Meningitiis Antibiotics Flashcards
Neisseria meningitides
- Pathogen category: G- diplococcus, aerobic, intracellular
- Source: human reservoir, nasopharynx, spread by respiratory droplets
- Virulence factors: capsule (allow for it to travel through the body- petechiae and eventual purpura in patient with meningoccemia), lipoooligosaccharide (LOS), IgA protease
- Clinical: meningococcemia
- Immune response: antibodies to capsule; LOS triggers septic shock
- Treatment/Prevention: vaccination to ACWY serogroups as part of standard CDC recommendation for early teens; separate later teen vaccine for B serotype for at risk individuals, including outbreaks in college dorms; rifampin prophylaxis for exposed and carriers; third generation cephalosporin as treatment, with penicillin as a traditional alternative for penicillin-susceptible strains; B vaccine more difficult to make because B antigen mimicked brain tissue
Neisseria meningitidis, the meningococcus, is a Gram-negative diplococcus that shares a number of virulence features with the gonococcus, N. gonorrhoeae, such as outer membrane proteins for adhesion. The major feature for the meningococcus is its capsule, which allows it to be distributed throughout the body, e.g., the image of petechiae and eventual purpura in a patient with meningoccemia.
Uptaken by cells then w/ strong neutrophilic response, capsule protects it from point of infection developing further and can go bacteremia w/ pilli allowing it to attach into endothelial and nerves. Petechia progressing to purpura (neutrophil response) indicate developing into sepsis.
Gonoccous (local inflammation in genital tract pyuria)
Acanthamoeba species
- Pathogen category: free-living ameba
- Source: natural water and soil; very widespread
- Virulence factors: cyst formation
- Clinical: amebic keratitis (corneal ulceration in soft contact users); meningoencephalitis (similar to Naegleria)
- Immune response: cell-mediated response; ICP more vulnerable
- Treatment/Prevention: changing of solutions and lenses, sterile fluid; difficult to treat, chlorhexidine + propamidine (interferes with DNA activities) for several weeks aong with possible debridement of trophozoites and cysts
Species of the free-living amoeba genus Acanthamoeba (similar to legionella can get introduced into eye feeding on epithelia and gets established) have been known to generate corneal ulceration in soft contact lens users with poor contact lens and solution hygiene.
Chlamydia trachomatis (eye)
- Pathogen category: intracellular bacterium with LPS but not peptidoglycan
- Source: human reservoir
- Virulence factors: elementary body (what is released) and reticular body (intracellular) forms; depends on ATP from host cell
- Clinical: chlamydial disease; trachoma (eye infection can be spread easily with poor hygiene; repeated infection can lead to scarring of the eyelid and subsequent corneal scaring)
- Immune response: strong inflammatory and cell-mediated response; generated antibodies are not long-term protective
- Treatment/Prevention: handwashing and face washing’ macrolides or doxycycline
As a reminder from the respiratory section, chlamydiae are intracellular pathogens with reticulate bodies (replicative) that then release elementary bodies to infect elsewhere. Once the body catches up to it has a strong response the response is not effectively establishing a memory (unless cleared will continue on).
Infection then strong immune response and scarring contract and pull eyelids in (entropean over the cornea developing permanently blidning or sight altering corneal abrasions).
Antibiotics- good cell uptake and prolierfation of bodies developing anti-cyclonal
There are many serotypes of chlamydia (which we will discuss more under STIs in the next part of the course), but trachoma as an eye infection can be spread easily with poor hygiene, and with repeated infections can lead to inward turning of the eyelid and subsequent corneal scarring.
Cryptococcus neoformans
- Pathogen category: yeast (dimorphic fungi)
- Source: environmental reservoirs (bird droppings)
- Clinical: cryptococcal meningitis in ICP (slow onset)
- Immune response: cell mediated
- Treatment/Prevention: meningitis in AIDS patients: amphotericin B + flucytosine
- Traditionally diagnosed from India ink preparation but antigen detection is more useful
- Fluconazole used for suppression; severe cases will need amphotericin B to start
Cryptococcus neoformans (dimorphic fungi) is an inhaled fungus (hatches into yeast), and can set up a mild lung infection (pneumonia), but has a predilection for creating a meningitis in immunocompromised patients, usually only ones who develop infection. Unlike a bacterial meningitis, the onset will be slow. Exposed in pigeon dropping
Traditionally, viewing the capsule was done by an India ink preparation, such as seen here; currently, antigen detection is a more useful tool. Fluconazole useful for suppression, or for severe infections such as meningitis, patients will still need amphotericin B (with flucytosine as an inhibitor of fungal nucleic acid synthesis) initially (Sanford Guide 2019).
Ampinterase b targets ergosterol
Enteroviruses
- Pathogen category: +ssRNA unenveloped virus (picornaviruses)
- Source: human reservoirs
- Virulence factors: persistence in GI tract an ongoing sheeding
- Clinical: GI disease, often asymptomatic; depending on viremic spread, may generate other illnesses (like meningitis)
- Immune response: post-infectious humoral
- Treatment/Prevention: supportive care
- Includes coxsackieviruses and echoviruses; associated with respiratory, meningeal, or cardiac illnesses (most subclinical)
The enteroviruses are common entities for viral meningitis (85%). These include coxsackieviruses and echoviruses. These are +ss RNA viruses (picornaviruses-unenveloped) that may be associated with respiratory, meningeal, or cardiac illnesses, although many infections are subclinical.
Rhinovirus- uri
Enteroviruses- taken up by the intestine, peyer patches going into lymphoid tissue that develops viremia unenveloped. (cocksackie goes into skin or heart myocarditis); poli and cocksackie into brain and spinal cord
Poliovirus
- Pathogen category: unenveloped +ssRNA picornavirus
- Source: human reservoirs
- Virulence factors: ability to spread by oral-fecal pathways; targeting of CNS lower motor neurons
- Clinical: polio
- Immune response: cell-mediated and antibody responses
- Treatment/Prevention: vaccine (killed-Salk or oral attenuated-Sabin); viral treatment not available
As with other enteroviruses, poliovirus is also spread oral-fecally, but after the lymphatic uptake and viremic spread, preferentially targets motor neurons of the central nervous system, either by crossing the blood-brain barrier or direct neuronal ascent. The major interest in polio is the attempt to eradicate it worldwide, as the current low numbers indicate. Can spread in the water and use that as a resoervoir
Sabin Injected vaccines. Developed in the 50s and have lately gone back to this one because of decrease in it
Sabin oral Weakened attenuated virus covering lots of people as it is shared among the household when changing diapers (higher risk of polio from reversion) newer. - Oral/fecal spread then uptake by lymphatics and viremic spread
Coxsackieviruses
- Strains can be associated with pericarditis and myocarditis
o Following viremia the virion that uptaken by those tissues
o Strong humoral/cell response to less viremic load decrease risk for cardiomyopathy
o Being chronically exposed but not clearing fully can still lead to chronic response causing the same problems
Viral infection direct cytopathic damage (bursting cell)> macrophage (IL1,2, IF-gamam, TNF, NK cells)> subclinical myocarditis cytotoxic b and t cells infecting virus creating chronic fibrotic response developing into heart failture w/ over development of the problem. If exposed and unable to clear can develop into the damaging picture (chronic lyme disease)
We saw hand-foot-and-mouth disease from coxsackieviruses as part of the respiratory items two weeks ago. Other coxsackievirus strains can be associated with pericarditis and myocarditis. Following viremia, the virions then are uptaken by those tissues. A strong humoral and cell-mediated response to lessen the viremic load would decrease the risk for cardiomyopathy. This flowchart should make sense as helping to demonstrate a combination of direct viral damage and immune response can lead to myocarditis, when there is sufficient virus present to trigger the immune activity. Overall, the rate of myocarditis is difficult to determine, e.g., 1/100,000 US population.
Postnatal Conjunctivitis
- Conjunctivitis- inflammation of conjunctiva
- Keratitis- inflammation of the cornea
- Follicles- nonspecific conjunctival response; small translucent bumps from lymphatics
- Papillae- tissue mounds (anchors of conjunctiva by connective septa) from vascularity as from an inflammatory response
- Staph. aureus is the most common bacterial cause accounts for discharge
o Treated with fluoroquinolone
- Adenovirus usually viral cause and allergic conjunctivitis won’t have purulence and inflammation
Herpes simplex keratitis
- Triggers corneal scarring and blindness; ulcerations appear in a distinctive branching pattern
- Proliferation in corneal epithelium
- Trifluridine drops or ganciclovir gel drops for acute treatment; consider adding acyclovir or valacyclovir
Herpes simplex keratitis (infection of the cornea- dendritiic branches on the iris-corneal epithelium being more specialized developing inflammatory response at proliferation stage must recognize and treat right away) can trigger corneal scarring and blindness. The ulcerations appear in a distinctive branching pattern. Trifluridine drops (shut down prolieration) or ganciclovir ophthalmic gel would be necessary as acute treatments, with consideration of adding oral acyclovir or valacyclovir (Sanford Guide 2019).
conjunctivitis
Conjunctivitis: (pinkeye); inflammation of conjunctiva
Keratitis: inflammation of the cornea
Follicles: nonspecific conjunctival response; small translucent bumps from lymphatics
Papillae: tissue mounds (as the conjunctiva are repeatedly anchored by connective septa) from vascularity as from an inflammatory response
Bacterial infections, such as those from Staphylococcus aureus (the most common), can account for discharge. Ophthalmic drops of a variety of treatments, e.g., fluoroquinolone, can be used for those. More common viral conjunctivitis (most commonly adenovirus-pink eye) or allergic conjunctivitis will not present with such purulence and inflammation (staph. Aureus-skin, petechiae- capillary leakage of pneumococcas similar to purulent sputum, h. infleunzae- associated w/ uri infections.
Beta Lactam Drugs
bind to PBPs (penicillin-binding protein, e.g., transpeptidases-crosslinking of sugar and dangling side chain) and thereby lead to inhibition of peptidoglycan cross-linking in cell wall synthesis.
The beta-lactam ring is opened by beta-lactamases and so loses its chemical similarity to the D-ala-D-ala when that occurs.
Beta lactam drugs are the most common means of interfering with the cell wall
Glycopeptides
with glycopeptides such as vancomycin representing the “step before” interference with the transpeptidation surrounding alanine side chain (dangling at end) to prevent next step.
Bacitracin
used as a topic antibiotic (triple antibiotic ointment), with cycloserine as a rarely-used second-line TB drug, because of their toxicities onto peptide side chain in the first place .
Penicillin G
(the original penicillin) is given IM or IV, while penicillin V is an oral form. Different classes of penicillins depend on side groups added, which may protect against -lactamase activity. These can allow for narrow spectrum vs. broad spectrum antibiotics. In general, the penicillins are useful for Gram+ coverage.
Penicillin binding site have different cross linking going on- drug can fit right into one pathogen versus another.
Peniccilin v- oral
Ampcillin & Amoxacillin
Ampcillin-injectable vs. amOxacillin (not broken down metabolism)- bulking up to not make it easier to cancel it out
penicillin G: the natural penicillins have a short half-life, so require frequent dosing. Benzathine penicillin G is a depot form to allow for longer activity, e.g., in use for syphilis (Treponema pallidum).
the amine group makes it more polar, so as to better go through the outer membrane porins of Gram negative bacteria, but are not protecting against beta-lactamases. Amoxicillin has better oral bioavailability.
Pipercillin
has antipseudomonal activity, but has vulnerability against beta lactamases.
Clavulanic Acid
a beta-lactamase inhibitor that binds to bacterial beta-lactamases, such as seen in the amoxicillin/clavulanate mixture Augmentin®.
Beta lacatamases from harder to kill gram negative
This strategy of penicillin/beta-lactamase inhibitor can be seen in other combinations, e.g., piperacillin/tazobactam (Zosyn®) for antipseudomonal coverage.
Utilize decoy to take care of beta lactamase
Cephalosporins
Cephalosporins tend to generate fewer hypersensitivity reactions than do the penicillins. Note that the cephalosporins have two R groups compared to the one R group of the penicillins. This potentially allows for more pharmacological manipulation of the group, e.g.,
Manipulation against beta-lactamases
Entrance through Gram-negative porins
Enhancement of PBP binding
Generation of Cephalosporins
1st-5th generation w/ increasing generation to take care of resisting patterns. 1st generation small and utilization gram + coverage.
Cefaclor- polar group gram negative while being able to target gram +
Ceftrizone (rosephin)- gram – coverage IV/IM treating gonorrhea
Cefemine- hard to kill gram –
Ceftaroline- fight MRSA (altered peniccillin binding protein so cannot be targetted because of it only treat very severe hospital acquired MRSA infection)
Ceftolozane- similar to pyprocillin hard to kill pathogen like pseudomonas
There are several generations of cephalosporins with different antibiotic spectra.
First generation: example of cephazolin; narrow spectrum, sensitive to beta-lactamase. Used prior to surgery to decrease surgical wound infections.
Second generation: example of cefuroxime; extended spectrum, broader Gram-negative activity. Also used for preoperative surgery prophylaxis.
Third generation: example of ceftriaxone; more resistant to cephalosporinases, and more able to penetrate to the CSF compared to the first and second generation medications. Ceftriaxone is once daily (except in meningitis), to cover Gram- infections.
Fourth generation: example of cefepime; additional Gram- coverage, with continued Gram+ coverage. Used for empirical coverage of nosocomial infections.
Fifth generation: example of ceftaroline; engineered to bind to the PBP 2a of MRSA, so has MRSA coverage in addition to Gram- coverage (but not useful for Pseudomonas).
Aztreonam
has great aerobic Gram- coverage, as it binds well to the PBP form seen in Gram- bacteria, but no Gram+ or anaerobe coverage. More of a high end drug, it can be used for pseudomonal infections. Can go through porin and PBP of gram – so high level hospital based infections
Carbapenems
examples of meropenem and doripenem, are powerful, broad-spectrum antibiotics, e.g., for empirical coverage of a mixed infection in a seriously ill patient while awaiting culture results. Again, these are high-end medications. High end gram posiitve and negative culture (kill everything you can) don’t use for routine infections
These drugs also utilize a beta-lactam ring, but have different side chains and overall size, which allows:
Resistance to β-lactamases
Wide affinity for different PBPs
Ability to pass through Gram- porins
Unnervingly, there are increasing reports of organisms such as Klebsiella pneumoniae with a New Delhi metallo-beta-lactamase 1 (NDM-1) that deactivates carbapenems, as well as other specialized beta-lactamases found the CREs (carbapenem-resistant Enteriobacteriaceae) opens up beta lactam ring. These numbers are still low in the US, but climbing (380 patients with NDM-producing CRE as of December 2017), with resistance patterns of isolates being noted worldwide.
