*Anti-infectives Flashcards
Define antibiotics
* An antibiotic is a chemical substance originating from various species of microorganisms (bacteria, fungus, actinomyces) that suppresses growth or destroys other microorganisms
Activity Spectrum of Gram + and -
- Gram+ & Gram-
- Secrete unique antigenic non-enzymatic heat sensitive protein
exotoxins
- Secrete unique antigenic non-enzymatic heat sensitive protein
- Gram-
- Release pyretic, heat stable, mildly antigenic endotoxin (LPS) upon lysis
Metabolic Profiles
- Aerobic
- Anaerobic (facultative vs obligate): commonly indigenous flora thriving in a poorly perfused environment
- Obligate intracellular species
Bactericidal vs bacteriostatic
- Bactericidal: kill target cells; cells may lyse or remain intact
- Bacteriostatic: prevent target cell replication
THERAPEUTIC CONCERNS
- Route Of Delivery
- Highest ocular concentrations are delivered locally (topical, contact lens, injection etc.)
- Dose
- Dependent on weight, height, organ function
- Duration Of Therapy
- Longer isn’t always better; see resistance
- Drug Safety
- Liquid antibiotics are among the few drug formulations that
are not recommended for use after expiration dates*
Antibiotic cover at a glance
Antibiotic cover
ANTIBIOTIC TOXICITY PROFILE
(bactericidal vs bacteriostatic)
Cell wall inhibitors
- β-Lactam Antibiotics
- • Penicillin [PCN]
- Cephalosporin
- Stand-alone Antibiotics (no structural relatives)
- Bacitracin
- Vancomycin
The cell wall and inner peptidoglycan layer found in bacteria are not
found in humans thus make great targets for antibiotic therapy
Penicillin
- Predominantly useful for treating Gm+ infections & anaerobic infections Drug of choice for syphilis
- PCNase Sensitive
- Pen G (IV, IM) & Pen V (PO); the original (non-synthetic) penicillins
- PCNase Resistant
- Methicillin, Flucloxacillin, Dicloxacillin
- *Aminopenicillins
- Ampicillin, Amoxicillin
- Anti-pseudomonal (Gm-) Coverage
- Carboxypenicillins: Carbenicillin and Ticarcillin
*Sulbactam or Clavulanate inhibit PCNase and are therefore
Often combined with PCNase sensitive formulas
Penicillin
Adverse reactions of Penicillin
- No topical formulas exist since allergy risk is too high
• Hypersensitivity
• Penicillin haptens bind to RBC surface proteins which then become
immunogenic and stimulate IgE (Type I: anaphylaxis) and/or IgG
(Type II: hemolysis) reactions
Cefalosporins
- Like PCN, these drugs also have a β-lactam ring structure
with 6 members (vs 5) - In contrast to PCN, these drugs are less susceptible to
PCNase
The first 3 of 4 Generations include oral formulations
• No topical formulas exist
• Newer generations have greater Gram- coverage
Adverse reactions of cephalosporins
- Hypersensitivity reactions similar to penicillin
- 1st generation cephalosporins are cross-reactive with
penicillins
BACITRACIN
- Available in a topical ointment ONLY due to profound nephrotoxicity
- AK-Tracin® Ointment
- Gm+ coverage
- Polysporin® Ointment
- Also contains Polymyxin B
- The combination provides additional Gm- coverage including pseudomonas
- Also contains Polymyxin B
VANCOMYCIN
- I.V. drug of choice for MRSA and MRSE infections and
bacterial endophthalmitis - Gm+ coverage only
- Poor oral absorption
- Adverse Reactions
• Red Man Syndrome: IV-induced mast cell degranulation
CELL MEMBRANE TOXINS
Polymyxin-B
Gramicidin
Only available topically due to systemic toxicity
Polymyxin-B
• Cationic detergent/surfactant
• Topical use only; never stand-alone
Gramicidin
• Same mechanism of action as Polymyxin B
• Often found in combination products
POLYMYXIN-B OPH COMBOS
Polytrim Solution
• Polymyxin-B + Trimethoprim used for most common
paediatric ocular infections: H influenzae and S pneumoniae
• Excellent option for resistant S epidermidis & MRSA
infections
Polysporin Ointment
• Polymyxin B + Bacitracin
Neosporin Ointment
• Polymyxin B + Neomycin + Bacitracin
Neosporin Solution
• Polymyxin B + Neomycin + Gramicidin
PROTEIN SYNTHESIS INHIBITORS
Act by binding to and inhibiting the 30S or 50S ribosomal
subunit
30S
• Aminoglycosides
• Tetracyclines
50S
• Macrolides
• Lincosamides (Lincomycin, Clindamycin)
• Chloramphenicol
AMINOGLYCOSIDES
Neomycin (Neosporin® Combo Ointment/Solution)
• The oldest aminoglycoside
• Topical use primarily; never stand-alone
• Broad spectrum coverage except pseudomonas
Gentamicin (Garamycin® Ointment/Solution)
• Used for severe infections
Tobramycin (Tobrex® Ointment/Solution)
• Similar use as Gentamicin
Adverse reactions of aminoglycosides
(Neomycin,gentamycin,tobramycin)
- Adverse Reactions
- Type IV Delayed Hypersensitivity reaction
Neomycin
• 5-10% contact dermatitis risk: avoid routine use
• Allergy: 50% patients are X-reactive w/ Gentamicin
Gentamicin
• Idiopathic Intracranial Hypertension
• Corneal epithelial toxicity most pronounced
TETRACYCLINES
Anti-inflammatory benefits arise through inhibition of
MMPs, neovascularization & bacterial lipases
Short Acting
• Tetracycline, Oxytetracycline
Long Acting
• Doxycycline, Minocycline
• Oracea® is a 40 mg doxycycline capsule; 30 mg is
immediately released; 10 mg is delayed release; indicated
for rosacea
Indications of tetracyclines (minocycline,doxacycline)
- Minocycline
• Acne rosacea - Doxycycline (50mg qd x 1-6 months)
• Acne rosacea
• Chlamydia
• Syphilis (vs 1st choice intramuscular PCN)
Adverse reactions of tetracyclines (minocycline and doxycycline)
General adverse reactions
- Photosensitivity
- Impaired absorption w/ food due to divalent cation binding;
doxycycline ⇩ 20% vs tetracycline ⇩ 50% w/ milk; avoid lying
down for 2 hrs following administration - Blood dyscrasias
- “Idiopathic” Intracranial Hypertension [IIH]
- Impaired bone growth, tooth development
- Fanconi’s Syndrome: renal toxicity from expired tetracyclines
Distinct adverse reactions
- Minocycline
- Vestibular toxicity within 2-3d of therapy in up to 70%
- Doxycycline (Vibramycin®)
- Exhibits least divalent chelation (20% w/ milk)
- Risk of erosive esophagitis*
- No azotemia due to fecal (vs renal) elimination pathway
- Excellent option for resistant S epidermidis infection (MRSE)
Contraindications for the use of tetracyclines (doxycycline,minocycline)
- Pregnancy
- Nursing mothers
- Children under 8 yrs of age
- Renal failure (except Doxycycline)
MACROLIDES
Erythromycin QID (Ilotycin® Ointment)
• Replaced AgNO3 for neonatal gonorrhea
• Unstable in gastric acid
Azithromycin (Oral & AzaSite® Solution w/ *Durasite®)
• The ONLY macrolide available in a drop formulation
• Extended half-life* permits minimal dosing
Clarithromycin BID (Biaxin® oral) • Reduced dosing compared to Erythromycin due to greater stability in GIT
E-Mycin and Azasite are two of very few antibiotics that have a safer pregnancy rating
Adverse reactions and cautions for the use of macrolides (erythromycin,azithromycin,clarithromycin)
Adverse Reactions
• None applicable to ophthalmic conditions or findings
Contraindications
• Pregnancy
CHLORAMPHENICOL
Adverse Effects
• Grey Baby Syndrome
Ocular
• Optic neuritis with prolonged therapy
• High oral toxicity limits use to topical only in USA
• Grey Baby Syndrome: results from IV use in newborns with immature
liver function- unmetabolized drug causes reduced blood pressure and
cyanosis (grey color) results
P37
FOLIC ACID INHIBITOR COMBOS
Polytrim Solution
• Polymyxin B + Trimethoprim is the drug of choice for
paediatric bacterial conjunctivitis
Sulfadiazine + Pyrimethamine
• These two drugs are used together to treat toxoplasmosis
Sulfamethoxaxole + Trimethoprim (Bactrim®)
• Oral drug of choice for MRSA
Adverse reactions and contraindications of folic acid inhibitors (Sulfamethoxazole, Sulfacetamide, Sulfadiazine,Pyrimethamine, Trimethoprim)
Adverse Reactions
• Hypersensitivity
Ocular: (Sulfonamides)
• Myopia +/- astigmatism (reversible)
Contraindication
• Pregnancy
DNA SYNTHESIS INHIBITORS (fluoroquinolones)
- The most commonly used class of antibiotics
- Newer generations provide greater gm + coverage over and
above the excellent gm - coverage - Nalidixic acid is the original, 1st gen fluoroquinolone; not used in
eyecare - Ciprofloxacin is available as an ointment also; the solution has no
age restrictions
Bactericidal; inhibit DNA gyrase and topoisomerase IV
- 1st Generation
- Nalidixic acid
- 2nd Generation
- Norfloxacin, Ciprofloxacin, Ofloxacin
- 3rd Generation
- Gemifloxacin, Levofloxacin
- 4th Generation [2003] (“Respiratory Quinolones”)
- Moxifloxacin, Delafloxacin
Fluoroquinolone adverse reactions and contraindications (Ciprofloxacin,ofloxasin,moxiflox)
Adverse Reactions
• CNS disturbances: insomnia, confusion, impaired memory, delirium…
Contraindications
• MG
• QT prolongation, arrhythmias, cardiopathies
Black Box Warnings
• Tendonitis, tendon rupture
• Peripheral neuropathy, CNS effects
• Avoid in myasthenia gravis (exacerbation of muscle weakness)
CHEMOTHERAPEUTIC ANTIBIOTICS (Mitomycin)
*
Adverse effects of topical mitomycin (chemotherapeutic antibiotic)
Adverse Reactions
• Ocular: Blebitis, corneal reaction, endophthalmitis, hypotony,
iritis
Severe:
• Ocular: Cataracts, retinal detachment, vision loss
ANTIBIOTIC RESISTANCE
- 80% of the 35 million lbs of ABX used annually in the US is for animal growth promotion
- In 2019, antibiotic resistance was responsible for the death of 40,000 Americans
- Resistance is notably problematic with fluoroquinolones and macrolide antibiotics
- Only ABX have transmissible resistance; Gm⊖ are especially adept at exchanging DNA within their phyla
- Antibiotic treatment regimens are routeinely exaggerated in length; many studies have shown that shorter intervals (3-7 days) are as effective as longer intervals (7-15 days)
- 1 to 2-week regimens date back almost 1700 years when Roman Emperor Constantine the Great ruled that there would be 7 days in a week
- Drug companies are motivated to create drugs intended for long term or chronic use; new ABX are increasingly uncommon
ANTIBIOTIC RESISTANT BACTERIA
ESKAPE Bacteria
Gm ⊕
- Enterococcus (VRE)
- Staph. Aureus (MRSA)
Gm ⊖
- Klebsiella
- Acinetobacter
- Pseudomonas
- ESBL (e.g. E. coli, Enterobacter)
ESBL: extended spectrum beta-lactamase producing bacteria
- Rational use of antibiotics is essential to reduce the ongoing development of antimicrobial resistance
- Select drugs with the narrowest spectrum necessary for the causative organism
- Use older agents whenever possible; use later generations or fortified formulations for more serious infections
New Paradigms
- Treatment to enhance immunity or disarm pathogens, reducing virulence without cidal actions
- Modulate the host inflammatory response
- Chelate metals etc. that microbes need to thrive
- Use probiotics to crowd-out pathogens
- There is no data to support the claim that a full treatment course must be completed after symptoms are gone; encourage patients to call once symptoms resolve
Antivirals
- In contrast to viricides and many antibiotics, antiviral agents are designed to inhibit viral replication or proliferation
- Because viruses replicate only upon entering cells, they are “hidden” and “protected” within cells
- Cells that host viral particles may experience collateral damage when
antiviral agents are used - Viral mutation affects antiviral drug therapy efficacy; like antibiotics,
antiviral resistance is a common concern - DNA viruses, which are much more abundant that RNA viruses, live with us for a lifetime
- RNA viruses have simple structures, mutate rapidly, and are responsible for many historic epidemics: measles, Ebola, Zika, influenza, and Corona virus
Common ocular viruses
- Adenovirus is a cold virus that is the most common cause of
eye infection- It results in a highly infectious conjunctivitis and/or keratitis
commonly called pinkeye - There is currently no FDA-approved treatment for ocular
adenovirus infections which are normally self-resolving - Palliative care and proper hygiene precautions are advised
- It results in a highly infectious conjunctivitis and/or keratitis
- Herpes Simplex Virus (HSV) is the most common virus of the human body: like Herpes (Varicella) Zoster Virus (HZV), it resides in the ganglia of nerves for life
- By the 4th decade of life, approximately 65% of the US population is seropositive for HSV-1 and 25% for HSV-2; women are infected with HSV-2 more often than men
- Unlike HSV, HZV is responsible for a common childhood infection
- HZV: Chicken Pox (children); Shingles (adults)
- HSV: Type I (orofacial & genital); Type II (genital)
- HZV and HSV can infect both the anterior and posterior segments of the eye
- Human Immunodeficiency Virus (HIV), a retrovirus, has RNA in its genome but
behaves like DNA in the host
• Patients with HIV have an increased risk of 2° infection by cytomegalovirus (CMV)
with AIDS
ANTIVIRAL AGENTS FOR HERPES
- Purines are the two-carbon nitrogen ring bases that are used to produce the DNA/RNA nucleotides adenine and guanine
- Pyrimidines are the one-carbon nitrogen ring bases that are used to produce the DNA/RNA nucleotides thymine and cytosine
- Commonly antiviral agents for herpes (simplex and keratitis) are analogs of pyrimidines (topical ophthalmic formulas only) or purines
PURINE ANALOGS
- Acyclovir (Zovirax®) 200/400/800 mg pO (now in liquid)
- Poorest GI absorption vs Valacyclovir and Famciclovir
- Contains gluten
- Valcyclovir (Valtrex®) 500/1000 mg pO
- Acyclovir prodrug w/ very long plasma half-life
- X-sensitivity seen w/ Acyclovir
- Famciclovir (Famvir®) 125/250/500 mg pO
- Penciclovir prodrug w/ extended plasma life
FUNGAL INFECTIONS
70,000 + species of fungi (eukaryotes)
• Budding unicellular yeasts
• Branching filamentous molds
Ocular involvement
• Cornea, conjunctiva, lens, ciliary body, vitreous body, uvea
• Yeasts: Candida, Cryptococcus
• Molds: Aspergillus, Fusarium, Curvularia
• Enhanced risk of infection w/ contact lens wear, steroids, trauma (inc
LASIK), immunocompromise
Therapeutic concerns
• Drug adverse effects, narrow spectrum of drug activity, poor tissue
penetration, drug resistance
ANTIFUNGALS
Polyenes
• Amphotericin B
• Natamycin (only FDA approved topical; Pregnancy: C)
Pyrimidines
• Flucytosine
Azoles
• Ketoconazole*, Fluconazole, Posaconazole, Voriconazole# ,Itraconazole, Miconazole
Echinocandins
• Caspofungin, Micafungin, Anidulafungin
Mechanism of action of polyenes (amphoteracin b, natamycin)
- Bind fungal ergosterol- increased membrane permeability
(fungistatic low dose/ fungicidal high dose)
Mechanism of action of Pyrimidines (Flucytosine) antifungal
- (developing resistance; rarely used alone)
• Inhibit thymidine synthesis (fungistatic)
Mechanism of action of azoles(ketoconazole, clotrimazole,fluconazole,itraconazole)
- (developing resistance)
• Impair ergosterol synthesis (fungistatic) & some cytochrome
P450 enzymes: may reduce metabolism of other drugs
Mechanism of action of Echinocandins (Caspofungin, Micafungin, Anidulafungin) antifungal
- Inhibit glucan synthesis- weaken cell wall
- Poor oral availability
Adverse reactions relating to topical opthalmics with antifungals
- None applicable to ophthalmic conditions or findings
