Principles of Antibacterial Therapy Flashcards
1
Q
Why not use Augmentin for everything?
(4)
A
- Cost ($10/15 vs $50)
- 3x more side effects
- Resistance
- In the person exposed,
primarily - Stewardship
- Analogy – moving from
studio/1BR apartment
2
Q
Why risk using amoxicillin rather than clindamycin?
Risk of using amoxicillin:
* No risk if the reaction is (4)
A
GI, headache, yeast infection, family history
3
Q
- Any non-SJS rash history to amoxicillin, re-exposed to amoxicillin –% tolerate with no subsequent reactions
- Risk of a severe reaction is –%
- Risk for sever reaction if initial ‘allergy’ was immediate onset, –%
A
93-94
0.001
0.29
4
Q
Risk of Clindamycin
* Among oral antibiotics commonly
prescribed by dentists, — has
the highest fatal (2.9/million
prescriptions), serious (233.2/million
prescriptions), and overall (337.3/million
prescriptions) ADR rates
A
clindamycin
5
Q
Among oral antibiotics commonly
prescribed by dentists, clindamycin has
the highest fatal (2.9/million
prescriptions), serious (233.2/million
prescriptions), and overall (337.3/million
prescriptions) ADR rates.
* — any other dental antibiotic
* >– times higher than amoxicillin
* — has the lowest fatal
(0.1/million prescriptions), serious
(11.9/million prescriptions), and overall
(21.5/million prescriptions) ADR rates
A
Double
15
Amoxicillin
6
Q
Risk of C. difficile
Infection By Antibiotic
* Clindamycin —fold increased risk
* Augmentin —fold
* Cephalexin (Keflex) —fold
* Amoxicillin —fold
* Penicillin —fold
A
25
8.5
3
2
1.8
7
Q
–% mortality rate
within 30 days of
initial CA-CDI
– of patients with
recurrent CDI die
within 6 months
A
1.3
1/3
8
Q
Functional Gastrointestinal Sequelae Is Common
* –% of subjects with C.
difficile later identified with one
functional gastrointestinal
disorder
* 1 additional case of functional
gastrointestinal disorder for
every – diagnoses of C. difficile
A
14.1
12
9
Q
Longer exposure to antibiotics and multiple antibiotics increases —
A
risk
10
Q
Proton Pump Inhibitors Double Risk for CDI
CDI — as high in patients
prescribed a PPI + antibiotic versus
antibiotic alone (OR 2.2; 95% CI
1.52-3.23)
Exposure to PPI prior to initial CDI
event — risk of recurrence
(OR 2.02; 95% CI 1.59–2.55)
A
twice
doubles
11
Q
May consider for higher risk individuals:
(5)
A
- 65yo+
- recent hospitalization or nursing home
- weak immune system (HIV/AIDS, cancer, or
taking immunosuppressive drugs) - previous C. diff infection
- taking proton pump inhibitors
12
Q
Penicillin Class Considerations Review
(4)
A
- Spectrum of Activity
- Penicillin covers…
- Amoxicillin covers…
- Augmentin covers if…
- Early vs. Progressed
- Diarrhea
- Costs
13
Q
Cephalosporins
* Most — do not reduce activity of cephalosporins
A
beta-lactamases
* Active against Gram negatives producing b-lactamase
14
Q
- Several “Generations”
- Each successive generation includes more Gram—- activity
A
negative
15
Q
Cephalosporins
(5)
A
- Most beta-lactamases do not reduce activity of cephalosporins
- Several “Generations”
- Limited side effect profile
- Safely tolerated in penicillin intolerance history
- Poor against anaerobes
16
Q
1st Generation Cephalosporins
* Excellent GRAM POSITIVE Coverage – (2)
* some gram negative activity:
(2)
A
Strep. spps. & Staph aureus
- Proteus, E. coli, and Klebsiella (PEcK)
- Limited oral gram negatives- NO P. gingivalis
17
Q
1st Generation Cephalosporins
Orals
(2)
A
cephalexin (Keflex™)
cefadroxil (Duricef™)
18
Q
2nd Generation Cephalosporins
* Still excellent GRAM POSITIVE Coverage – (1)
* Some additional gram negatives:
(2)
A
Strep. spps.
- Morexella, Haemophilus, Enterobacter, Neisseria
(More HEN PEcK) - Still overall limited oral gram negative- YES P. gingivalis
RX: Cefuroxime 500mg po BID x 5 days
19
Q
2nd Generation Cephalosporins
Orals
(3)
A
cefaclor (Ceclor™)
cefuroxime (Ceftin™)
cefprozil (Cefzil™)
20
Q
Cephalexin Considerations
* Compared to Amoxicillin
* Pro:
* Con:
* Compared to Augmentin
* Pro:
* Con:
A
21
Q
*Individuals allergic to amoxicillin may receive cephalexin as long as the reaction
was not
A
anaphylactic-like.
22
Q
Metronidazole (Flagyl)
●Bactericidal against all —
Bacteroides spps. and Fusobacterium
●Breaks DNA structure directly through production of —
●
A
obligate ANAEROBES
free radicals
Antiprotozoal: amoeba (Entamoeba), Trichomonas, Giardia.
23
Q
Metronidazole
Adverse Reactions:
(4)
A
- Metallic taste, dry mouth
- Dark urine
- Skin rashes
- Disulfiram reaction? (headache, flushing, N/V)
avoidance of alcohol no longer required
24
Q
CYP2C9 Inhibitor: DRUG INTERACTIONS
(3)
A
ÞWarfarin
ÞLithium
ÞPhenytoin
25
Consistent INR elevations
observed with Warfarin’s BFFs
(3)
Bactrim
Flagyl
Fluconazole
26
Warfarin Interactions
CYP2C9 Culprit
(3)
› TMP-SMX
› Metronidazole
› Fluconazole
27
Empiric Warfarin Dose Reduction
* Retrospective, cohort study in a pharmacist-managed anticoagulation clinic
* Anticoagulation patients initiating metronidazole
* Preemptive dose reduction (PDR) of warfarin vs increased monitoring
* Mean warfarin PDR 34.6% ± 13.4%
* PDR patients had no significant increase in INR (p=0.61)
* Mean INR difference +1.28 (p=0.01), monitoring vs PDR
* INR values >4.0 (PDR 0% vs. increased monitoring 46%, p=0.05)
Suggests benefit of ---% preemptive reduction in mean daily warfarin
dose for patients started on concomitant CYP2C9 inhibitor
30%-35
28
Metronidazole (Flagyl)
●General Medical Uses:
(2)
●Resistance is not a problem. Given (2)
Deep space abscesses
Gastrointestinal infections
IV or orally
29
Metronidazole (Flagyl)
DENTAL USES:
(3)
●Combined w/ -Lactams - 1st Line for serious orofacial
infections
“poor man’s Augmentin”
●Management of refractory or progressive periodontitis.
●Rx: Metronidazole 500mg po Q8h x 5days, #15
30
General Antibiotic Mechanisms of Action
Non-Cell Wall Active
(5)
Ribosome, protein synthesis inhibition
* Macrolides
* Clindamycin
* Doxycycline
DNA inhibition
* Metronidazole
* Trimethoprim-sulfamethoxazole
31
General Antibiotic Mechanisms of Action
Cell Wall Active
(3)
* -Lactams
* Penicillins
* Cephalosporins
32
Protein Synthesis Inhibitors
(3)
* Clindamycin – STATIC
* Macrolides - STATIC
* Tetracyclines – STATIC
33
Clindamycin (Cleocin™) – IV and PO
Activity for Gram Positives and Anaerobes
(3)
* Strep. & Staph. including MRSA
* Anaerobic gram negatives: Actinomyces, Bacillis, Bacteroides (increasing resistance)
* No aerobic gram-negatives
34
Clindamycin (Cleocin™) – IV and PO
Clinical advantages
(2)
* PVL toxin inhibition
* Biofilm inhibition/penetration
35
Clindamycin (Cleocin™) – IV and PO
Disadvantages
(3)
* C. difficile infection
* Clindamycin oral suspension unpleasant taste
* High doses of oral clindamycin (>450 mg Q6H) may cause esophagitis
36
Clindamycin (Cleocin™) – IV and PO
Additional Dental Advantages
(2)
●High penetration into saliva, gingival tissues, and bone
●Minimal renal concerns
37
Clindamycin (Cleocin™) – IV and PO
●In dentistry:
Late or severe endodontic infections & abscesses
with severe PCN allergy
■Rx: Clindamycin 150mg po TID x 5days, #15
■May use 300mg – likely more GI side effects; reserve
for SEVERE infections
38
Movement Away from
Use in ‘Allergies’
Single dose clindamycin associated with
significant rates of fatal and nonfatal
ADRs
* Amoxicillin : 0 fatal and 22.62 non-fatal
ADRs per million prophylactic courses
* Clindamycin : 12.6 fatal and 149.1 non-
fatal ADRs per million prophylactic courses
Review of Minnesota CA-CDI, 15% of
cases had antibiotics prescribed for
dental procedures
* Cases 5x more likely to be prescribed
clindamycin (P < 0.001
clindamycin is no longer recommended to be prescribed for dental tx
39
--- is no longer recommended for antibiotic prophylaxis for a dental procedure
clindamycin
40
Greater Reliance on Cephalosporins in Allergies
Fatal anaphylaxis from a single dose of a cephalosporin in patients
with no history of a serious reaction <
1 per 1 million doses
41
Tetracyclines
- Tetracycline (Achromycin), Doxycycline (Vibramycin), Minocycline (Minocin)
(5)
* MOA: Bind to 30S subunit of Ribosome
● Bacteriostatic
● Broad spectrum activity but mostly for gram positives
● Requires active transport into cells- source of resistance
● Chelate/Bind divalent cations.
- Binds with Ca++, Mg++, antacids, iron or multivitamins.
● No renal or hepatic adjustment
- cleared totally unchanged in fecal excretion
42
Limited Risk for C. difficile as Respiratory Agent
Meta-analysis, antibiotic class and risk CA-CDI
* Tetracyclines demonstrated
no increased risk (OR, 0.92) vs no antibiotic
exposure
43
Doxycycline Tooth Discoloration in Pediatrics
(3)
No tetracycline-like staining observed in any of the exposed children’s teeth
(0/58), and no significant difference in tooth shade versus controls (P = .20)
* Low concern for tooth discoloration for doxycycline
* May consider overall doxycycline exposure for child
44
Doxycycline Considerations
(7)
* Tooth Discoloration:
* Avoid during pregnancy
* GI upset
* Erosive esophagitis – avoid taking at bedtime, drink full glass of water
* Peak plasma concentration may be reduced ~20% by high-fat meal or milk
* Phototoxicity (skin rashes) may occur
* Renal/hepatic disease patients can use doxycycline
45
* Tooth Discoloration:
Updated recommendations from the American
Academy of Pediatrics permit doxycycline for ≤21 days in children of all ages
46
* GI upset
* More common with ----
* --- less acidic, better tolerated
hyclate salt
Monohydrate
47
Tetracyclines
Dental Uses:
Periodontal only.
●No longer used for odontogenic infections due to resistance:
■Management of localized juvenile periodontitis (Aggressive Periodontitis) – Aggregatibacter
actinomycetemcomitans (AA) –make -lactamase
■AA sensitive to Tetracyclines, Fluoroquinolones, Bactrim™... ?Augmentin.
■Additive Effects:
Concentrates in the gingival crevice extremely well, 7–20 times more than any other drug
Anticollagenase
Anti-inflammatory
Inhibition of bone resorption
Promotes reattachment
48
Tetracyclines
Low-dose systemic doxycycline for refractory agg. periodontitis
● Periostat™ (100 mg PO daily)
● Local application in adjunctive tx for resistant periodontitis:
(2)
Atridox™ gel (doxycycline)
Arestin™ (minocycline microspheres)
49
Macrolides
Azithromycin, Clarithromycin, Erythromycin
* MOA:
Binds to 50S Ribosome (Static), prevents transpeptidation
* Time Dependent Killing Effect
50
Macrolides
ERTHYROMYCIN: NOT USED
●Narrow spectrum:
■ Adverse effects: (4)
■ Strong inhibitor of --- –many drug interactions.
■ Highest --- prolongation risk among antimicrobials
LOTS of resistance
Prokinetic, GI disturbances, diarrhea, cramping
CYP3A
QTc
51
Macrolides
Clarithromycin (Biaxin) –AVOID USE
Liver metabolism:
Moderate CYP3A inhibitor.
Prodrug: metabolized to active compounds
Less drug-drug interactions than
Erythromycin but more than azithromycin
●H.pylori – chronic dyspepsia, peptic ulcer
development, and gastric cancer
Triple Therapy (PPI, amox, clarith) or Quadruple (PPI,
amox, Flagyl, and bismuth)
●Taste Disturbances: Metallic taste
52
MacroliCYP3A4 Suppression & Drug Interactions
(2)
* Both Erythromycin and Clarithromycin slow CYP3A4
* Azithromycin limited effect on CYP3A4
53
* Both Erythromycin and Clarithromycin slow CYP3A4
* Accumulation of other drugs that are metabolized through 3A4
(4)
* Benzodiazepines
* Transplant Drugs (cyclosporine, tacrolimus)
* HIV Drugs
* CCBs (amlodipine, diltiazem)
54
Macrolides
Azithromycin (ZPack; Zithromax) – IV and PO
(2)
● Improved infected tissue penetration and half life
- Concentrates in tissues, phagocytes, & fibroblasts giving it a long half-life.
● No phase I metabolism.
- Eliminated unmetabolized – no drug interactions
- Long half-life (60hrs) - qday dosing.
- Must use loading dose. (2x)
55
Macrolides
Azithromycin (ZPack; Zithromax) – IV and PO
Side Effects:
(2)
* Possible reversible tinnitus with large doses
* Liver reports – jaundice, necrosis, failure
56
Macrolides
Dental uses:
Used in odontogenic and periodontal infections in early, non-abscess
infections as 2nd alternative or in severe penicillin allergies
■ No activity against Bacteroides, common in dental abscesses
■ Alternative antibiotic in odontogenic infections.
■ Less effective than - Lactams (2nd choice)
■ Overall limit use due to already high resistance rates.
■ 50% of viridans group Streptococci resistant
57
Macrolides
Prescriptions:
Orofacial Infection:
Perio Infection:
500mg, then 250mg PO Daily x 4 days
500mg PO Daily x 5 days
58
Drug Selection Factors
(6)
* Common pathogens = Empiric Therapy Targets
* Site of Infection
- Ability to penetrate infection site
* Patient Allergies and Drug Adverse Reactions (Tolerance)
* Renal and Hepatic Function, Patient’s Age
- Clearance and Metabolism of Antibiotics
* Concomitant Medications (drug interactions) and Past Medical History
* Pregnancy or Breastfeeding
59
Teratogen –
Agent that can potentially cause a birth defect or negatively alter cognitive and
behavioral outcomes
* Physical, cognitive, behavioral
60
Teratogenicity
Determinants –
(4)
* Dose of toxicant
* Half-life of toxicant
* Placental permeability
* Stage of development
61
Pregnancy and Lactation
* Good Safety
(4)
* Avoid
(4)
* Cephalosporins, penicillins, clindamycin, azithromycin
* Doxycycline – Ca++ chelation
* Fluoroquinolones – kidneys/cartilage
* Sulfamethoxazole/trimethoprim – various/kernicterus
* Metronidazole in 1st Trimester – limited data
62
* Prophylactic Therapy
(2)
–To prevent an infection
–i.e. Amoxicillin prior to dental work
63
* Empiric Therapy
(2)
–To cover most likely pathogens
–i.e. Augmentin for acute periodontal abscess
64
* Directed Therapy
(2)
–Target toward specific pathogen
–i.e. Cephalexin for MSSA skin infection
65
When Are Antibiotics Indicated/ Recommended?
Yes
(4)
* NUG – systemic symptoms or
immunocompromised
* Aggressive Periodontitis
* Fascial space infection
* Endo/Perio with systemic symptoms
66
When Are Antibiotics Indicated/ Recommended?
No
(4)
* Endodontic conditions
* Chronic Periodontitis or Gingivitis
* Periodontal Abscess
* NUG – no systemic symptoms
67
Consider Systemic Antibiotics
(5)
Signs/symptoms of systemic spread – pyrexia, malaise and worsening of general condition
Rapid onset and progress
Infection in immunocompromised patients
Swelling involving submental/submandibular or parapharyngeal spaces (potential airway compromise)
Presence of trismus indicates involvement of peri-mandibular spaces and is a serious sign
68
Antibiotics in Odontogenic Infections
Antimicrobial agents are indicated if
fever and regional lymphadenopathy are
present, or when infection has perforated the bony cortex and spread into
surrounding soft tissue.
69
* Early Infection (< 3 days)
●Penicillin VK or Amoxicillin
●If recent mild/mod intolerance – ---
●If severe allergy - ---
●No Improvement (48 hrs)
(4)
Ceftin
clindamycin
●B-lactamase producing? Anaerobic?
●Discontinue Penicillin –Switch to:
● Augmentin® or
●amoxicillin + metronidazole (cheaper but
bigger pill burden)
70
* Late Infection (abscess or > 3 days)
think anaerobes and Gram negative
(4)
●Augmentin®
-Amoxicillin + Metronidazole
-Cephalosporin + Metronidazole
-Severe allergy, Clindamycin
71
Bacterial Infective Endocarditis (BIE):
85% are (2)
~5% caused by ...
Infection of endocardium or valves from blood born bacteria.
Staphylococci spps & Streptococci spps
HACEK group Gram-Negatives
(Haemophilus spps, A. actinomycetemcomitans, Cardiobacterium
hominis, Eikenella corrodens, Kingella kingae)
72
* HACEK are --- with potential for infection.
oral flora
73
Rationale for Prophylaxis
Pathogenesis involves following sequence of events:
(4)
* Formation of a small thrombus on an abnormal endothelial surface
* Bacteria access blood circulation (bacteremia)
* Secondary infection of thrombus with bacteria circulating in bloodstream
* Proliferation of bacteria resulting in cardiac vegetation on endothelial surface
74
* Formation of a small thrombus on an abnormal endothelial surface
(2)
* Surgical Intervention
* Turbulent blood flow produced by congenital or acquired heart disease
75
Antibiotic Prophylaxis & Infective Endocarditis
Meta-analysis of three case-control studies observed no statistically significant
association between IE cases and failure to use antibiotic prophylaxis (odds
ratio 0.59, 95% CI 0.27-1.30, P=0.14)
Antibiotic prophylaxis reduces bacteremia
› Meta-analysis of 21 trials of antibiotic prophylaxis observed a reduction in
post procedural bacteremia (RR 0.53, 95% CI 0.49-0.57, P<0.01).
The occurrence of bacteremia is crucial to initiate an episode of BIE, in theory
preventing or promptly treating transient bacteremia will prevent BIE
76
Prophylaxis against IE is reasonable before dental procedures that involve
manipulation of gingival tissue, manipulation of the periapical region of
teeth, or perforation of the oral mucosa in patients with the following:
(5)
1. Non-native cardiac valves
2. Cardiac valves repaired with prosthetic material
3. Previous IE
4. Cardiac transplant with valvular regurgitation
5. Pediatric - Unrepaired cyanotic congenital heart disease or repaired
congenital heart disease, with residual shunts or valvular regurgitation
77
Benefit in High-risk Patients
* Analysis of 3,774 patients with IE
* Prophylaxis for IDPs in high IE risk patients
resulted in over --% reduction in IE risk
(P < 0.002) compared with no prophylaxis
* Primary benefit in extractions (--% reduction)
and oral surgical procedures (>--% reduction)
* No benefit observed for other IDPs or in
moderate or low/unknown IE risk
70
87
90
78
Avoid Antibiotic Prophylaxis
(7)
› Routine anesthetic injections through noninfected tissue
› Dental radiographs
› Placement of removable prosthodontic appliances
› Placement or adjustment of orthodontic appliances
› Placement of orthodontic brackets
› Shedding of deciduous teeth
› Bleeding from trauma to the lips or oral mucosa
79
Normal Flora of Mouth
(5)
› Viridans Group Streptococci
› Strep spps.
› Lactobacillus
› Actinomyces spps.
› Prevotella spps
80
Notable Changes in
2021 AHA Statement
* Consideration of adverse drug
reactions –
* Specific statement about ---
allergies
* Consideration of drug resistance –
resistance rates for --- higher
than for penicillin
clindamycin
penicillin
macrolides
81
Allergies:
Amoxicillin Versus Cephalexin Versus Azithromycin
Amoxicillin for:
(6)
Non-allergic ADR Hx
Vomiting
Nausea
Runny Nose
Cough
Family Hx of Allergy
82
Allergies:
Amoxicillin Versus Cephalexin Versus Azithromycin
Cephalexin for:
(4)
Low risk ADRs Hx
Diarrhea
Non-Hive Rash
Itching
83
Allergies:
Amoxicillin Versus Cephalexin Versus Azithromycin
Azithromycin for:
(7)
High risk ADRs Hx
Lip/Facial Swelling
Breathing
Difficulty/Wheezing
Skin Peeling
Mouth Blisters
Drop in Blood Pressure
Hive Rash (per guidelines)
84
Antibiotic Considerations
* Antibiotic should be prescribed and administered --- procedure
* --- dose only
* If patient forgets to take antibiotic before procedure, instruct to take within ---
hours following procedure
* If procedure spans --- days, a separate preventative dose is recommended
for each procedure
before
Single
2
multiple
85
* Invasive dental procedures cause bacteremia, which can be complicated by
IE in
those at increased risk of the disease
86
* Patients with (3) are at highest risk of IE
prosthetic heart valves, previous infective endocarditis, and some
types of congenital heart disease
87
* Patients undergoing procedures that involve (3)
are at highest risk for bacteremia
manipulation of gingival tissue,
manipulation of the periapical region of teeth, or perforation of the oral mucosa
88
* --- reduces the incidence of bacteremia, but no high level
studies exist to confirm that this reduces the incidence of IE
Antibiotic prophylaxis
89
* Warn high risk patients undergoing high risk dental interventions of the risk of
infective endocarditis. Offer these patients
antibiotic prophylaxis, and discuss
with them the risks and benefits of this option
90
* --- prior to dental procedure preferred
Amoxicillin 2gm X1 dose 30-60mins
91
Matched Case-Control study; 339 patients with PJI versus 339 without
* Reviewed dental procedure exposure in previous 6-24 months
* Controlled for potential confounder variables
* No increased risk of PJI following ...
* Antibiotic prophylaxis in high- or low-risk dental procedures not associated
with reduced PJI risk (OR, 0.9; 95% CI, 0.5–1.6 and 1.2; 95% CI, 0.7–2.2)
high- or low-risk dental procedure not
administered antibiotic prophylaxis (OR, 0.8; 95% CI, 0.4–1.6)
92
