapadakou, 2014)
- Sanofi-Aventis’ telithromycin (RU 66647, HMR 3647, Ketek®),
- Withdrawn from clinical development
- Controversial FDA approval concerning rare, irreversible hepatotoxicity that included deaths
Cethromycin (formerly ABT-773)
- Cyclic carbamate group at the 11, 12-position in addition to the 3-keto group
- Exhibits good antibacterial activity against a broad range of respiratory pathogens
- Including multiresistant Streptococcus pneumoniae
- Staphylococci
- Haemophilus influenzae
- Moraxella catarrhalis
- Legionella spp.
- Mycoplasma pneumoniae [15]
- In vitro activity of macrolides and telithromycin against C. pneumoniae is variable
- clarithromycin showing the lowest MICs
- Followed by telithromycin, azithromycin and erythromycin [15]
- Data on the activity of cethromycin against C. pneumoniae are limited [15]
- Cethromycin for treatment of C. pneumoniae pneumonia
- 100% efficacy in eradication of the organism from the nasopharynx of patients with CAP [15]
- Attractive additions to antibacterial tool kit for mild-to-moderate CAP (Georgopapadakou, 2014).
- Originally developed by Abbott
- Completed phase III clinical trials
- Filed New Drug Application,
- Denied by the FDA in 2009
Modithromycin (EDP-420)
- Currently in Phase II in Japan
Solithromycin (CEM-101)
- Recently entered clinical trials (Golparian et al., 2012)
- MIC90 values against both C. pneumoniae and C. trachomatis were only two-fold less than that of azithromycin (Roblin et al., 2010)
Lincosamides
- Lincomycin
- Bacteriostatic protein synthesis inhibitor
- Causes premature dissociation of peptidyl-tRNA from the ribosome [1]
- In vitro-generated lincomycin-resistant C. trachomatis mutants
- Recovered at very low frequencies (<5 × 10-10)
- By growing and passaging infected cells in subinhibitory concentrations of antibiotic
- Mutations in both 23S rRNA genes
- Corresponding to sites in E. coli that conferred similar resistance [1]
Macrolides
- Clinical studies on erythromycin A, clarithromycin and azithromycin
- Cultures were carried out
- Effective drugs for the treatment of respiratory infection associated with C. pneumoniae [15]
- Macrolides are potent weapons for slowering evoluting atherosclerotic processes
- Able to provoke arterial thrombosis
- Eradication therapy by antibiotics has to be continued for years and years [67]
- With arrests becoming shorter and shorter [67]
Rezistence k makrolidům
- Mutation of the 23S rRNA at the macrolide contact site
- With single copies of the rRNA in their genome
- Usually leads to high-level resistance [23]
- Demonstrated to occur in C. trachomatis
- Methylation of this site by adenine N-methyltransferase enzymes encoded by the erm gene family
- Mutation of the L4 or L22 ribosomal protein that is expected to contact the macrolides
- Development of various degrees (4x) of macrolide resistance in
- Escherichia coli
- Bacillus subtilis,
- Streptococcus pneumoniae
- C. trachomatis
- Some L22 mutants of were also associated with clinical failure [23]
- Drug efflux pump mechanism [23]
Nízké koncentrace azithromycinu or clarithromycinu
- In continuously infected HEp-2 cells prevented host cell lysis
- Initial increase in the inclusion number
- This early increase in inclusions could be interpreted as nonefficacy of the drug in a short-term MIC assay [23]
- Only at later time points did these more typical inclusions disappear almost completely [23]
- Inclusions that were seen became progressively irregular in the low-dose-macrolide-treated host cells
- Not like the “atypical inclusions” described in the chronic-infection model without antibiotics [23]
- Inclusions stain less intensely
- Appear amoeboid
- Seem to have a disrupted border
- Similar inclusions have also been noted after azithromycin treatment of an established C. trachomatis infection
- Much of the chlamydial lipopolysaccharide detected by antibody appears to be extracellular
- As infectious elementary bodies
- Or, more likely, as debris [23]
Takže se nemusí jednat nutně o perzistenci, když se zmenší a změní Chlamydiové inkluze, ale stačilo by vytrvat v léčbě - lépe s vyšší dávkou - a vyléčení by se mohlo dostavit.
- Stable viable chlamydiae could not be recovered after the macrolide regimens
- Despite an initial successful round of replication after removal of the drug
- Some residual macrolide was being transferred in these assays, leading to continued inhibition of chlamydial development
- Effects of macrolide levels below the MIC on the continuously infected cultures
- Similar to those of high levels (at least 16 times the MIC)
- Comparable to those found in the lung after typical dosing regimens
Postantibiotický efekt dovolující pauzu v dávkování ?
- Macrolides should be quite potent against C. pneumoniae in vivo, if levels were maintained long enough [23]
- May not apply to monocytes
- Documented failures of eradication
- Sanctuary sites, which are unable to concentrate macrolides ? [23]
Makrolidy x chinolony
- Azithromycin treatment of C. trachomatis infection (at the minimal bactericidal concentration)
- Led to loss of infectivity
- Quinolone treatment of C. trachomatis
- Seemed to maintain viable chlamydiae after drug withdrawal
- Disruption of chlamydial development by macrolides
- Seems to be more complete than that which occurs with quinolones
- Perhaps is less likely to allow opportunities for resistance to develop
- May occur because of intraepithelial cell concentration of the macrolide drugs
- Effectively higher drug exposure [23]
- Repeated passage in subinhibitory concentrations of various antibiotics including macrolides
- Reproducibly induces resistance in other bacteria
- C. pneumoniae is different from C. trachomatis and other bacteria
- High-level resistance to ofloxacin and sparfloxacin
- In C. trachomatis after 4 passages in sub-MIC (50%) of the drugs [23]
- Resistance to ofloxacin and ciprofloxacin
- In C. trachomatis after more than 30 passages in sub-MIC quinolones
- But not in C. pneumoniae [23]
- Sparfloxacin
- Viable forms of C. pneumoniae seemed to occur after passage
- But could not be propagated [23]
- High-level antibiotic resistance very readily (1/8 MIC) in vitro chronic-infection model [23]
Clarithromycin
Dávkování
- Dospělí: 500 mg 2xd for 10 - 14 days [25]
- Pediatric 7.5 mg/kg/day divided twice a day [25]
Azithromycin
- Především azithromycin a klarithromycin jsou dva makrolidy, u kterých byla in vitro prokázána vysoká aktivita proti C.p.
- Azithromycin dosahuje vyšších koncentrací v alveolárních makrofázích
- Vede k signifikantnímu nárůstu fagocytózy apoptotických epiteliálních buněk a neutrofilů alveolárními makrofágy [121]
- Vyšší dávky azithromycinu snižují i hladinu prozánětlivých cytokinů [121]
- Attach to the bacterial ribosome 50S subunit
- Inhibiting protein synthesis at translocation phase
- Azithromycin is the most capable of transferring into tissues
- And also accumulating into white blood cells
- Gold standard in the treatment of C. pneumoniae
- Bacterial protein synthesis inhibitor
- Front-line drug for the treatment of chlamydia infections
- High-level resistance to AZM was selected
- C. psittaci 6BC
- C. caviae GPIC
- C. trachomatis L2 strain
- Selected for in lower concentrations of AZM
- Cultivation of resistance was unsuccessful in C. pneumoniae clinical isolates with elevated MICs to AZM [1]
- AZM-resistant C. psittaci strains
- Also resistant to other macrolides as well as a lincosamide
- Share similar 23S rRNA target sites
- Resistant strains were stable and survived passage in the presence and absence of these drugs
- Modestly resistant (AZM tolerant) C. trachomatis strain
- Isolated only after exposure to subinhibitory concentrations of antibiotic
- Harbored a mutation in rplD that encodes the ribosomal protein L4
- In vitro AZM resistance imposes a competitive defect
- Resistant C. psittaci
- Delayed in their differentiation from EB to RB compared with wild-type strains
- Slower doubling rate
- Produced significantly smaller plaques
- Outcompeted in the absence of selection by the wild-type parent strain
- Drug-tolerant C. trachomatis strain
- Did not grow well in the absence of antibiotics
- Formed smaller plaques
- Produced fewer infectious particles than wild-type parent strains
- C. caviae AZM resistant strains
- Mutations in the 23S rRNA of their single rRNA operon
- Produced fewer infectious particles in vitro
- Were less fit in vivo, compared with the wild-type strain [1]
- Clinical isolates of C. pneumoniae, from two patients with pneumonia
- Stable fourfold increase in the MIC of azithromycin developed after treatment [23]
- Isolates were obtained at days 0 and 18 after starting azithromycin therapy
- Increase in the MIC of azithromycin and erythromycin from 0.031 to 0.125 µg/ml [23]
- Isolates obtained at 0, 9, and 37 days after starting therapy
- MIC of azithromycin increased from 0.062 to 0.250 µg/ml for the latter isolates
- Higher MICs still overlapped those for other wild-type C. pneumoniae isolates
- MICs were stable upon subculture in antibiotic-free medium [23]
- Induce macrolide resistance by prolonged exposure of C. pneumoniae to macrolides
- In a standard model of acute C. pneumoniae infection
- In vitro models [23]
- Macrolide and fluoroquinolone
- Possess anti-inflammatory activities
- Despite the insufficient effects of these antibiotics on chlamydia eradication
- Might significantly attenuate the formation of autoimmune responses against self-Hsp60 [100]
- Diabetic, smoking male patients gained significantly from the treatment
- Treatment was started within 48 hours after an acute cardiac event
- Positive impacts of the treatment on the cardiovascular end points [100]
- The half-life period of azithromycin is up to 68 hours
- With clear target-cell effect
- Make use of phagocytic cells as carriers for drug movement to the inflamed part, to improve its concentration over sixfold.
- Actual clinical curative effect of azithromycin may be more effective than the result in vitro
- Azithromycin has been a choice drug of MP infection clinically
- Combined treatment of clindamycin and azithromycin is better than the individual use of azithromycin [174]
Dávkování azitromycinu
- For treatment of community-acquired pneumonia in children 6 months - 16 years
- 36 of 456 (8%) of children had C. pneumoniae isolated from pre-treatment nasopharyngeal cultures
- Eradicated after treatment in 19 of the 23 (83%) [25]
- Open study of azithromycin (1.5 g total oral dose over 5 days) for community-acquired pneumonia in adults
- C. pneumoniae infection was identified by culture in 10 of 48 (21%) patients at enrollment
- Seven of those 10 patients were culture-negative after treatment
- Persistently infected patients had an MIC four times higher (0.25 µg/mL vs. 0.062 µg/mL) than at enrollment
- Although the higher MIC was still within the range considered to represent antibiotic susceptibility
- All patients improved clinically
- Azithromycin and clarithromycin are likely to be at least as effective as doxycycline or erythromycin
- Achieve high tissue and intracellular levels
- Demonstrated effective against C. pneumoniae in vitro
- Better tolerated than erythromycin
- Fewer gastrointestinal side effects
- Adults 500 mg on day one, then 250 mg /d for 2 - 5 days [25]
- Pediatric 5-12 mg/kg 1xd [25]
Glucocorticoid treatment combined with azithromycin
- Immunosuppressive cortisone during persistent infection reactivate chlamydia infection in mouse lungs
- Followed by antimicrobial treatment, might be useful in eradicating persistent chlamydia
- Concurrently for four days, starting four days after inoculation
- Combination was significantly more active in reducing chlamydia in lungs compared to azithromycin alone !!! [100]
- Treatment of rabbits with azithromycin after three repeated C. pneumoniae inoculations
- Decreased significantly the infection-induced intimal thickness of the thoracic aortas and the plaque area index
- Early azithromycin or clarithromycin treatments
- Started five days after an initial inoculation
- Versus delayed treatment started two weeks after a third C. pneumoniae inoculation
- Early treatment had a superior effect in lesions of atherosclerosis
- Delayed treatment with azithromycin
- Even seemed to increase the presence of chlamydial antigens in the aortic segments [100]
Erythromycin
Dávkování
- Erytromycin 500 mg 4xd for 14 days
- Erythromycin 250 mg 4xd for 21 days may be used if the higher dose is not tolerated
- Erythromycin (30-50 mg/kg/day divided q 6h) is the drug of choice in younger children [25]
- Many patients treated with 1 gm of erythromycin p.o./d for 5 - 10 days
- Did not have resolution of symptoms
- This therapy was inadequate [25]
- Grayston et al. then recommended
- 2 g of tetracycline/d for 7 - 10 days
- 1 gm / day for 21 days [25]
- Randomized controlled trial children 3 - 12 years - RTG+ community-acquired pneumonia
- clarithromycin (15 mg/kg per day for 10 days)
- Erythromycin suspension (40 mg/ kg of body weight per day for 10 days)
- 260 children enrolled in the study
- 74 (28%) had evidence of infection with C. pneumoniae - PCR + = bacteriologic eradication was documented in:
- 79% (15/19) - clarithromycin
- 86% (12/14) erythromycin [25]
- MICs to erythromycin and clarithromycin of isolates obtained from children positive both before and after therapy did not change during treatment
- Children with persistent infection improved clinically, with complete resolution of the chest x rays [25]
Roxithromycin
- Treatment of C. pneumoniae seropositive men
- For one month
- Prevented the progression of peripheral arterial occlusive disease during a follow-up period of 2.7 years
- 30 days of roxithromycin therapy
- Less progression of intima-to-media thickness (IMT) of the common carotid artery
- In patients with ischemic stroke [100]
- Two years patients with C. pneumoniae IgG antibodies (?1:64) showed significantly decreased IMT
- IMT progression was to similar values as before the treatment during the third and fourth follow-up years [100]
- Roxithromycin for 28 days
- Less growth of abdominal aortic aneurysms during the follow-up of 18 months [100]
Metronidazol
- Development of resistance to metronidazole is possible but unlikely
- Reduced to highly active metabolites
- Break the DNA at the AT base pairs
- Breaks are single-stranded
- Bacterium has a mechanism called the SOS 'last ditch' system
- Repairs DNA breaks
- Pushing in any base-pair which comes
- System is mutagenic
- Most mutations are neutral or deleterious
- Mutation delivering resistance is possible
- The SOS DNA repair system requires the production of at least 15 unique proteins
- Block by protein-synthesis inhibiting antibiotics:
- Doxycycline
- Macrolide
- Rifamipicin [45]
- Low danger of developing resistance to metronidazole during use of protein-synthesis inhibitors
- Can be given in cautious intermittent pulses [45]
Rifamycins
Rifampin (RIF)
- Bactericidal antibiotics
- Interact with the ß-subunit of RNA polymerase
- Inhibit bacterial transcription
- Possess strong in vitro activity
- Therapeutic option in the treatment of clinical infections
- Rapid emergence of resistance in vitro in C. trachomatis, C. pneumoniae, C. caviae, C. psittaci, C. suis and C. muridarum
- After exposure to subinhibitory concentrations of drug [1]
- Amino acid substitutions in the RNA polymerase (RNAP) ß-subunit
- Decrease the binding capacity of RNAP to RIF
- Allows bacterial survival even under high concentrations of drug
- Many bacterial species develop resistance
- Nucleotide changes in the RNAP ß-subunit gene, rpoB
- RIF-resistant Chlamydiae
- Variety of conserved and unique nucleotide changes in the central region of rpoB
- Singular amino acid substitution
- Leads to low-level resistance
- Acquisition of an additional substitution
- Increases the MIC several fold
- Single mutations increased the MIC from 0.008 µg/ml
- To between 0.5 and 64 µg/ml in C. trachomatis serovar D
- To between 4 and 64 µg/ml in serovar K
- The nucleotide at position 471 of rpoB (Escherichia coli position 526)
- Most common site mutated in resistant clones of C. trachomatis serovars D and K
- This nucleotide change in combination with one additional mutation
- MIC increased from 64
- To 512 µg/ml for a serovar D
- To 256 µg/ml for a serovar K [1]
- RIF-resistant C. pneumoniae strains
- Increases in resistance were modest
- Often took repeated passage for success
- Associated with mutations in rpoB [1]
Rifampicin
- Semisynthetic rifamycin derivative
- High efficacy against C. trachomatis infections in clinical trials
- Effective in vitro against C. pneumoniae
- Develop resistance to RZL when passaged in subinhibitory concentrations of the drug and acquire mutations in rpoB [1]
- Strains of C. pneumoniae can be selected for resistance to low concentrations of RZL
- And require more passages to develop resistance
- RZL maintains activity against both RIF-resistant C. trachomatis and C. pneumoniae mutants
- Clinical resistance to rifamycins in chlamydia has not been documented [1]
- Ability of these organisms to quickly accumulate mutations in vitro raises concern about the use of these drugs in treating infections [1]
- Seems to have high activity against C. pneumoniae
- Showing MIC and minimal chlamidiacidal concentration values ranging from 0.005 to 0.01 mg/L [26]
- Rifampicin should never be given in isolation becouse of rapid resistance developement [45]
Rifalazil
- Newer derivative
- Indication is discouraged
- Developing resistance relatively fast (Kutlin et al., 2005)
- Interfere with bacterial folate synthesis
- Critical for DNA synthesis, repair and methylation
- Stable trimethoprim-resistant mutants
- Arise at very low frequencies (<5 × 10-10) in C. trachomatis cultured in vitro in subinhibitory concentrations
- C. trachomatis L2, C. psit-taci 6BC and C. suis
- All sensitive to SFM
- C. pneumoniae and all other tested strains of C. psittaci
- Naturally resistant
- SFM resistance in other bacteria
- Horizontal acquisition of mobile elements
- Mutations in the folate synthesis genes targeted by the drug
- Specific insertions, repeats and point mutations in the folP gene (dihydropteroate synthase)
- Mutations in the folA gene (dihydrofolate reductase)
- Can confer resistance to trimethoprim [1]
- Iclaprim
- New dihydrofolate reductase inhibitor currently in development
- Maintains activity against both C. trachomatis and C. pneumoniae in vitro [1]
- Infection in the polarized Calu-3 cells was resistant to doxycycline
- Several cytokines were released mainly on the apical side of the polarized cells in response to C. pneumoniae infection
- Growth of chlamydiae was altered in the filter-grown epithelial culture system
- Diminished production of infective progeny of C. pneumoniae
- Resistance to doxycycline
- Polarized secretion of cytokines from the infected Calu-3 cells
- This model is useful for examining epithelial cell responses to C. pneumoniae infection
- Might better resemble in vivo infection in respiratory epithelial cells [164]
- Block bacterial protein synthesis
- X aminoacyl tRNAs from interacting with ribosomes
- Gram-negative, Gram-positive, atypical bacteria (Chlamydia, Mycoplasma, Rickettsia) and even some protozoa respond to therapeutic doses
- Do not accumulate in cells
- May be present at insufficient concentrations
- Quite common
- Chlamydias - proteins that function against a broad range of TET derivatives
- Patient persistently symptomatic after doxycycline therapy [24]
- Shigella dysenteriae in 1953
- 38 genes that encode
- TET efflux pumps
- Ribosomal protection proteins
- Inactivating enzymes [1]
- Mid-1990s isolated from diseased and normal pigs in the Midwestern USA [1]
- High level resistance to TET
- Stable resistance to sulfadiazine
- Strains were passaged up to 15 times in antibiotic-free media
- Survived in media containing antibiotics without showing obvious signs of morphological abnormalities
- Presence of foreign genomic islands
- Ranging in size from 6 to 13.5 kb
- Genes encoding
- TET efflux pump
- Regulatory repressor (tet[C] and tetR, respectively)
- unique insertion sequence (IScs605)
- 3-10 gens involved in plasmid replication and mobilization
- Identical to the tet(C) gene in the cloning vector pSC101 and a wide range of other vectors
- 2008 14 additional C. suis strains collected in Italy
- 100% nucleotide identity with the tet(C) gene from the original US strains
- 12 of these isolates grew in the presence of TET
- C. suis tet(C) islands
- More than 99% identity to sections of the resistance plasmid pRAS3.2
- Isolated from Aeromonas salmonicida [1]
- Gram-negative pathogen of salmon and trout
- Laribacter hongkongensis shared 100% nucleotide identity to IScs605 of C. suis [1]
- Community-acquired gastroenteritis and travelers’ diarrhea in humans
- Two of the genes identified in the islands were part of a novel insertion element (IScs605)
- Related to other insertion sequence elements found in Helicobacter spp.
- IScs605
- Mediated site-specific transposition and integration in a heterologous system
- Transposed DNA localized adjacent to a conserved pentameric sequence (5'-TTCAA) in 36 of 38 sequenced clones [1]
- Pig industry
- Prophylactic delivery of TET [1] [23]
- Use of fish as a significant feed source
- Ideal environment for the acquisition of DNA by chlamydia that commonly infect the porcine intestinal epithelia
- Should not be given routinely to children under 8 years
V rámci chronické formy zvažuji spíše 200 mg a aspoň na 3-4 týdny s kde čím dalším.
- Doxycycline and minocycline
- Powerful immunomodulants
- Inhibit microglial activation in CNS
- Numerous other inhibitory effects on the immune system
- Downregulation of proinflammatory cytokines [47]
- Doxycycline
- Inhibits the inflammatory response to bacterial infections
- Inhibits the action of matrix metalloproteinases [47]
- Withdrawal of immumodulatory antibiotics
- May give rise to worsening of symptoms
- Flu-like symptoms and loss of energy
- Within a few weeks of stopping doxycycline
- V.s. increased destruction of dead bacterial remnants by a strengthened immune system
- Unlikely to be due to regrowth of bacteria
- Had taken years, even decades, to produce significant disease [47]
- Studie se 4-měsíčním podáváním doxycyklinu nemocným s elevací protilátek IgG, IgA a pozitivními imunokomplexy, provedená v roce 1998
- Sérologické parametry infekce C. pneumoniae zůstaly nezměněny
- Monoterapie doxycyklinem neeradikovala chronickou infekci C. pneumoniae [121]
- Broad-spectrum tetracycline antibiotic
- Broader spectrum than the other members of the group
- Bacteriostatic antibiotic
- Long-acting type
- Serum levels 2–4 times that of the simple water-soluble tetracyclines
- Most lipid-soluble of the tetracycline-class antibiotics
- Greatest penetration into the prostate and brain
- Greatest amount of central nervous system (CNS)-related side effects
- Vertigo
- Common side effect is diarrhea
- Uncommon side effects (with prolonged therapy)
- Skin discolouration
- Autoimmune disorders that are not seen with other drugs in the class
- Poor choice for urinary pathogens
- Solubility in water and levels in the urine are less than all other tetracyclines
- Metabolized by the liver and has poor urinary excretion
- Patented in 1961
- Commercial use in 1971
- Not a naturally occurring antibiotic
- From natural tetracycline antibiotics by Lederle Laboratories in 1966
- Evidence of synergy in vitro
- MIC/MBC of these strains were typical of other reported strains
- Many of the combinations tested demonstrated synergy
- Most effectively eradicated from lung tissue by the combination regimen of azithromycin and rifampin
- Azithromycin alone was less effective
- Animals that were culture negative after antibiotic treatment
- Could be made culture positive again following treatment with corticosteroids
- Reactivation of persisting infection with immunosuppression [23]
- No development of resistance if rifampin + azithromycin
- More efficient than azithromycin alone
- Suppression of rRNA synthesis occurred earlier [36]
- Protokol je určen lidem, kteří trpí roztroušenou sklerózou,
- Kterým při razantní antbiotické terapii hrozí neurologické komplikace
- Proto je jeho součástí jen velmi opatrné navyšování antibiotik - dávek a frekvence
- A nesčetné protizánětlivé a neuroprotektivní potravní doplňky ve vyšších dávkách v kombinaci, které mají synergicky převzít protizáněltivou roli steroidů (aniž by vyvolávali imunosupresi a podporovali další rozvoj infekce Chlamydia pneumonia) a ochránit tak nervovou soustavu před další atakou demyelinizace / urychlit hojení poškozených neuronů.
- A proto tato léčba není ze strachu a z nedostatku uznaných dobrých výsledků oficiální medicínou přijímána
- Pro úplnost informací to zde však uvádím
- Relatively inexpensive
- Relatively risk-free
- Act synergically against test strains of the organism
- Both together would be the equivalent of giving a four-fold increase of each drug were it to be given alone
- Work on different steps in the bacterial protein synthesis pathway
- Combination reduces the emergence of resistance
- Both drugs pass into the brain
- Both reach good levels inside cells
- Very important [27]
- Both are well tolerated
- An alternative to roxithromycin
- They deplete the organisms slowly
- Release of bacterial endotoxins should not be sudden [27]
- May also be considered
- Synergic with doxycycline
- Penetrates the brain
- Active intracellularly
- Not suitable for intermittent use [27]
- Highly active - in patients with a large bacterial load may give rise to intense reactions [27]
- Transformation from EB to RB is an active change
- Implies the retention of at least some of these pathways
- Ones with the most utility for this purpose would be anaerobic
- Thus susceptible to metronidazole [27]
- Block the replicating phase
- Inhibiting protein synthesis
- Expected to force the organism to maintain itself by using its own primitive anaerobic respiratory mechanisms
- In this suspended state it would be susceptible to anti-anaerobic agents such as metronidazole [27]
- Borne out by clinical evidence
- Administration of metronidazole after doxycycline in a patient with likely high-load Chl pneumoniae infection
- Causes a bacteriolytic reaction
- More severe than that following the original administration of doxycycline [27]
- no risk of the emergence of resistance
- Organism is unable to replicate
- Metronidazole need thus be given in courses only as long as can be tolerated
- Intermitentně [27]
- Five-day courses of metronidazole at three-week intervals
- During continuous treatment with doxycycline and roxithromycin
- At first, metronidazole may be limited to one or two doses on one or two days to judge the severity of reaction [27]
- The eventual aim would be to give all three agents intermittently = final leg of treatment
- Once a month:
- Doxycycline and roxithromycin - 14 day course
- Both anti-inflammatory activity
- Which may prevent a reaction to the organisms killed by metronidazole [27]
- Metronidazole - from day five for five days
- After several months the intervals between the antibiotics would be cautiously extended [27]
- Doxycycline against C. pneumoniae in vitro
- Luteolin, quercetin, rhamnetin, and octyl gallate
- Did not increase the efficacy of treatment
- Some combinations had antagonistic effects
- resveratrol 40 µM or quercetin 20 µM
- Followed by either clarithromycin or ofloxacin
- Both phenolic compounds exhibited significant inhibitory effects when combined with clarithromycin or ofloxacin, in comparison to controls
- Linked to the decreased IL-17 and IL-23 production in a time-dependent manner in C. pneumoniae-infected cells [96]
- Kontroverzní téma, ale hledání by nebylo uplné, kdyby tu nebylo pro srovnání
- Strikes all stages of the organism's life-cycle
- Other equally good schedules are possible
- With plenty of water [27]
- When this is well tolerated, přidá se:
- Roxithromycin, 150mg 2xd is an alternative [27]
- When these are well tolerated
- Slow to minimize any reactions caused by bacterial die-off [27]
- Demyelinisation atack prevention
- Esp. in rapidly progressive MS
- This combination is taken continuously 2-3 měsíce
- Doxycycline and azithromycin may be expected to slowly deplete the chlamydial EB load by destroying them as they enter host cells [27]
- Cycles of intermittent oral Metronidazole are added
- First cycle metronidazole
- Given only for the first day [27]
- If well tolerated the period of administration in each cycle is increased to five days
- no reason for the intermittent use of metronidazole other than acceptability
- If able to take longer cycles of metronidazole then it seems reasonable that they should do so [27]
- If it is suspected that a patient may have a heavy chlamydial load a smaller daily dose may be given initially [27]
- Should be taken continuously
- Acetylated sulphur-containing amino-acid
- May be expected to cause chlamydial EBs to open prematurely, killing them
- Should be started at the lower dose of 600mg daily
- Dose should be doubled when well-tolerated
- Offers liver protection [27]
- The period of continuous treatment needs to be of the order of a year
- Very important, as the organisms are extremely difficult to remove from certain cell-types
- Recommendations for acute infection
- Typically 2 - 6 weeks monotherapy with doxycycline or a macrolide are totally insufficient
- Organism is not killed by such treatment
- Instead is driven deeper into a persistent state
- This is recognised but not widely appreciated
[Woessner R, Grauer MT, Frese A et al., Long-term Antibiotic Treatment with Roxithromycin in Patients with Multiple Sclerosis. Infection. 2006; 34(6): 342-4.]
- Roxithromycin alone for three 6-week periods
- Did not help these patients
- This outcome was predictable
[Villareal C, Whittum-Hudson JA, Hudson AP. Persistent Chlamydiae and chronic arthritis. Arthritis Res. 2002;4(1):5-9.]
- Effective treatment needs to be addressed to all stages of the organism's life-cycle.
- Eventual aim is to give all three agents intermittently
- 14 day course of doxycycline and roxithromycin
- Five day course of metronidazole in the middle
- Given once a month
- After several months the intervals between the antibiotics may be cautiously extended
- Rifampicin is not suitable for intermittent use
- Azithromycin may be given instead
- The sicker a patient is, the slower they should go
- Started out with only one antibiotic and one dose
- Gradually adding the next dose/antibiotic as the reactions to each dose/antibiotic become apparent
- Reactions can be delayed- days to weeks [41]
- All patients should start with supplements/vitamins before they start any antibiotics
- Do liver test and follow every 3-4 months
- More frequently when INHi is added [41]
- NAC to the supplements
- Lepší než penicilin nebo penicilinamin...
- 1.Azitromycine
- Start with a macrolide - azithromycin
- 1x 250 mg and wait two weeks if there is any reaction [41]
- Potom 2 x 250 mmg
- One on Monday
- One on Wednesday and wait two weeks [41]
- Continue in this way until the patient was taking 250 mg of azithromycin MWF (3x týdně)
- If severe reactions = can't work - slow down the process [41]
- 2. + Doxycyklin
- After the azithromycin, I'd add doxycycline
- Doing this very slowly
- 3. + Metronidazole
- After added doxycycline add metronidazole pulses
- Slowly up to a once a month pulse [41]
- 4. + Rifampin
- After metronidazole 1x měs. toleruje dobře, I'd add rifampin
- 150 mg BID [41]
- Once this was tolerated, I would add INH [41]
- 5. + INH - isoniazid
- 300 mg QD to the metronidazole pulse
- Slowly
- Lze podat metronidazole and INH together [41]
- 6. Pokračovat v tom všem
- This regimen without any reactions, I would continue
- At least a year and probably three for MS [41]
- Might take a year or two (or longer) to get to the point where there is no reaction to the metronidazole/INH pulse
- Depending on the chlamydia load [41]
- Followed by 1-3 years of therapy
- This might be a 5 year program [41]
- But should allow the patient to continue to work with minimal disruption
- Should also be gradually improving during this time [41]
- The sicker the patient is, the longer the therapy is going to be [41]
- Due to the possible CNS damage that might occur by going slowly, I would move more quickly unless there were major reactions [41]
- Compressing what might have taken a year into several months [41]
- Where MS is rapidly progressive, I too would speed things up with the protein-synthesis inhibitors, paying the price of reaction for stopping progression. [41]
Sulfonamides(SFM) & trimethoprim
Tetracycline in polarised cells and tetracycline C.p. resistance
Tetracyclines
TET resistance
TET resistance acquired through horizontal gene transfer in any obligate intracellular bacteria
Stably resistant Chlamydia suis (psittaci)
Dávkování
Tetracycline 500 mg 4xd times daily for 14 days
Doxycycline 100 mg 2xd for 14 days
Minocycline
ATB synergie - kombinace
Wheldon protokol
Doxycycline + roxithromycin / azithromycin
Azithromycin
Rifampicin
Metronidazole
Doxycycline and roxithromycin
Antibitics + polyfenols
Doxycicline
Clarithromycin or ofloxacin
David Wheldon protokol při RS
Doxycycline 100mg p.o. 1xd
Azithromycin 250mg p.o. 3x týdně
Doxycycline is increased to 200mg denně
Metronidazol 400mg three times a day 3x týdenní cykly
N-acetyl cysteine (NAC) 600mg daily - 1,200mg twice a day
Poznámky
Final leg of treatment
