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Week 17 – Antibiotics: Bugs and Drugs
Approach to Learning about Drugs for Bacterial Infections
- HUGE topic area
Areas of focus:
- Basic principles of antibiotic therapy (Lehne Chap 83) and bacterial resistance
- Host factors impacting antibiotic therapy and success
- Nursing implications for antibiotic therapy (assessment and monitoring, adverse effects, patient education)
** Will not be tested on specifics of antibiotic spectrum of activity or pathogens involved in specific types/sites of infection
Approach to Thinking about Bacteria
- Enormous number of bacterial species
- Systems for describing and classifying bacteria are helpful because
Provides a mental framework
Gives insight into the properties of organism(s) involved in an infection
Has implications for treatment decisions – i.e. drugs which are effective against one bacteria in a class more likely to be
effective against others in the same class
Describing and Classifying Bacteria: 1. Gram Staining Test
- Examines bacteria under microscope after applying a stain
- “Gram positive” have a thick cell wall and retain the stain
- “Gram negative” have a thin cell wall and do not retain the stain
- Important pathogenic and biochemical differences between gram positive and negative bacteria and their sensitivity to antibiotics
Describing and Classifying Bacteria: 1. Gram Staining Test – Examples
Gram positive
Staphylococcus (aureus, epidermidis)
Streptococcus (pneumococcus, viridans)
Enterococcus (faecium, faecalis)
Gram negative
Escherichia coli, Salmonella, Shigella
Haemophilus influenza
Klebsiella, Enterobacter, Proteus, Pseudomonas aeruginosa
Describing and Classifying Bacteria: 2. Shape
- Examining bacteria under the microscope to determine shape
- Rod shaped – called “bacillus/bacilli”
- Spherical shaped – called “coccus/cocci”
- Spiral shaped – called “spirillum/spirilla”
Describing and Classifying Bacteria: 3. Bacterial Respiration
- Nutrients are converted into energy in the process of bacterial respiration
- This process may or may not require oxygen
- “Aerobes” – thrive in oxygen-rich environment
- “Anaerobes” – grow best without oxygen
Implications?
- can help to predict what bugs may be present at the site of infection (anoxic or not)
- e.g. skin infection – aerobic bacteria
- e.g. bowel infection, abscess – anaerobic bacteria (areas with low O2)
Describing and Classifying Bacteria: 3. Bacterial Respiration – Examples
Aerobes
Gram positive: Staphylococcus (aureus, epidermidis), Streptococcus (pneumococcus, viridans)
Gram negative: Escherichia coli, Haemophilus influenza, Pseudomonas aeruginosa
Anaerobes
Gram positive: Peptococcus, Peptostreptococcus, Clostridia
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Gram negative: Bacteroides fragilis
Types of Antimicrobial Drugs
- Antibacterials (Antibiotics) – our main focus
- Antivirals
- Antifungals
Selective Drug Toxicity
- Ability of a drug to injure a target cell without injuring neighboring/host cells
- Antibiotics can be highly toxic to microbes but benign to host cells
- Drugs exploit differences between bacterial and mammalian cells
e.g. targets = bacterial cell walls, unique enzymes, bacterial protein synthesis
Classifying Antibiotics by Mechanism of Action
Disrupt bacterial cell wall
Penicillins/cephalosporins/carbapenems ( lactams)
Vancomycin
Isoniazid
Daptomycin
Disrupt bacterial cell membrane
Disrupt bacterial biochemical reactions
Sulfonamides
Trimethoprim
Disrupt bacterial DNA structure or synthesis
Fluoroquinolones
Metronidazole
Rifampin
Inhibit bacterial protein synthesis
Macrolides
Aminoglycosides
Clindamycin
Tetracyclines
Linezolid
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Bactericidal vs. Bacteriostatic Agents
Bactericidal
 Kill organism by cell lysis
 Rely less on host immunity for clearing infection
 Preferred for infection at sites of poor penetration
Bacteriostatic
 Inhibit bacterial replication
 Do not kill the organism but allow host immune system to clear infection * not good for compromised immune systems
Basic Principles of Antimicrobial Therapy
Therapeutic Goal
- Achieve maximal antimicrobial effects (killing) with minimum harm to host
- “Match the bug with the drug”
- Key considerations in antibiotic selection:
 What is the infecting organism?
 Is the infecting organism sensitive to the drug?
 Host factors (site of infection, status of host defenses)
What is the Infecting Organism? Gram Staining Test
- Probes cell wall structure (gram positive vs. gram negative) – important for antibiotic penetration
- Bacterial shape (e.g. bacilli, cocci) also determined on microscopic examination
- Relatively rapid test, helps with preliminary diagnosis and empiric antibiotic selection
What is the Infecting Organism? Speciation
- Different tests/combinations of tests may be used in the Microbiology Lab to identify bacterial species
 Morphologic characteristics, biochemical tests and susceptibility tests most common
 Other less common tests include serologic tests, PCR or nucleic acid amplification tests
Is the Organism Sensitive to the Drug? Culture & Sensitivity (C&S) Testing
- Sample is cultured (in tubes or disks) in presence of antibiotics and growth is measured
- Provides information on sensitivity to different antibiotics
- Organism reported as either:
 sensitive (S)
 intermediate (I)
 resistant (R)
- to each antibiotic tested
- little growth…organism is sensitive to antibiotic; in some cases it is unclear, might see intermediate reported.
Limitations of C&S Testing
- Can take several days for results
- Don’t always grow something (anaerobic bacteria or fungi difficult to culture in a test tube/disc)
- Organism(s) identified may not be the causative pathogen
- Samples (e.g. blood, urine, sputum) must be obtained before starting antibiotics
- Problems with getting a good sample (e.g. sputum)
- Positive culture may represent colonization, contamination or infection
Is the Organism Sensitive to the Drug? Empiric Antibiotic Selection
- Ideally, want to identify pathogen and determine drug sensitivities before starting therapy (C&S)
BUT….
- Usually need to start therapy before C&S results available
- C&S may not yield any useful info
Approach?
Make an educated guess in choosing appropriate initial therapy – once C&S results available, tailor therapy as appropriate
Is the Organism Sensitive to the Drug? Empiric Antibiotic Selection
- Choice based on knowledge of bacteria usually causing infection at that site
- Normal flora
 bacteria normally residing in a given area, protect against invasion by pathogenic bacteria
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 under the right circumstances normal flora may cause infection
Skin, nasopharynx, pharynx: Staphylococcus, Streptococcus
Stomach: Helicobacter Pylori
Bowel: Bacteroides, E. coli, enterococcus
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Host Factors: Empiric Antibiotic Selection
- Factors affecting normal flora:
 Disease states (e.g. COPD, smokers)
- Where patient lives/works
 Hospitalized patients (and health care workers) have  proportion of gram negatives
- Previous/recent antibiotic use
 May allow overgrowth of resistant bacteria
Host Factors: Empiric Antibiotic Selection
Also must consider:
 Host defenses
 Site of infection
 Age
 Pregnancy and lactation
 Allergies
 Recent exposures (e.g. travel, contact with other infected individuals)
Host Factors: Empiric Antibiotic Selection
- Host defenses
 Antibiotics work together with patient’s immune system to resolve infection
 goal of therapy is to suppress growth to the point at which balance is tipped in favour of host
- Immunosuppressed patients (e.g. patients receiving cancer chemotherapy, transplant patients, AIDS, etc.) may need more
aggressive treatment
Host Factors: Empiric Antibiotic Selection
Site of Infection
- Antibiotics must get to site of infection to work
- Generally have poor penetration to:
 Brain (i.e. meningitis) – BBB
 Bone (i.e. osteomyelitis)
 Heart (i.e. endocarditis)
 Abscesses – require surgical drainage
- Need  doses to sites of poor penetration
Host Factors: Empiric Antibiotic Selection
- Some agents cross placenta and may impact fetal development – need to choose wisely
- Generally considered safe in pregnancy:
 Pencillins, cephalosporins, clindamycin, erythromycin (most forms), azithromycin
- Avoid in pregnancy:
 Fluoroquinolones, Septra, tetracyclines, metronidazole
- Others - weigh risk vs. benefit, may depend on trimester
Host Factors: Empiric Antibiotic Selection
- Age
 Infants and elderly – may not be able to use certain agents due to poor drug metabolism or elimination
- Allergies
 1-10% of patients
 Range from mild (e.g. maculopapular rash) to severe (anaphylaxis)
 Drugs with similar structure (e.g. penicillins and cephalosporins) may be cross-reactive although this has been overestimated
in the past
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Antibiotics: Combination Therapy
Combining antibiotics may result in:
Additive response
 Antimicrobial effect = sum of effects of each agent
Synergistic response
 Antimicrobial effect > sum of effects of each agent
Antagonistic response
 e.g. when combining a bactericidal agent with bacteriostatic agent
Combinations may be appropriate for:
1. Initial therapy of severe infection (esp. in immunocompromised patients)
2. Mixed infections with multiple infecting organisms (e.g. brain abscess, pelvic infection)
3. Prevention of resistance (e.g. tuberculosis)
4. Decreasing toxicity (allows for  doses)
5. Synergistic activity (esp. for hard to kill bugs such as Pseudomonas)
Antibiotic Dosing
Factors to consider:
 Patient weight (some drugs dosed mg/kg)
 Site of infection
 Route of elimination – Change to dosing regimen needed for renally eliminated agents in patients with renal impairment
 Time vs. concentration-dependent killing
Minimum Inhibitory Concentration (MIC)
- Lowest concentration of antibiotic required to inhibit visible bacterial growth in vitro
 a measure of activity of an antibiotic against a specific bug – i.e., if a drug has a low MIC against a particular bacteria, it
means that it is very active against that bacteria…doesn’t take a lot of that drug to inhibit the bacterial growth
--if the MIC is high, it takes a lot of that drug to inhibit the bacterial growth = not a good choice to be using against that
infection
- Correlates to dosage regimen or amount of antibiotic required for clinical efficacy
- Need serum and tissue concentrations to exceed the MIC to be effective (4-8 times the MIC for it to be effective)
Time vs. Concentration Dependent Killing
 Time-dependent killing
- Rate and extent of killing determined by length of time drug level remains above MIC
e.g. penicillins, cephalosporins, erythromycin
 Concentration-dependent killing
- Rate and extent of killing improved with high peak drug concentration
e.g. aminoglycosides, fluoroquinolones
Renal Dose Adjustment
- Required for agents with high renal elimination
- Time-dependent killing – better to  dose
 Beta-lactams, cephalosporins (most), sulfonamides
- Concentration-dependent killing – better to  interval – rate and extent of killing depends on peak drug cctn and MIC; keep dose
as it is and increase dosing interval (i.e., keep dose the same 500mg, but over more time 24h vs 12h)
 Fluoroquinolones, aminoglycosides, vancomycin
Antibiotics: When to start?
Treatment
- Clinical suspicion of infection (signs and symptoms)
- Start ASAP
 Higher rates of cure and lower mortality when therapy started early
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Antibiotics: When to Stop?
- Antibiotics should never be discontinued prematurely due to risk of recurrent and potentially more treatment-resistant infection
 Patient education: complete course of therapy even if feeling better
- But…. should not prolong duration due to potential for developing resistance
- Duration variable according to host factors, organism, site of infection; 7 to 14 days is a common duration
Antibiotics: When to Stop?
 Status of host defenses – may need longer treatment if immunocompromised
 Site of infection – need longer treatment for sites of poor penetration e.g. osteomyelitis - minimum 6 weeks
 Infecting pathogen – harder to kill bugs may need longer treatment
 Repeat cultures are negative
 Patient response -- What to monitor?
Patient Assessment and Monitoring
1. Fever (oral temp > 37.8ºC (100ºF))
 less pronounced in elderly, debilitated, immunocompromised – can’t mount febrile response effectively
 may be associated with chills or rigors
 some drugs can cause fever
 may have  temp in severe infection
*treating fever itself doesn’t harm or help…but relieves symptoms; low-grade fever might be better not to treat, but
high temps esp. in critical care can increase metabolic demands, so good to cool in those situations
2. Affect
 light-headedness, weakness, myalgias, arthralgias, headache, anorexia, malaise, confusion, delirium
3. Leukocytosis
  WBC,  neutrophils
4. Metabolism – catabolic response
 loss of nitrogen, Mg2+, K+, PO45. Cardiovascular effects
  HR,  RR,  BP
6. Renal effects
 Proteinuria, dehydration and  BP,  renal perfusion,  urine output
7. Site-specific symptoms
 UTI: frequency, dysuria, flank pain
 pneumonia: cough, sputum production, chest pain
 meningitis: neck rigidity, headache
Antibiotic Efficacy Evaluation
- For most infections, signs and symptoms should start to improve within 1 day
- When to be concerned:
 Fever unresolved after 3 days
 Increasing signs and symptoms
 Continued symptoms after course of therapy complete
 need to re-evaluate patient and antibiotic selection
When to Give Antibiotic Prophylaxis?
- Use when suspected or anticipated exposure to pathogenic organism (e.g. travel, contact with known infected person, surgery,
etc.)
- Use minimum duration possible
Common Indications for Antibiotic Prophylaxis
1. Surgical procedures
2. Bacterial endocarditis
 Prosthetic heart valves or congenital heart disease – need antibiotics prior to surgery, dental work
3. Neutropenia
 High risk patients (e.g. receiving chemotherapy)
4. Other
 Recurrent UTI, HIV +, other immunosuppressed patients (e.g. transplant)
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Bacterial Resistance
- Growing problem – drugs which were once effective are now useless against resistant bugs (~20%)
- Examples of resistant bugs (“superbugs”):
 Enterococcus – becoming resistant to vancomycin (i.e. VRE)
 Staphylococcus aureus – becoming resistant to penicillins (i.e. MRSA)
 Escherichia coli
 Pseudomonas aeruginosa
- Knowledge of local resistance patterns important in antibiotic selection
Bacterial Resistance
- Leading cause of bacterial resistance is misuse and overuse of antibiotics
- Bacteria become resistant due to adaptive changes in structure or function:
  drug metabolizing enzymes
  active uptake of drugs
 Change in microbial drug receptors
 Synthesis of compounds that antagonize drug action
- Bigger problem with broad spectrum agents
Examples of Antibiotic Misuse
- Wrong drug
 use of broad spectrum agent to treat highly susceptible bacteria
 incorrect drug selection for pathogen
- Wrong dose (esp. sub-therapeutic)
- Wrong timing (esp. starting too late)
- Wrong duration
- Use in viral infection (e.g. common cold)
- Treatment of fever of unknown origin in immunocompetent patient
Other Contributors to Bacterial Resistance
- Failure to follow infection control practices
- Omission of surgical drainage (e.g. abscesses), not removing catheter
- Medication error
- Medication non-adherence
- Self-medicating or antibiotic sharing
The Importance of Antimicrobial Stewardship *vid
How to Promote Appropriate Antibiotic Use?
STRATEGY
DESCRIPTION
Antimicrobial specificity
Target drugs to bugs, minimize use of broad
spectrum agents
Appropriate duration
Limit duration of use
Appropriate route
Step down from IV to PO
Surgical prophylaxis
Timing – within 30 min of first cut
Duration – usually no more than 24 hrs post-op
Follow established guidelines
Timing of administration
Prompt and timely; initiate early for suspected
sepsis
Right dose, therapeutic
drug monitoring
Maximize efficacy and minimize toxicity
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Outpatient antibiotic
therapy
Decreases hospital length of stay, risk of
healthcare associated infections and costs
Totally optional
….but a great article
Comprehensive Overview of Antibiotic Resistance in Canada (Canadian Antimicrobial Resistance Alliance)
Available at: http://www.can-r.com/mediaResources/ComprehensiveOverview.pdf
The Antibiotics
Beta-Lactam Antibiotics
- Contain a beta-lactam ring
- Mechanism of action: inhibit bacterial cell wall synthesis (bactericidal)
 Target penicillin-binding protein (PBP) on cell cytoplasmic membrane
 PBPs are responsible for cell wall synthesis
- Safe drugs since mammalian cells lack cell wall and PBPs (basis of selectivity)
- Drug classes: penicillins, cephalosporins, carbapenems
The Bacterial Cell Envelope
envelope encompasses both cell membrane and cell wall that make up outer later of bacteria
gram positive – thick – two layers
gram – positive – cell wall is thinner but they have extra outer membrane that makes treatment a bit more challenging
Penicillins
- Many agents, all have suffix “-cillin”
- Types:
 Natural penicillins (narrow spectrum)
 Penicillinase-resistant penicillins
 Aminopenicillins
 Extended-spectrum penicillins
 Penicillins + beta-lactamase inhibitor
- Resistance arises due to penicillinases and gram negative cell envelope (more difficult for penicillins to penetrate)
Natural Penicillins
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Penicillin G = IV form (not orally bioavailable)
Penicillin V = oral form (stable in stomach acid)
Common therapeutic uses
 Infections caused by sensitive gram positive cocci (e.g. Streptococcus)  some pneumonia, endocarditis, meningitis
cases
Narrow spectrum, inactivated by penicillinases
 Most staphylococci produce penicillinases making them resistant to natural penicillins
Bacterial Resistance to Penicillin
- Bacteria produce enzyme (“beta-lactamase” aka “penicillinase”) that cleaves the β-lactam ring to inactivate penicillin
Penicillinase-Resistant Penicillins
- Prototype: cloxacillin
- Resist inactivation by penicillinase
 Only agents in penicillin class that are effective against staphylococcus
- Common therapeutic uses
 Uncomplicated skin and soft tissue infection
- Not effective against MRSA = Methicillin Resistant Staph Aureus
 Bacterial strain with altered PBPs to which penicillins cannot bind
Aminopenicillins
- Main agents: ampicillin (IV/PO), amoxicillin (PO)
- Broader spectrum – active against some gram negative bugs (e.g. E. Coli) due to ability to penetrate gram negative cell envelope
- Common therapeutic uses
 UTI, respiratory tract infection, otitis media
- Amoxicillin preferred over ampicillin for oral use (higher bioavailability, less diarrhea)
Antipseudomonal Penicillins
- Main agent: piperacillin (IV)
- Even broader spectrum due to even better ability to penetrate gram negative cell envelope
 Active against Pseudomonas
- Common therapeutic uses
 Serious infections (e.g. sepsis) due to Pseudomonas, especially in the immunocompromised host
 Often combined with other anti-pseudomonal agents (e.g. aminoglycosides)
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Penicillins + Beta-Lactamase Inhibitor
- Combining penicillin with a -lactamase (penicillinase) inhibitor broadens spectrum of activity
- Common examples:
 Amoxicillin + clavulinic acid (Clavulin®) (PO)
 Piperacillin + tazobactam (Tazocin®) (IV)
- Only available in fixed-dose combinations
Cephalosporins
- All names start with “ceph-” or “cef-”
- Most widely used class of agents, very safe
- 4 “generations” available in Canada
- As  generation:
 more resistant to beta-lactamases
  gram negative,  gram positive coverage
  CSF penetration – cross BBB, preferred for meningitis
Cephalosporins: Examples and Common Therapeutic Uses
- First generation (cefazolin IV, cephalexin PO)
 Skin and soft tissue infections
 Surgical site infection prophylaxis
- Second generation (cefaclor PO, cefuroxime PO/IV)
 Respiratory tract infections
- Third (e.g. ceftriaxone, ceftazidime) and fourth generation (e.g. cefepime IV)
 Empiric therapy in severe infections (meningitis, febrile neutropenia)
Carbapenems
- Names end in “-penem”
- Broadest spectrum agents available
- Generally resistant to pencillinases
- Reserve for infections not susceptible to narrower spectrum agents
- Parenteral forms only
- e.g. imipenem, meropenem
Beta-Lactams: Side Effects
- GI: nausea, vomiting, diarrhea
- Neurologic: seizures (penicillins; imipenem at high IV doses – avoid if seizure history)
- Dermatologic: thrombophlebitis (minimize by diluting solution and slowing infusion time)
- Allergic reactions (0.4-7% with penicillins) – many people outgrow them, esp. after ~10yr
 range from mild (rash) to severe (anaphylaxis)
 generally avoid penicillins unless benefits outweigh risks
 avoid cephalosporins/carbapenems only if reaction to penicillin is severe (estimated 1% cross reactivity)
Antibiotic Allergy
- Symptoms: itching, rash, swelling (face, tongue, lips), urticaria, flushing, dizziness, syncope, wheezing, throat tightness, trouble
breathing
- Most occur early (monitor with first dose) but delayed reactions possible
- Educate patient on symptoms
- Patients with known antibiotic allergy should carry wallet card or wear Medic Alert bracelet
- Management: antihistamines, corticosteroids, epinephrine
Beta-Lactams: Pharmacokinetics and Drug Interactions
- Most have short half-lives, dosed 3 to 4 times daily (some exceptions)
- Some have better absorption if taken on empty stomach (e.g. cloxacillin)
- Most require renal dose adjustment – time dependent killing
- Combo of aminoglycosides + beta-lactams can increase bacterial killing
But… must not be mixed together in IV bag due to direct chemical interaction
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Vancomycin
- Mechanism of action: inhibits cell wall synthesis (bactericidal)
- Large molecule, not orally absorbed
- Common therapeutic uses:
 Drug of choice for MRSA
 Treatment of serious infections in penicillin-allergic patients
 C. difficile (only if given orally) – infection of the gut, and Vancomycin is a large molecule (won’t be absorbed PO); all
other is parenteral
Vancomycin: Side Effects
- Dermatologic: “Red Man Syndrome”
 Histamine-mediated reaction – flushing of trunk, neck and face; hypotension
 Prevention/management
 slow infusion rate (i.e. extend infusion time from 1 hour to 2 hours)
 pre-medicate with antihistamine
 Not a true allergic reaction, does not preclude future use
- Renal: nephrotoxicity (~5%)
 Minimize risk with therapeutic drug monitoring in at risk patients (avoid high trough levels)
 Higher levels of serum levels, higher risk of renal toxicity (pre-existing renal dysfunction, pts on prolonged therapy, and
pts on high doses)
Vancomycin: Dosing and Administration
- IV and PO forms
 Oral used for gut infections such as C. Difficile
- Renal dose adjustment required (IV only)
 Therapeutic drug monitoring used to titrate dosing regimen  “trough” level drawn immediately before dose is due
Aminoglycosides
- Prototype: tobramycin
- Mechanism of action: disrupt bacterial protein synthesis (bactericidal)
- Large, positively charged molecules, not orally absorbed
- Common therapeutic uses
 Serious gram negative infections (e.g. Pseudomonas) or gram positive infections (if combine with beta-lactam)
 Ophthalmic/otic infections
Aminoglycosides: Drug Interactions
- Combo of aminoglycosides + beta-lactams or vancomycin can increase bacterial killing
 But… must not be mixed together in IV bag due to direct chemical interaction
- Increased risk of renal damage if combined with other nephrotoxic drugs (e.g. vancomycin, NSAIDs)
Aminoglycosides: Side Effects
- Renal: nephrotoxicity (usually reversible)
 monitor serum creatinine, avoid in renal impairment where possible
- Neurologic
 Ototoxicity – tinnitus (ringing in ears), vertigo, headache; may be irreversible
 Paresthesias, seizures
 Monitor and advise patient to report symptoms
-  risk if high trough levels and prolonged duration
 Therapeutic drug monitoring and once daily dosing help to reduce risk
Aminoglycosides: Dosing and Administration
- Once daily dosing preferred over traditional dosing (3 times daily)
 Higher peak = more effective (recall: concentration-dependent killing)
 Post-antibiotic effect = washout period = safer
 More convenient
- Renal dose adjustment required
- Therapeutic drug monitoring used to titrate dosing regimen  “trough” levels ; formulations: parenteral, eye/ear drops
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Aminoglycosides: Post-Antibiotic Effect
PAE: Continued inhibition of bacterial growth despite very
low levels of drug in blood
- red line  blood levels with a once daily dose vs blue line  3X daily dose
- shaded grey area – level of drug in drug that allows “washout” – low enough serum levels to not accumulate in the kidney, ear, etc;
therefore risk of those AE is minimized
- once a day dosing – still continued inhibition of bacterial growth, even though level of the drug in the blood is low
therefore once a day is more effective than 3X a day
Macrolides
- Erythro-, clarithro- and azithromycin
- Inhibit bacterial protein synthesis (bacteriostatic)
- Common therapeutic uses
 Respiratory tract infections (e.g. pneumonia)
 Chlamydia, diphtheria
 Alternative to penicillin in allergic patients
Macrolides: Side Effects and Drug Interactions
- GI: nausea/vomiting, diarrhea – more pronounced with macrolides
 occurs with PO and IV formulations
 worst with erythro- Erythro- and clarithro inhibit CYP450 enzymes – increase levels of theophylline, CBZ, warfarin
- Azithro – do not take with Al3+/Mg2+/Ca2+ containing products
- Macrolides antagonize effects of clindamycin (bind to the same target)
Macrolides: Dosing and Administration
- PO and IV formulations
- Erythromycin – dosed TID to QID
 various products, food may  absorption
- Clarithromycin – dosed once or twice daily
- Azithromycin – dosed once daily
 Long half-life
 Loading dose commonly used (double dose on first day)
 Shorter treatment duration (“Z-Pak” = 5 days)
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Fluoroquinolones
- Prototype: ciprofloxacin
- Names end in “-floxacin”
- Mechanism of action: inhibit bacterial DNA synthesis and replication (bactericidal)
- Common therapeutic uses
 UTI, pneumonia, infection of bones, joints, skin, soft tissue and gut infection (e.g. traveller’s diarrhea)
 Ophthalmic/otic infections
Fluoroquinolones: Side Effects
- GI: nausea, vomiting, diarrhea
- Neurologic: headache, dizziness, peripheral neuropathy
- MSK: joint/muscle pain, tendinitis, tendon rupture, cartilage growth suppression – avoid in pregnancy and age < 13
Fluoroquinolones: Drug Interactions, Dosing and Administration
-  bioavailability if taken together with dairy products, antacids (Ca 2+/Mg2+), minerals (Ca2+, iron) – space apart by ≥ 2 hours
- IV, PO, eye and ear preparations
- Once or twice daily
- Renal dose adjustment required – cctn dependent killing – increase interval
Sulfonamides
- Main agent in use today is sulfamethoxazole + trimethoprim (Septra ®)
- Mechanism of action: disrupt folate synthesis so bacteria cannot make DNA, RNA, protein (bacteriostatic)
- Common therapeutic uses
 UTI
 Pneumocystis carinii pneumonia (PCP) – now known as Pneumocystis jiroveci
Sulfonamides: Side Effects
- Hypersensitivity reactions (~3%)
 Mild rash, drug fever, photosensitivity are most common
 Stevens-Johnson syndrome rare but high mortality
 Key patient education points – stop taking if rash occurs, minimize sun exposure
- Hematologic:  WBC,  platelets, hemolytic anemia (rare)
- GI: nausea, vomiting, diarrhea
Sulfonamides: Drug Interactions
- Highly protein bound – will displace other protein bound drugs and  drug exposure
 Warfarin, phenytoin, sulfonylureas (narrow therapeutic window – increase in amt of free drug can lead to toxicity)
- “Sulfa” allergy and cross-reactivity
 Very little data to support cross-reactivity between sulfonamide antibiotics and other “sulfa” drugs (e.g. HCTZ,
furosemide, sulfonylureas); often used and generally considered safe
Sulfonamides: Dosing and Administration
- Sulfamethoxazole – used in fixed dose combination with trimethoprim (Septra®); PO and IV forms
- Dosing usually once or twice daily
- IV form may be given up to 4 times daily in treatment of severe infections
- Renal dose adjustment required
Clindamycin
- Mechanism of action: inhibits bacterial protein synthesis (bacteriostatic)
- Common therapeutic uses
 Mixed infections with gram positive and anaerobes (skin and soft tissue, aspiration pneumonia)
 Abdominal and pelvic infections
 Alternative to penicillins in beta-lactam allergy
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Clindamycin: Side Effects, Dosing and Administration
- GI: DIARRHEA
 May indicate infection with C. difficile
 High vigilance needed – stop clindamycin if significant diarrhea
- Key patient education point: report significant diarrhea to MD (≥ 5 watery stools per day)
- Oral dose QID, IV dosed TID
Clostridium Difficile (“C. Diff”)
- Aka, antibiotic-associated diarrhea, pseudo-membranous colitis
- C. difficile (anaerobic gram positive bacilli) spores ingested  overgrowth in gut when competing gut flora wiped out by recent
antibiotic use
- Profuse watery diarrhea, abdo pain, fever, WBC
- Can occur during or after Abx therapy (PO and IV)
 Clindamycin, fluoroquinolones, 3rd generation cephs
- High morbidity and mortality
- Must monitor and report diarrhea
C. Difficile Treatment and Prevention
- Treatment
 PO metronidazole or PO vancomycin
 Discontinue any precipitating antibiotics
 Avoid anti-diarrheal agents which decrease bowel motility (e.g. loperamide (Imodium ®), opioids) – prolong time it takes
for C.diff to be expelled
- Prevention
 Proper antibiotic prescribing
 Infection control practices (i.e. contact isolation, strict hand hygiene, Chlorox cleanser to kill spores)
 ↑ risk with acid suppressing drugs (e.g. proton pump inhibitors) – minimize use where possible
Metronidazole (Flagyl®)
- Mechanism of action: disrupt DNA synthesis (bactericidal)
- Common therapeutic uses
 Drug of choice for C. difficile
 Treatment of anaerobic infections of CNS, abdomen, bone, joint, skin, soft tissue, pelvis
 Prophylaxis of surgical site infection (abdominal, colorectal, gyne surgery)
 Treatment of protozoal infections (not discussed)
Metronidazole: Side Effects and Drug Interactions
- GI: nausea, vomiting, diarrhea, metallic taste
- Neurologic: dizziness, vertigo
- Other: brown urine discoloration (harmless)
- Alcohol – serious contraindication
 inhibits aldehyde dehydrogenase, leads to build up of alcohol metabolite acetaldehyde  headache, n/v, flushing, SOB
 must warn patients to avoid alcohol during treatment and for 3 days after
Metronidazole: Dosing and Administration
- PO and IV forms
- Dosed 2 to 3 times daily
Patient Education: Summary
- Symptoms of infection and expected resolution
- Antibiotic directions for use (doses/day, food/empty stomach)
- Antibiotic duration (must complete prescribed course of therapy)
- Expected side effects
- Possible serious effects – when to stop taking and contact MD
- Drug interactions
 Metronidazole (alcohol), fluoroquinolones (dairy foods, minerals)
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Exercise: Antibiotic Monitoring Summary
Parameter
Description, Nursing Implications and Interventions
GI
Nausea, vomiting, diarrhea  all antibiotics cause to some degree
Extra vigilance with agents predisposing to C.Diff (clindamycin, FQ, cephs)
Taking with food may minimize effects (but erythro, cloxacillin absorbed better on empty stomach)
Dermatologic
Neurologic
MSK
Renal
Hematologic
Other