Treatment of Bacterial PN Flashcards
What is the definition of pneumonia (PN)
Parenchymal infection in lower respiratory tract (i.e. respiratory bronchioles, alveolar ducts, alveoli)
What are the symptoms associated with PN?
- Fever, cough +/- sputum production
- Unproductive cough suggests viral or mycoplasma etiology
- Dyspnea, chest discomfort
- Infiltrates on CXR
What is the most important factor in successful treatment of PN?
EARLY INTERVENTION
Causes of CAP by AGE
- 0-6 weeks
- 6 weeks - 18 y/o
- 18-40 y/o
- 40-65 y/o
- >65 y/o
0-6 weeks: Group B strep, E. coli
**6 weeks-18 y/o: **Viruses (Influenza, Adeno-, Rhino-, RSV), Mycoplasma pneumoniae, Chlamydia pneumoniae, Strep pneumoniae
**18-40 y/o: **Mycoplasma pneumoniae, Strep pneumoniae
**40-65 y/o: **Strep pneumoniae, Haemophilus influenzae, Anaerobes (often part of normal flora), Viruses, Mycoplasma pneumonia
**>65 y/o: **Strep pneumoniae, Viruses, Anaerobes (often part of normal flora), Haemophilus influenzae, Gram + rods
Is streptococcus pneumoniae more common in young or older patients?
Older patients
What are two important independent risk factors for severe CAP?
**Alcohol Consumption: **decreased saliva production, which is an important component of mucosal defense.
**Diabetes: **Neutralizes the effects of protective proteins on suface of lungs. Higher risk for influenza and its complications (including PN).
What is the most common cause of PN in diabetic or alcoholic patients?
Klebsiella pneumoniae
What are the two most common cuases of nosocomial infections?
S. aureus
P. aeruginosa
Immunosuppressed patients are at an increased risk of what types of opportunistic infections?
Aspergillus
Pneumocystis
Nocardia asteroides
Legionella (Legionnaires Disease)
- Causative agent for what?
- Who does it commonly affect?
- Treatment?
- Atypical causative agent for Pneumonia
- More common in men >50, especially smokers, those with chronic lung disease, and immunosuppresed patients.
- Erythromycin (macrolide) remains the only antimicrobial labeled for this disease, however most MDs use newer macrolide (Azithromycin or Clarithromycin) or “Respiratory Quinolone”
- For severely ill patients a combination of one of these drugs wtih rifampin may be used.
What are the “Respiratory Quinolones” used in Legionnaires Disease?
Levofloxacin, Ciprofloxacin, or Moxifloxacin
Nosocomial PN
- Etiologic agents?
- All drugs have activity agaisnt what type of bactiera?
- Indicated and Alternative Treatment
- **No etiologic agent can be established in 50%. **
- All drugs have activity agaisnt gram - aerobes including Pseudomonas aeruginosa and Haemophilus influenzae.
- **Indicated: **Imipenem/Cilastin, Aztreonam, Ceftazidime, *Vancomycin*
- Alternative: Meropenem, Piperacillin/Tazobactam, Cefepime
What is Vancomycin reserved for the treatment of?
MRSA
Aspiration Pneumonia
- What gives rise to this type of PN?
- Etiologic agents?
- Indicated and Alternative Treatment?
- Aspiration of gastric acid, a foreign body, or normal oropharyngeal secretions can give rise
- Oropharyngeal secretiosn are most commonly in reduced consciousness (loss of protective mechanisms)
- 50% are from gram - enteric bacilli (16% are anaerobes, 12% are S. auereus)
- Indicated: Clindamycin
- Alternative: Ampicillin/Sulbactam
Once infection is controlled, what should occur in terms of route of delivery and duration of therapy?
Route may switch to oral from parenteral in severly ill once infection is controlled and oral dosing is practical.
- May be possible soner with drugs like doxycycline and fluoroquinolones where oral bioavailability is high, & later where oral delivery cannot achieve comparable drug levels.
Generally, how many days of parenteral therapy will stablize disease and reduce fever?
3-6 days
An effective drug regimen seeks to provide a local concentration of drug that exceeds what?
Minimum Inhibitory Concentration (MIC) for the infective microbe.
When you have a bug that becomes resistant to a drug, what happens to the MIC value?
MIC value increases becuase you need more of the drug to produce the same kill.
Do serum drug concentrations always reflect local tissue drug levels?
NO! Apart from interestitial fluid which closely mirrors the serum drug level.
What are 3 parameters important in defining drug activity AND based on these how can individual antimicrobial agents be characterized?
- AUC/MIC
- Cmax/MIC
- T>MIC
Indiviudal antimicrobial agents can be broadly characterized as being either concentration dependent (AUC/MIC, Cmax/MIC) or time dependent (T>MIC).
Describe time-dependent vs. concentration-dependent
The PK-PD profile of an ABX class is characterized as either:
- Concentration-dependent (fluoroquinolones, aminoglycosies), such that an increase in ABX concentration leads to a more rapid rate of bacterial death.
- Time-dependent (B-lactams, Vancomycin), such that the reduction in bacterial density is proprtional to the time that concentrations exceed the MIC
How are concentration-dependent and time-dependent drugs dosed?
- Concentration-dependent drugs are often given in large doses (relative to the MIC) at long intervals relatiev to the serum half life for the agent.
-
Time-dependent drugs are usually dosed more frequently, with an emphasis on the need to maintain the serum drug level above the MIC for 30-50% of the dose interval.
- Some MDs advocate prolonged/constant infusion of b-lactams to ensure maximal T>MIC
What are the two major forms of drug elimination and whats the importance?
- Elimination occurs either via the renal or hepato-biliary systems.
- Potential for a need to reduce the drug dose if the elimination occurs predominately in teh urine of patients with diminished renal fxn.
What drugs do not need dose adjustment for renal impairement?
- Azithromycin (biliary)
- Ceftriaxone (renal/biliary)
- Clindamycin (renal/biliary)
- Doxycycline (biliary)
- Erythromycin (biliary)
- Linezolid (metabolism)
Explain the principle of cross-sensitivity
Presence of the beta-lactam ring is responsible for cross-sensitivity in patients with pre-existing allergy to beta-lactams (i.e. a prior allergic reaction to a penicillin will predispose a patient to a simmilar allergy with a cephalosporin or a carbapenem)
What drug is not used for pulmonary infections?
Daptomycin: although drug distributes into lung tissue, it is inhibited by pulmonary surfactant so it should not be used to treat PN.
Bronchitis
- What is etiology by age and smoking status?
- Indicated drugs?
- If resistance is present, what drug do you use?
- Oral or IV treatment?
Etiology by age and smoking status:
- In younger patients most episodes are viral.
- In elderly patients with commorbidities, bacterial infection is more likely (Mycoplasma pneumoniae, Strep pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Bordetella pertussis)
- In smokers, H. influenzae is more common
Indicated: Amoxicillin+Clavulanic acid, Azithromycin, Clarithromycin, Doxycycline
With Resistance: Ciprofloxacin
Oral drug treatment is more convient but both doxy and cipro can be used IV in more severe cases.
Lung Abscess
- Treatment regimen?
- Organisms implicated?
- Drugs used?
- Treatment initially involves IV drug therapy with transition to a 2m oral regimen after a couple of weeks.
- Anaerobes
- Gram + cocci for community acquired
- Gram - baccilli for nosocomial
- Appropriate Drugs
- Clindamycin (proven supprior to penicillin d/t emergence of penicillin-resistant bacteroides)
- Metronidazole for nosocomial infections (should NOT be used alone d/t incomplete coverage but may be used with a thid generation cephalosporin such as ceftriaxone)
What is the general appraoch to treating CAP?
A macrolide (azithromycin) or respiratory quinolone (levofloxacin) is an appropriate 1st choice. Amoxicillin/clavulanate is another option.
- Macrolides “mycin” (Erythromycin, Azithromycin)
- Tetracyclines “cycline” (Doxycycline)
- Fluoroquinolones “floxacin” (Levofloxacin)
- Pencillins “cillin” (Amoxicillin+Clavulanic acid, Piperacillin+Tazobactam)
- Carbopenem (Meropenem)
- Cephalosporins “cef” or “ceph” (Cefazolin, Cefuroxime, Ceftriaxone, Ceftazidime, Cefepime)
- Aminoglycosides (Gentamicin)
B-lactams include what drug classes?
- Penicillins
- Carbapenems
- Cephalosporins
MOA of B-lactams
Bactericidal; inhibit cell wall synthesis
- binding to penicillin-binding proteins located in bacterial cytoplasmic membrane
- inhibit transpeptidation rxn that cross-links the linear peptidoglycan chain constituents to the cell wall
- activation of autolytic enzymes that cause lesions in bacterial cell wall
Why are B-lactamases inhibitors added to ABX?
Added to overcome resistance caused by B-lactamases and protect ABX from inactivation. Broad coverage; can be used with nosocomial PN and has anaerboic coverage.
Note: none of the additives possess any antimicrobial activity, rather these are metabolic inhibitors that preserve the lifespan/activity of the drug
B-lactamase inhibitors include what drug combinations?
- Amoxicillin/Clavulanic acid [Augmentin]
- Piperacillin/Tazobactam [Zosyn]
- Ampicillin/Sulbactam [Unasyn]
Penicillin G vs. Pencillin V
Penicillin G: limited spectrum of antibacterial and is susceptible to b-lactamases (e.g. staph aureus and neisseria gonorrheae). Pneumoccocal resistance is d/t changes in PBP located in bacterial cytoplasmic membrane.
Pencillin V: oral drug used mainly in oropharyngeal infections
What is a broad-spectrum penicillin?
Piperacillin (co-administered with Tazobactam; “Pip/Tazo”)
- Modification of aminopenicillins (added nitrogen and carbon atoms)
- Sensitive to b-lactamases
- Used for pseudomonas aeruginosa
Narrow spectrum penicillins and usage?
Can you remember the mneominc?
Mnemonic: “i MET a NAsty OX”
- Methacillin
- Nafcillin
- Oxacillin
Contain larger molecule on penicillin molecule side chain that confers steric hindrance resulting in resistance to b-lactamases but reduced specrum of activity.
- Adminstered IV
- Treatmetn of known or suspected staph infections
What are the carbopenems?
Imipenem and Meropenem
- Differ from penicillins in that the 5-membered ring contains a carbon rather than sulfur atom
- Broadest spectrum of activity and stable in presence of b-lactamases
- Active against p. aeruginosa and acinetobacter
What do you administer with Imipenem?
Cilastin
- Reversible, competitive inhibitor of dehydropeptidase-1 (DHP-1) found in brush border of proximal tubular cells of the kidney that breaks down Imipenem to inactive metabolites
- Prevents renal metabolism of Imipenem and minimizes nephrotoxicity
Aminopenicillin Drugs and Usage?
Drugs: Ampicillin, Amoxicillin
- IV ampicillin is commonly used with other ABX such as aminoglycosides (gentamicin) for broad Gram - coverage (“AMP-GENT”)
Usage
- Broader Gram - coverage d/t presence of amino group that makes the molecule more hydrophilic and able to cross LPS
- Covers enterococci (synergistic with aminoglycosides)
- When used in combo with inhibitors of penicillinases (e.g. clavulanic acid), their antibacterial activity is enhanced
What is Aztreonam?
- Monobactam: B-lactam ring contains a sulfonic acid group
- Resistant to b-lactamases
- Can only be used for Gram - organisms
Cephalosporin Structure and General Rule
- 6-membered ring attached to B-lactam ring
- More acid stable than penicillins
- Gram positive activity is lost with each successive drug generation, but gram negative activity is gained
What drugs are included in each generation of cephalosporins and whats their usage?
First Generation: useful in treating skin infections which are commonly Strep or Staph (gram + cocci)
- Cephalexin: oral, outpatient use
- Cefazolin: IV, surgical prophylaxis
Second Generation: good for mild gram negative bacteroides infection (anerobic), which can occur iwth intrabdominal infections.
- Cefuroxime
Third Generation (“tri”): can penetrate the BBB
- Ceftriaxone: IV, STDs (gonorrhea), ped meningitis
- Cefepime: IV, pseudomonal infections
Fourth Generation: reserved for severe nosocomial infection, which have a tendency to be resistant to other ABXs (commonly caused by gram - organisms)
Vancomycin
- MOA
- Usage
- Absorption
MOA: glycopeptide that inhibits cell wall synthesis
- Binds to D-ala-D-ala terminal and prevents elongation of peptidoglycan chain and interferes with cross-linking. Resistance by replacement of terminal D-ala by D-lactate!
- Bactericidial in organisms that are dividing
Tagets drug resistant gram + organisms such as MRSA
Absorption: Must be administered IV becuase poorly absorbed from GI tract (unless infection that is being treated is inside GI tract such as bacterial enterocolitis with C. difficile)
What are the 5 important types of ABX that inhibit the function of the bacterial ribosome?
Hint: can you remember the mneomic?
Mneominc: “CLEan TAG”
CLEan: inhibits 50S
- Chloramphenicol and Clindamycin
- Linezolid
- Erythromycin
TAG: inhibits 30S
- Tetracycline and Tigecycline
- AminoGlycosides
Aminoglycoside MOA and Drugs
Hint: can you remember the mneominc?
MOA: Bactericidial; Binds to the 30S ribosomal subunit and interfere with protein synthesis in 3 ways
- blocks formation of initiation complex
- cause misreading of the code of mRNA template
- inhibit translocation
Drugs Mnemonic: “Attack The 30S Gram Negative”
- Amikacin
- Tobramycin
- Streptomycin
- Gentamicin*
- Neomycin
Aminoglycoside administration and usage
Adminstration: polar structure so penetration of biologic membranes is poor (don’t administer orally)
- Exception? Drug accumulates inside proximal tubule cells of kidney and is the basis of nephroxicity of this drug.
Usage: effective agaisnt gram negative bacteria including pseudomonas aeruginosa
- Not effective agaisnt anaerobes becuase anaerobes have less energy available for aminoglycoside uptake into bacteria cell.
Macrolide MOA and Drugs
MOA: bind to 23S rRNA molecule of 50S RSU and inhibit peptidyl transferase, blocking the transfer of the new amino acid onto the growing chain.
- Inhibition of protein synthesis (i.e. translocation) does not typically kill bacteria cells, so these agents are generally bacteriostatic.
- They are phagocytosed by macrophages, which is a benefit becuase WBC preferentially travel to sites of infection
Drugs: nomenclature is simmilar to that of aminoglcyosides except “thro” preces “mycin”
- Erythromycin (1st generation)
- Azithromycin (3rd generation)
- Clarithromycin
- Telithromycin (ketolide)
What must be administerd with erythromycin?
Unstable in gastic acid and therefore must be administered with salts or esters or via enteric-coated tablets when administered orally
Lincosamides MOA and Drugs
MOA: Bacteriostatic; binds to 23 rRNA molecule of 50S RSU and inhibit peptidyl transferase, blocking the transfer of new amino acid onto the growing chain
Drugs: Clindamycin
- Beneficial in toxin-producing infections: most bacterially produced toxins are proteins, so an added benefit of a protein synthesis inhibitor is reduced toxin production, in addition to slowed bacterial growth.
Tetracycline MOA and Drugs
MOA: Bacteriostatic; bind reversibly to the 16S subunit of the 30S RSU and inhibit translocation (protein synthesis).
Drugs contain “cycline”
- Doxycycline
- Tigecycline
- Minocycline
Mupirocin MOA and Administration
MOA: inhibits bacterial protein synthesis by reversible binding and inhibiting of isoleucyl transfer-RNA synthase
Administration: applid topically and is bactericidal against many gram negative bacteria (effective agaisnt strep pyogenes and MRSA)
Chloramphenicol MOA
MOA: binds to 50S RSU at the peptidyltrasferase site and inhibits the transpeptidation rxn.
- Do NOT administer with macrolide ABXs as chloramphenicol binds near their site of action; may interfere with each others actions.
Fluoroquinolones MOA and Drugs
MOA: inhibit DNA replication by binding to and inhibits DNA gyrase (i.e. topo II) and topoisomerase IV; leads to buildup of DNA fragments which leads to cell death (Bactericidal)
- Inhibit DNA gyrase in gram negative and topo IV in gram positive
Drugs: Ciprofloxacin and Levofloxacin
Rifamycin MOA and Drugs
MOA: inhibits bacterial RNA synthesis by binding RNA polymerase and preventing initiation of RNA synthesis (but not elongation of RNA). Action on RNA synthesis is limited to bacterial (i.e. not human) RNA
Drugs: Rifampin and Rifaximin
What is an important property of Rifampin?
HIGHLY LIPOPHILIC so can easily cross lipophilic membranes.
- Mycobacterial cell walls contain mycolic acids, which are long FAs and therefore lipids.
- Biofilms (e.g. S. epidermidis and S. aureus) generate a barrier that ABXs generally cannot enter.
- CNS distribution is high so can be used for bacterial meningitis
- Enters phagocytic cells and therefore can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and organisms inside abscesses
Nitroimidazole-Metronidazole
Metronidazole is a prodrug that must be converted to its active form. The nitrogen group must be reduced by a a nitroreductase enzyme called ferredoxin, which results in the production of toxic products (hydroxylamine) and other free radicals that damage DNA.
- Converted to active form in anaerobic bacteria, where oxygen is absetn and ferrodoxin is present.
Cotrimoxazole MOA and Usage
Cotrimoxazole is a combination drug composed of trimethoprim and sulfamethoxazole (TMP-SMX)
MOA: DHFR inhibitor; actions on two steps of the enzymatic pathway for the synthesis of tetrahydrofolic acid, which is essential for one-carbon transfer reactions.
Usage: uncomplicated UTI and for acute exaccerbations of chronic bronchitis. Also effective agaisnt infection by pneumocystis jiroveci
Daptomycin MOA
MOA: Bactericidal; lipopetide that interferes with the integrity of cell wall structure in gram positive bacteria. Binds to bacterial membranes and cause a rapid depolarization of membrane potential. The loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis, and eventually bacterial cell death.
Inactivated by pulmonary surfactant!
What is the mnemonic for Bactericidal Drugs?
Mnemonic: “Very Finely Proficient At Cell Murder:
- Vancomycin
- Fluoroquinolones
- Penicillin
- Aminoglycosides
- Cephalosporins
- Metronidazole
What is the mnemonic for Bacteriostatic Drugs?
Mnemonic: “We’re ECSTaTiC”
- Erythromycin
- Clindamycin
- Sulfmethoxazole
- Tetracyclines
- Trimethroprim
- Chloramphenicol
CAP Drug Resistance
- Macrolides
- Tetracyclines
- Fluoroquinolones
- Penicillins
- Cephalosporins
- Aminoglycosides
- Clindamycin
- Vancomycin
- Macrolides: ribosomal methylation and mutation of 23S RNA; active efflux
- Tetracyclines: decreased entry into and increased efflux from; target insensitivity
- Fluoroquinolones: mutation fo DNA gyrase; active efflux
- Penicillins: drug inactivation (b-lactamase); altered PBPs (target insensitivity)
- Cephalosporins: decreased permeability of gram negative outer membrane (altered porins); active efflux
- Aminoglycosides: drug inactivation (aminoglycoside modifying enzyme); decreased permeability of gram negative outer membrane; active efflux; ribosomal methylation
- Clindamycin: methylation of bindign site; enzymatic inactivation
- Vancomycin: replacement of D-ala by D-lactate
Unusual Organ Toxicity of CAP Drugs
- Erythromycin: CYP3A4/Pgp inhibitor; cholestatic jaundice; QT prolongation
- Gentamicin: neprho- and ototoxicity; neuromuscular paralysis
- Imipenem: partial cross-reactivity with pen/ceph hypersensitivity; seizures
- Levofloxacin: tendon rupture adults; cartilage damage young children
- Meropenem: partial cross-reactivity with pen/ceph hypersensitivity; seizures
- Vancomycin: nephro- and ototoxicity; Red Man’s syndrome
Which drug is heavily implicated in developmental dysfunction?
Doxycycline: GI distress; teeth discolored; photosensitivity; decreased bone growth.
What drugs had potential for interaction wtih concurrent non-antimicrobial agents?
Linezolid: bone marrow suppression; non-specific MAO inhibitor
What drugs are not to be used with breastfeeding?
Clarithromycin
Linezolid
Metronidazole
Piperacillin
