Pemberian Antibiotik Melalui Rute Intratekal

PEMBERIAN
ANTIBIOTIK
MELALUI RUTE
INTRATEKAL
BLOOD BRAIN BARRIER 
Molecular Size
Tight Junction Lipophilicity
Metabolism Plasma
within the Protein
CNS Binding
Active
Transport
Nau, R., Sorgel, F., & Eiffert, H. (2010). Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections. Clinical Microbiology Reviews,
23(4), 858–883. doi:10.1128/cmr.00007-10
PENETRATION OF ANTIBIOTIC IN INFLAMMATION
 In bacterial meningitis, the blood-CSF/blood-brain barrier is becoming leaky by the opening

of intercellular tight junctions of the vessel walls particularly within venules
 The CSF outflow resistance increases, leading to a moderate reduction of the CSF production
and absorption rates, and the activity of P-gp (glikoprotein) can be inhibited by
proinflammatory cytokines
23(4), 858–883. doi:10.1128/cmr.00007-10
ANTIBIOTIC CONCERNING PENETRATION
INTO THE CNS
B-LACTAM
 B-Lactams are compounds with a molecular mass of around 400 Da and plasma protein
binding ranging from 0 to 95%. They are weak acids
 Their affinity for drug efflux pumps varies from strong (cephalothin) to almost absent
(ceftriaxone)
 epileptic seizures after intrathecal and intravenous up to 33% of children treated with
imipenem. For this reason, meropenem instead of imipenem is recommended for the therapy
of CNS infections.
 Because of their relatively low systemic toxicity and high potential to induce epileptic seizures
after intracerebroventricular application, B-lactam antibiotics are not good candidates for
intraventricular use
23(4), 858–883. doi:10.1128/cmr.00007-10
AMINOGLYCOSIDES
 Aminoglycosides are hydrophilic compounds with a molecular mass of around 400 Da and
low plasma protein binding.
 Their CSF penetration is considered to be particularly poor
 The therapeutic index of aminoglycosides is low
 because of nephro and ototoxicity, the systemic dose of aminoglycosides can be increased in
narrow limits only. This impedes the attainment of effective CSF concentrations, particularly
when inflammation is mild to moderate.
 The indications for i.v. use of aminoglycosides for meningitis have decreased over the last
decades with the introduction of less-toxic antibiotics into clinical practice.
23(4), 858–883. doi:10.1128/cmr.00007-10
FLUOROQUINOLONES
 lipophilic drugs with a molecular mass of around 300 Da and low binding to plasma proteins
(approximately 20 to 40%)
 Their penetration into the CSF in the absence of meningeal inflammation is much higher than
that of B-lactam antibiotics.
 Fluoroquinolones are of great value for the treatment of CNS infections by Gram-negative
aerobic bacilli (ciprofloxacin) and by Mycobacterium tuberculosis (moxifloxacin)
 Since several fluoroquinolones enter the CNS readily, intrathecal injections of
fluoroquinolones are unnecessary.
23(4), 858–883. doi:10.1128/cmr.00007-10
MACROLIDES
 Macrolides penetrate well into tissue, but because of their relatively high molecular mass
(around 750 Da) and probably also because of their affinity for P-gp, they do not reach
sufficient CSF concentrations
 Due to a lack of bactericidal activity in experimental S. pneumoniae meningitis, their role in
the treatment of CNS infections is limited to Mycoplasma sp. and Legionella pneumophila
encephalitis.
23(4), 858–883. doi:10.1128/cmr.00007-10
METRONIDAZOLE
 Metronidazole is a small lipophilic compound that is active against most anaerobic bacteria
penetrating well into most tissues, including abscess contents.
 In animal studies, metronidazole readily penetrated the blood-CSF/blood-brain barrier, and
data regarding the entry into human CSF and brain abscess confirmed this finding
 Metronidazole is part of the standard therapy of bacterial brain abscess
23(4), 858–883. doi:10.1128/cmr.00007-10
METHODS TO INCREASE DRUG CONCENTRATIONS IN
CNS
 increase the systemic doseSeveral anti-infectives possess low toxicity. Therefore, the daily
dose can be increased without severe side effects
 By the artificial temporary disruption of the diffusional barriers between blood, CSF, and brain
tissue, e.g., by the intra-arterial injection of hyperosmotic compounds or alkyl glycerols 
This strategy used in experimental tumor therapy is dangerous for CNS infections, because it
can aggravate brain edema
 intraventricular injection in addition to intravenous administration  To antibiotics with a low

penetration into the CSF and/or a high systemic toxicity, which precludes increasing the daily
systemic
23(4), 858–883. doi:10.1128/cmr.00007-10
 Intrathecal administration is indicated in CNS infections by multiresistant pathogens when drugs that
can reach adequate CSF
 should not be used when effective systemic therapy is available
 pH and osmolarity of the solution are compatible with intrathecal administration.
 Medications should be preservative free.
 Injections must be performed slowly
 a small volume in order to avoid a rise of the intracranial pressure in patients with increased CSF
outflow resistance.
 concomitant systemic therapy.
 The ventricular drain should be clamped for 15 to 120 min to facilitate the distribution to CSF space
 Do not advise rinsing the catheter with saline because this may increase the risk of infection.
23(4), 858–883. doi:10.1128/cmr.00007-10
PHARMACODYNAMICS
Restricted nutritional supply and acidic pH of CSF  pathogens multiply in the CNS less
rapidly than in blood or broth.
+
Fast intended dose to be reached through intraventricular/lumbar administration
=
Optimal & quick sterilization
Nau, R., Blei, C. and Eiffert, H. (2020) ‘Intrathecal antibacterial and antifungal therapies’, Clinical Microbiology Reviews, 33(3), pp. 1–24. doi: 10.1128/CMR.00190-19.
ANTIBACTERIALS AND ANTIFUNGALS THAT SHOULD
NOT BE ADMINISTERED INTRATHECALLY
 Antibiotics that readily pass the blood-brain and blood-CSF barriers and/or have low toxicity
and thus allow for an increase in the daily dose should not be used for intrathecal therapy.
 At very high doses or in the presence of renal failure, even after intravenous infusion 
neurotoxic can induce confusion, encephalopathy, myoclonus, and epileptic seizures,
including status epilepticus, particularly in patients suffering from various neurological
disorders
 Experimental evidence suggests that intrathecal therapy has a higher risk of seizures than
systemic application
 Among the B-lactam antibiotics frequently used in critically ill patients, the relative potencies
to induce epileptic seizures  cefazolin (2.94), cefepime (1.60), and imipenem (0.71)
 epileptogenic potencies  ampicillin (0.21), ceftazidime (0.17), meropenem (0.16),
ceftriaxone (0.12), piperacillin (0.11), and cefotaxime (0.088),
THE INTRATHECAL
ADMINISTRATION IS NOT
INDICATED
fluoroquinolones penicillin G piperacillin cefotaxime ceftriaxone
ceftazidime meropenem B-lactamase inhibitors linezolid fosfomycin
metronidazole chloramphenicol co-trimoxazole rifampin pyrazinamide
posaconazole flucytosine voriconazole fluconazole ethambutol
tetracyclines isoniazid
due to low toxicity that makes it possible to increase the daily dose or because
they readily penetrate the blood-brain and blood-CSF barriers is not indicated
ANTIBACTERIALS AND ANTIFUNGALS ELIGIBLE FOR
INTRATHECAL THERAPY
vancomycin teicoplanin gentamicin tobramycin netilmicin

amikacin streptomycin colistin polymyxin B daptomycin
amphotericin B caspofungin
 The following anti-infectives are too large and/or too toxic to achieve high concentrations in the CNS
after intravenous administration
EVIDENCE FOR THE EFFECTIVENESS AND SAFETY OF
INTRATHECAL ANTI- INFECTIVE THERAPY
 A recent meta-analysis on ventriculitis/meningitis caused by Gram-negative pathogens (11

studies with 348 adult patients) found that intraventricular plus intravenous therapy was
superior to intravenous therapy alone in the eradication of pathogens
 (odds ratio [OR], 10.06; 95% confidence interval [CI], 2.62 to 38.65), infectious mortality
(OR, 0.1; 95% CI, 0.03 to 0.36), and overall mortality (OR, 0.22; 95% CI, 0.08 to 0.60) in the
management of carbapenem-resistant bacteria.
 For infections with other bacteria, combined intraventricular plus intravenous therapy did not
prove superior to standard intravenous therapy
PHARMACOKINETICS
Intraventricular 
 direct access to the extracellular central nervous compartments
 High CSF levels can be reached with comparatively small doses, and the side effects are
minimal to moderate when adequate formulations
 its distribution throughout the CSF space (unless there is a complete block of the CSF
circulation, e.g., in the cerebral aqueduct or by an obstruction of the spinal canal)
 In neonates with bacterial meningitis, injection of amikacin into one ventricle resulted in
approximately equal drug levels in both ventricles 10 h after dosing.
 Therapeutic peak lumbar CSF concentrations 2 to 10 times lower than the simultaneous
intraventricular levels were reached 2 to 4 h after intraventricular dosing
Intralumbar
 After injection, the distribution in the CSF space is far less homogeneous:
 drug concentrations in ventricular CSF are highly variable and may not reach therapeutic
levels.
 Although clinical studies did not prove a lower efficacy of the administration of antibiotics via
lumbar drainage than with the ventricular route in patients with meningitis, pharmacokinetic
data strongly suggest the intraventricular route  requires the implantation of an external
ventriculostomy
VOLUME OF DISTRIBUTION
Volume of Distribution  the volume needed for a drug to be homogenously distributed
throughout the body in a concentration found in the blood or plasma
 The volume of the CSF space is variable, depending on the size of the ventricles, basal
cisterns, and the subarachnoid space over the convexities and in the spinal canal 
communicating or non comm hydrocephalus
ELIMINATION
 The total clearance from CSF to blood =
 CSF bulk flow + retrograde diffusion across the blood-CSF-BBB
 Large hydrophilic molecules are mainly eliminated by CSF bulk flow. After intraventricular
dosing, their elimination is slower in hydrocephalic patients than in patients with a normal
ventricle size.
 Small or lipophilic molecules or molecules with a high affinity for efflux pumps are eliminated
by bulk flow, by retrograde diffusion across the blood- brain and blood-CSF barriers, and/or
by active transport.
ELIMINATION
Depend on
 CSF production rate  is not constant, circadian variation
 Half-life of antibiotic
 CSF volume  in large ventrikel, decrease the peak concentration after drug instillation
 CSF flow  CSF diversion with a ventriculostomy or shunt may increase drug elimination
throughout the dosing period, potentially leading to subtherapeutic concentrations immediately
before the next dose
SIMULTANEOUS INTRATHECAL AND
INTRAVENOUS THERAPY
 simultaneous intraventricular and intravenous administration probably helps to prevent
compartments with subinhibitory antibiotic concentrations, thus reducing the probability of the
selection of resistant bacteria and relapse.
 Numerous studies reporting the successful intrathecal administration of antibiotics used
concomitant intravenous therapy  is strongly recommended
INDICATIONS FOR INTRATHECAL ADMINISTRATION OF
ANTI-INFECTIVES AND DURATION OF TREATMENT
 According to Infectious Diseases Society of America (IDSA)  intrathecal administration of

anti-infectives “should be considered for patients with healthcare-associated ventriculitis and
meningitis in which the infection responds poorly to systemic antimicrobial therapy alone.”
 The decision to start intrathecal antimicrobial therapy depends on the results of quantitative
susceptibility testing and the lack of anti-infectives that reach the required CSF concentrations
for a rapid cidal effect with low toxicity to the host
 The evidence does not support the prophylactic intrathecal administration of antibiotics
 The duration of treatment is highly individualized depending on the clinical conditions (e.g.,
infected CSF shunt or another intracranial device versus no foreign body) and the pathogen
 In uncomplicated cases, intrathecal anti-infective therapy is stopped 48 to 72 h after the CSF
culture has become sterile.
 patients with repeated positive CSF cultures despite adequate anti-infective therapy  IDSA
guidelines recommend continuing therapy for 10 to 14 days after the last positive CSF culture
 Drugs suitable for injections into the intraventricular must following 
 sterile, pyrogen free, endotoxin free, and essentially free of particles of foreign matter and must not
contain other contaminants.
 The drug must be dissolved in water for injection or a sterile sodium chloride solution
(concentration, <0.9%).
 The solution must not contain any added coloring agents.
 The European Pharmacopoeia  free of antimicrobial preservatives and must be filled in
single-dose containers.
POTENTIAL FOR PATIENT HARM FROM
INTRATHECAL ADMINISTRATION OF
PRESERVED SOLUTIONS
 Sulfites are often added to foods and drugs for their preservative and antioxidant properties.
 In general, sulfites are avoided in drugs delivered into the CNS due to concerns about
neurotoxicity  can induce confusion, encephalopathy, myoclonus, and epileptic seizures,
including status epilepticus, particularly in patients suffering from various neurological
disorders
 Neurotoxicity attributed to sulfites stems from reports in the early 1980s of adverse neurologic
events following inadvertent intrathecal administration of bisulfite-containing chloroprocaine..
 Today, a number of drug formulations exist that are labeled as preservative-free and contain a
sulfite, most commonly seen in relatively low concentrations as antioxidants.
 Sulfite containing products are listed as preservative-free only for products labeled for use
within the CNS.
 Therefore, products labeled as preservative-free may contain sulfites, but only in small
amounts as antioxidants deemed by the manufacturer to be safe for CNS use.
 Preservatives are often added to multidose containers to prevent contamination
TERIMA KASIH

Pemberian Antibiotik Melalui Rute Intratekal

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pemberian Antibiotik Melalui Rute Intratekal

Uploaded by

Copyright:

Available Formats

PEMBERIAN

Tight Junction Lipophilicity

 In bacterial meningitis, the blood-CSF/blood-brain barrier is becoming leaky by the opening

 intraventricular injection in addition to intravenous administration  To antibiotics with a low

vancomycin teicoplanin gentamicin tobramycin netilmicin

 A recent meta-analysis on ventriculitis/meningitis caused by Gram-negative patho- gens (11

 According to Infectious Diseases Society of America (IDSA)  intrathecal administration of

You might also like