Block 2 Flashcards
(267 cards)
1
Q
this many antibiotic prescriptions written in the outpatient setting are unnecessary
A
50%
2
Q
these are among the most commonly prescribed antibiotics
A
Azithromycin and amoxicillin
3
Q
2 problems contributing to antibiotic resistance
A
- unnecessary outpatient prescriptions
- farm animals given human antibiotics
4
Q
this many people are infected by drug-resistant bacteria every year in the US and this many die
A
- 2 million infected
- 23k die
5
Q
epidemic in India
A
infants born with bacterial infections that are resistant to most known antibiotics
6
Q
antibiotic definition
A
Natural substance produced by microbe to kill other microbes
7
Q
antimicrobial definition
A
antibacterial, antifungal, and/or antiviral
8
Q
4 Main Mechanisms of Action of Antimicrobial Agents
A
Inhibition of:
- cell wall synthesis
- cell memb fcn
- protein synthesis (translation + transcription)
- nucleic acid synthesis
9
Q
examples of Folate synthesis inhibitors
A
- Sulfonamides
- Trimethoprim
10
Q
examples of RNA Polymerase inhibitors
A
Rifampin
11
Q
examples of Cell membrane inhibitors
A
- Amphotericin
- Ketoconazole
- Polymixin
12
Q
examples of Cell Wall synthesis inhibitors
A
- Bacitracin
- Fosfomycin
- Vancomycin
- Beta-lactams
- carbapenems
- cephalosporins
- monobactams
- penicillins
13
Q
examples of DNA gyrase inhibitors
A
Fluoroquinolones
14
Q
examples of Protein synthesis inhibitors
A
- Aminoglycosides
- Chloramphenicol
- Clindamycin
- Macrolides
- Mupirocin
- Streptogramins
- Tetracyclines
15
Q
Bacteriostatic agents
A
- Inhibit microbe growth but do not reduce # of viable microbes (neutrophils reduce #)
- Ex: reversible bacterial protein synthesis inhibitors
16
Q
Bactericidal agents
A
- kills susceptible microbes – reduces # viable microbes
- Ex: bacterial cell wall synthesis inhibitors
17
Q
this type of drug inhibits microbe growth but doesn’t reduce # viable microbes
A
bacteriostatic
18
Q
this type of drug kills susceptible microbes, thereby reducing # viable microbes
A
bactericidal
19
Q
bactericidal agents at low concentrations may do this
A
At low serum concentrations many bactericidal agents may only be bacteriostatic
20
Q
can a drug be bactericidal and bacteriostatic? how?
A
A few antimicrobial agents are bactericidal against some microbes but bacteriostatic against others
21
Q
which line represents control drug?
A
blue line
22
Q
which line represents bacteriostatic drug?
A
green line (tetracycline or similar)
23
Q
which line represents bactericidal drug?
A
red line (penicillin or similar)
24
Q
Mechanism for most antimicrobial agents
A
Time-dependent killing
25
Time-dependent killing rate
* Mechanism for most antimicrobial agents
* Ability to **kill** microbes depends on length of time antimicrobial conc. \> min **bactericidal** conc. (MBC)
* Ability to **inhibit** further microbe growth depends on length of time antimicrobial conc. \> min **inhibitory** conc. (MIC) at site of infection
26
Ability to kill microbes in time-dependent killing depends on this
length of time antimicrobial conc. \> minimum **bactericidal** conc. (MBC)
27
ability to inhibit further microbe growth in time-dependent killing depends on this
length of time antimicrobial conc. \> minimum **inhibitory** conc. (MIC) at site of infection
28
Concentration-dependent killing rate
Ability to kill microbes increases as antimicrobial concentration increases
29
examples of drugs that use concentration-dependent killing
* Aminoglycosides
* fluoroquinolones
* daptomycin
30
Post-antibiotic effect
* Microbial death / growth inhibition continues for a period of time after drug concentration drops below MBC or MIC at site of infection
* Depends on antimicrobial + specific bacterial species
31
what does a graph of Time- vs. Concentration-Dependent Action look like?
32
what does a graph of concentration-dependent killing look like?
33
what does a graph of post-antibiotic effect look like?
34
Combination Antimicrobial Therapy definition
Usually 2+ agents w/different mechanisms of action
35
Combination Antimicrobial Therapy uses
* single-microbe infections:
* particularly resistant
* difficult infection site
* decreases resistance
* polymicrobial infections:
* gram (+), gram (-), and/or anaerobic bacteria
* Diabetic foot infection, intra-abdominal wound infections, etc
36
try to identify pathogen of infection using these methods
* Site of infection
* Gram stain
* Adequate Culture
* Host factors
37
Types of Susceptibility testing
* Disk diffusion
* broth dilution
* Etest method
38
susceptibility usually based on this
Susceptibility usually based on **MIC** -- only obtain MBC by special request
39
what is the broth dilution test?
40
what is the Disk Diffusion Method?
41
susceptibility test determines/tells this about bacteria
* Usually susceptibility reports only list whether bacteria is sensitive or resistant to antibiotics tested
* Usually bacteria is reported to be sensitive to multiple antibiotics
* Does not list actual MIC for each antibiotic
42
use these parameters to select antibiotic based on susceptibility
* Select agent and dose that provides wide margin btwn achievable serum concentrations and the MIC or MBC
* Always try to select most narrow spectrum agent
43
should you choose an agent with a narrow or wide spectrum?
Always try to select most narrow spectrum agent
44
examples of Intrinsic Resistance
* Vancomycin vs gram-negative bacteria
* Penicillin vs enteric bacteria
* Aminoglycosides vs anaerobic bacteria
45
examples of acquired resistance
* Many bacterial species over last 50 years of antibiotic era via gene transfer
* New 'gene pool' created
46
7 mechanisms of antibiotic resistance
1. Bacterial enzyme inactivation of antibiotics
2. Alteration of cell wall target proteins
3. Increase in cell wall thickness
4. Decrease in cell membrane permeability
5. Alteration of ribosomal targets
6. Alteration of enzyme target
7. Alteration of efflux pumps
47
example of antibiotic resistance via alteration of cell wall target proteins
penicillin-binding proteins (PGPs)
48
example of antibiotic resistance via decrease in cell membrane permeability
Alteration of porin channels
49
example of antibiotic resistance via Alteration of ribosomal targets
targeting 23s ribosomal RNA
50
example of antibiotic resistance via Alteration of enzyme target
targeting DNA gyrase
51
summarize antibiotic resistance in a picture
52
Experiment Demonstrating Multiple Drug Resistance Process using subtherapeutic amounts of oxytetracycline on chickens
* 36 hrs: E. coli of chickens R to tetracycline
* 3 months: E. coli multi-drug resistant (MDR)
* 5 months: resistant intestinal E. coli appears in farm family members
* 6 months: human intestinal E. coli now MDR although family not taking antibiotics or eating chickens
* Intestinal flora of control chickens and farm neighbors remained normal
53
routes of antimicrobial administration
1. Oral
2. Parenteral
54
oral antimicrobial administration benefits/drawbacks
* Safest route
* Limitations:
* bioavailabilty
* drug/nutrient interactions preventing absorption
* GI irritability
55
parenteral antimicrobial administration benefits/drawbacks
* Fastest route giving the highest concentrations
* Limitations:
* toxicity (including catheter infections)
* complexity of care
* cost
56
ideal antimicrobial agent?
effective parenteral agent that can also be directly converted to oral form
57
can all antimicrobials be given via both administration methods?
no, some can only be given parenterally or orally
58
antimicrobial distribution in body
* High conc / successful treatment expected in well-perfused tissues (plasma, muscle, kidney, etc)
* Low conc / increased failure rates expected at sites not readily penetrated by most antimicrobials (bone, brain, prostate gland, abscesses, heart valves, etc)
59
antimicrobial metabolism
* Some metabolized by liver
* many excreted unchanged via biliary tract or kidney
* Some may induce / inhibit metabolism of other drugs that depend on CYP 450
* Macrolide antibiotics
* Azole antifungals
60
renal antimicrobial excretion
* Adjust dose in renal failure if renally excreted
* Renally excreted antimicrobials preferred if treating lower UTIs
* Doses generally lower for UTIs than for systemic infections due to high concentrations in urine – reduces chance for toxicity
61
antimicrobial doses for UTIs
Doses generally lower for UTIs than for systemic infections due to high concentrations in the urine – reduces chance for toxicity
62
Antimicrobial Toxicity
* usually related to dose of antimicrobial agent
* Must balance: enough to kill microbe at site of infection, but not enough to be toxic to human cells
* Hypersensitivity reactions most common (sulfa, penicillin)
63
examples of toxicity from dose of antimicrobial
* Most common:
* Phlebitis from parenteral agents
* photosensitivity reactions
* GI intolerance
* Renal failure possible for select drugs
64
Superinfection
* Secondary to use of broad spectrum agents over period of time
* Usually fungal infections
65
Idiosyncratic reactions to antimicrobials
* Hepatotoxicity
* Serum sickness
66
this determines choice of antimicrobial, dose, route, duration, and whether to use a combination regimen
Type of Infection:
* Localized or systemic?
* Signs of sepsis?
* Site of infection?
67
considerations for antimicrobial choice for local vs systemic infections
* May only need topical agent for small wound or ocular infection
* Systemic infection means bacteria have spread to multiple organ systems – greater chance of sepsis
68
bacterial sepsis
* Secondary to production of bacterial endotoxins
* Fever, chills, hypotension, shock, organ failure
69
aggressive treatment needed for infections at these sites
* blood
* brain
* bone
70
this may determine success/failure of treatment
immunocompetency
71
Immuno-incompetent
* Absolute neutrophil count (ANC) \< 500/ml3 (after chemo)
* Taking immunosuppressive drugs (steroids or monoclonal Ab's)
72
must use this type of therapy for immuno-incompetent patients
Must use bactericidal agents +/- combination therapy
73
Host Defense issues that can affect antimicrobial treatment
* immunocompetency
* concomitant disease states (diabetes)
* Prostheses (infected)
* Catheters (entry site; infected)
74
Direct Costs of Antimicrobial Therapy
* Acquisition cost of drug(s)
* Depends on cost of individual unit and duration of therapy
* From pennies to thousands of dollars
75
Indirect Costs of Antimicrobial Therapy
* Labor costs for parenteral administration (nursing and pharmacy time, bags, tubing, infusion devices, etc)
* Monitoring (chemistries, cultures, pharmacokinetic analysis, etc)
* Adverse reactions
76
Causes of Antimicrobial Failure
* Drug resistance
* Drug selection
* Subtherapeutic dosing
* Monotherapy
* Poor penetration at site of infection
* Inadequate duration
77
Reasons for Prophylactic Antibacterial Therapy
* Prevention of infection during invasive procedures
* Prevent disease transmission to close contacts of infected persons (Meningococcal, TB, flu)
78
When to use antibiotics for prevention of infection during invasive procedures
* During dental and oral procedures to prevent endocarditis in patients with valvular heart disease
* During surgical procedures to prevent systemic infection from bacteria on the skin or in the gastrointestinal tract
* Give before procedure, not during!
79
gram(+) vs gram(-) bacteria in pictures
80
Antibacterials that inhibit bacterial cell wall synthesis
* β-lactams
* Penicillins
* Cephalosporins
* Monobactams
* Carbapenems
* Bacitracin
* Fosfomycin
* Vancomycin
81
Antibacterials that inhibit bacterial cell membrane synthesis
* Daptomycin
* Colistin (a polymyxin)
82
Antibacterials that inhibit bacterial protein synthesis
* Macrolides
* Tetracyclines
* Aminoglycosides
* Clindamycin
* Linezolid
* Mupirocin
83
Antibacterials that inhibit nucleic acid synthesis
* Fluoroquinolones
* Trimethoprim & sulfamethoxazole
* Metronidazole
84
antitubercular agents
* Isoniazid
* Rifampin
* Pyrazinamide
* Ethambutol
85
picture of agents that inhibit bacterial cell wall and NA synthesis
86
Types of Penicillins
* Natural Penicillins
* Aminopenicillins
* Extended-spectrum penicillins
* Beta-lactamase inhibitor combinations
* Penicillinase-Resistant Penicillins
87
Types of Cephalosporins
1st-5th generation
88
Types of Monobactams
Aztreonam
89
Types of Carbapenems
* Imipenem-cilistatin
* Meropenem
* Ertapenem
* Doripenem
90
Penicillins mechanism of action
Bind to penicillin-binding proteins (PBPs) on cell wall to inhibit further synthesis
91
Penicillins resistance mechanisms
* Production of **β-lactamase** that destroy β-lactam ring of penicillin molecule (Staphylococcus sp, Hemophilus, Enterobacter, etc)
* **Mutation of PBP** to prevent binding by penicillin (MRSA, penicillin-resistant pneumococcus)
* Activity depends on affinity to PBPs or degree of resistance to β-lactamase enzymes
92
Penicillins Pharmacokinetics
* Relatively short half-lives
* Most eliminated by kidney unchanged
93
Penicillins adverse reactions
Hypersensitivity:
* Immediate: anaphylaxis, urticaria, edema (Type I)
* Accelerated: 1-72 hrs, urticaria
* Delayed: days to weeks, rash, fever, serum sickness
94
this is common among all penicillins
Cross-sensitivity -- Avoid if history of immediate or accelerated reaction with any of penicillin group
95
Penicillin G
* 1st penicillin
* Very acid-labile and only given IV with T ½ of 30 min
* Dosed in units (1 million units = 0.6 gm)
96
Procaine penicillin G
Suspension given IM that lasts from 1-4 days depending on dose
97
Benzathine penicillin G
Suspension given IM that can last up to several weeks
98
Penicillin V
Oral form of penicillin that is more acid-stable
99
Use of natural penicillins (G & V)
Narrow spectrum antibiotic active against
* Streptococci (S. pyogenes, S. pneumoniae)
* Neisseria meningitidis
* Clostridium sp
* Treponema pallidum (syphilis)
100
Aminopenicillins
First of semisynthetic penicillins, which are all produced from 6-aminopenicillinamic acid
101
Ampicillin
* Only used intravenously now
* T ½ of 80 min so must give 4 times/day
102
Amoxicillin
* Most common antibiotic prescribed
* Oral equivalent of ampicillin b/c of better absorption
* Can be given 2 to 3 times a day
* Higher doses used if suspicion of penicillin-resistant pneumococcus
103
Most common antibiotic prescribed
Amoxicillin
104
Idiosyncratic reactions to aminopenicillins
* Ampicillin rash with either product – up to 10% of individuals
* Up 60% incidence of rash if mononucleosis present or taking allopurinol for gout
105
uses of Aminopenicillins
* Active against common upper respiratory tract pathogens
* S. pyogenes
* S. pneumoniae (most strains)
* Hemophilus influenza (most strains)
* Some activity against Enterococcus and common community gram(-) bacteria (E. coli, Proteus sp)
* NO activity against Staphylococcus
106
these types of penicillin have NO activity against Staphylococcus
* aminopenicillins
* extended-spectrum penicillins
107
Extended-Spectrum Penicillins
aka anti-pseudomonal penicillins
* **Piperacillin** (Pipracil)
* Carbenicillin
* ticarcillin
* mezlocillin
108
piperacillin
* Most common extended-spectrum penicillin
* Only given IV
* Usually used in combination with tazobactam (Zosyn)
* Excreted via biliary tract
109
Carbenicillin, ticarcillin, mezlocillin
older extended-spectrum penicillins rarely used now
110
adverse effects of extended-spectrum penicillins
* Sodium overload with high doses
* Thrombocytopenia with high doses
111
Uses for Extended-Spectrum Penicillins
* Extended activity against **gram(-)** bacteria
* **Pseudomonas aeruginosa** activity
* Combine w/aminoglycoside antibiotic for serious P. aeruginosa infections
* Bacteremia, pneumonia, neutropenic fever
* Retains activity against **Enterococcus**
* **No** activity against **Staphylococcus**
112
β-Lactamase Inhibitor/Penicillin Combinations
* Clavulanic acid
* With amoxicillin = Augmentin (now generic)
* For diabetic foot wounds, bites, Staphylococcal infections
* Sulbactam
* With ampicillin = Unasyn
* Tazobactam
* With piperacillin = Zosyn
* Most widely used IV antibiotic in hospitals
* Active against most gram (+), gram (-), and anaerobic bacteria
113
Most widely used IV antibiotic in hospitals
Tazobactam (+ piperacillin = Zosyn)
114
β-Lactamase Inhibitor/Penicillin Combination Mechanism of Action
* β-lactamase inhibitors preferentially combine with bacterial β-lactamase enzymes and inactivate them
* Make penicillins more active against previously resistant bacteria (Staphylococcus, gram (-), anaerobes)
* Does not increase activity against bacteria resistant b/c of altered PBPs (ie. MRSA)
* Same kinetics, adverse effects, etc as penicillins used alone
115
Penicillinase-Resistant Penicillins
* Semisynthetic penicillins specifically developed to treat Staphylococcus resistant to penicillins
* First agent was methicillin, but removed from market secondary to cases of interstitial nephritis
116
Methicillin
* Penicillinase-Resistant Penicillin
* introduced in 1960
* 1st methicillin-resistant (MRSA) strain appeared in 1961 in London
* mecA gene codes for new PBP2a
* removed from market secondary to cases of interstitial nephritis
117
what happened to staph to make it MRSA?
mecA gene codes for new PBP2a
118
Nafcillin
* Penicillinase-Resistant Penicillin
* Only used IV
* Must give 4 to 6 times per day
* Risk: Can cause severe phlebitis at IV site as well as serum sickness reactions
119
Dicloxicillin
* Penicillinase-Resistant Penicillin
* Oral equivalent of nafcillin
120
mechanism by which beta-lactams develop antibiotic resistance?
* synthesize beta-lactamase --\> destroy penicillin beta-lactam ring
* mutation of PBP to prevent penicillin binding
121
most likely problem when a patient on chronic tetracycline for acne suddeny develops diarrhea cultured for C. diff?
superinfection
122
what antibiotic can be used in patients with history of penicillin or cephalosporin hypersensitivity reactions and/or patients with beta-lactam allergies?
Aztreonam (Azactam)
* Monocyclic β-lactam ring
* Activity similar to ceftazidime (3rd gen)
* Activity against many gram(-) bacteria, Pseudomonas
* No activity against gram-positive bacteria
123
preferred first-choice agent for MRSA treatment?
Vancomycin
124
Vancomycin resistance uses this mechanism
decreased binding of drug to cellular target
* remember, Vanco inhibits cell wall synthesis by blocking elongation of peptoglycan molecule
125
Other choices for MRSA treatment
* linazolic acid
* 1st gen cephalosporins
* streptograms
126
Ciprofloxacin mechanism of action
DNA gyrase / topoisomerase II & IV inhibitor (Fluoroquinolone antibiotic)
127
best choice for syphilis management
penicillin -- bind PBPs to inhibit cell wall synthesis
128
if a patient is allergic to one penicillin, can you give them a different one?
no, they are likely to be allergic to all penicillins
129
most appropriate treatment for infection around implanted catheter includes a drug that interacts with what substance?
D-alanyl-D-alanine dipeptide in cell wall (Vancomycin)
130
these drugs interact with transpeptidase enzyme in cell wall
penicillins, beta-lactam antibiotics
\*transpeptidase = PBP
131
imipenem would be contraindicated in a patient w/Hx of alcoholism and convulsions because of which of his conditions?
convulsions: has neurotoxicity at high doses and can actually cause seizures
132
carbapenems are contraindicated in patients with these conditions
* seizures
133
what can prevent tetracycline binding?
* Cations such as calcium will bind to tetracyclines and prevent absorption
* Avoid giving with dairy products or antacids
134
this drug is one of the most common causes of superinfection
tetracycline -- broad-spectrum, kills everything --\> C. Diff
135
Bacterial resistance tends to develop quickly with use of this type of drug
Cephalosporins -- that's why there are so many generations
136
patient w/an amoeba was treated w/first-line drug therapy. he drank whiskey that evening, and quickly developed severe nausea, vomiting, palpitations, chest pain, profuse sweating. what was the drug?
metronidazole (disulfiram-like effect)
137
patient presents to ED with fever, altered sensorium, and neck stiffness. what drug should be used?
Ceftriaxone
138
what drug could cause a serious adverse reaction if combined with common anesthesia drugs?
aminoglycosides (Gentamicin, etc) -- block NM junction
139
an antibiotic binds to 50s ribosomal subunit, inhibiting translocation (protein synth). it also causes severe diarrhea in this patient, who is being treated for chlamydia. what drug is causing the diarrhea?
Macrolide (Clindamycin, etc) -- stimulate motilin receptors
140
Pseudomonas aeruginosa treated with this
* Extended-Spectrum Penicillins
* if particularly bad, add aminoglycoside
141
Augmentin
* Clavulanic acid + amoxicillin
* β-Lactamase Inhibitor/Penicillin Combination
* For diabetic foot wounds, bites, Staphylococcal infections
142
Unasyn
* Sulbactam + ampicillin
* β-Lactamase Inhibitor/Penicillin Combination
143
Zosyn
* Tazobactam + piperacillin
* β-Lactamase Inhibitor/Penicillin Combination
* Most widely used IV antibiotic in hospitals
* Active against most gram (+), gram (-), and anaerobic bacteria
144
Cephalosporins
* Similar to penicillins (share β-lactam ring) but more stable to β-lactamases
* Semisynthetic drugs derived from Cephalosporium
* MOA – Similar to penicillin
145
Bacterial Resistance to Cephalosporins
* Bacteria producing variety of β-lactamase enzymes that destroy β-lactam ring of molecule
* No activity against MRSA except for new drug, ceftaroline
* No activity against Enterococcus sp or Listeria
146
ceftaroline
new cephalosporin w/activity against MRSA
147
Classification of cephalosporins
* Classified into 5 major groups (generations) based on spectrum of activity
* W/each succeeding generation, more gram (-) but less gram (+) activity
148
Pharmacokinetics of Cephalosporins
* Half-lives vary from short to very long
* Most eliminated by kidney unchanged
149
Important adverse reactions of cephalosporins
* Hypersensitivity reactions less common than penicillins
* Cross-sensitivity with penicillins is minimal unless history of anaphylactic reaction with penicillins
* Bacterial resistance tends to develop quickly with use – reason why so many cephalosporins were developed
150
1st Generation IV Cephalosporins
* Cefazolin
* (Kefzol, Ancef)
* usually given every 8 hrs
151
1st Generation Oral Cephalosporins
* Cephalexin (Keflex) – short T ½
* Cephradine (Velocef)
* Cefadroxil (Duracef) – long T ½
152
1st Gen Cephalosporin Uses
* Active against Streptococcus sp and methicillin-sensitive Staph (MSSA)
* Also active against strains of E. coli and Klebsiella sp
153
Cefazolin
* 1st Gen IV Cephalosporin
* widely used in hospitals for wound infections and surgical prophylaxis
154
Cephalexin
* 1st Gen Oral Cephalosporin
* widely used in community for Staph and Strep infections
155
2nd Generation IV Cephalosporins
* Cefuroxime (Ceftin)
* Cefoxitin
156
2nd Generation Oral Cephalosporins
157
Cefuroxime
* 2nd Generation IV/Oral Cephalosporin
* for upper respiratory infections
158
Cefoxitin
* 2nd Generation IV Cephalosporin
* for abdominal and gynecologic infections b/c of increased anaerobic activity
159
2nd Generation Oral Cephalosporins
* Cefuroxime (can switch from IV)
* Cefaclor
* Cefprozil
160
Uses for 2nd Gen Cephalosporins
* Increased activity against gram(-) bacteria incl Klebsiella pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis
* For community-acquired pneumonia and more resistant upper respiratory infections such as otitis media
161
Activity of 3rd Generation Cephalosporins
IV forms are much more active than oral forms
162
3rd Generation IV Cephalosporins
* Cefotaxime (Claforan) – short T ½
* Ceftriaxone (Rocephin) – long T ½, give once daily IM/IV
* Ceftazidime (Fortaz)
163
3rd Generation Oral Cephalosporins
* Cefixime (Suprax)
* Cefpodoxime (Vantin)
164
Uses for 3rd Generation Cephalosporins
* IV wide range of activity against gram (-) and gram (+) bacteria
* Used for nosocomial infections, pneumonia, meningitis, advanced Lyme disease
* No activity against anaerobic bacteria
165
Ceftazidime
* only 3rd gen w/activity against Pseudomonas
* Useful alternative to piperacillin
166
4th Generation Cephalosporin
* Cefepime (Maxipime) – only given IV
167
Cefepime
* 4th Generation Cephalosporin
* More resistant to chromosomal β-lactamase enzymes (produced by Enterobacter sp)
* Good activity against Enterobacteriaceae and Pseudomonas aeruginosa
* Unlike ceftazidime, good activity against penicillin-resistant Strep pneumoniae
168
5th Generation Cephalosporin
Ceftaroline (Teflaro) – only given IV
169
Ceftaroline
* First beta-lactam approved for MRSA
* high affinity for PBP2a encoded by mecA gene
* Otherwise, antibacterial spectrum most similar to 3rd generation cephalosporin, ceftriaxone
* As with ceftriaxone, no activity against Pseudomonas or Enterococcus species
170
First beta-lactam approved for MRSA
Ceftaroline
171
Monobactam
Aztreonam (Azactam) - only given IV
172
Aztreonam
* Monobactam
* monocyclic β-lactam ring
* No cross-sensitivity in pts w/Hx severe penicillin or cephalosporin hypersensitivity rxns
* Activity similar to ceftazidime (3rd gen) w/activity against many gram(-)bacteria, Pseudomonas
* No activity against gram(+) bacteria
* Used for patients with β-lactam allergies
173
this drug used for patients with β-lactam allergies
aztreonam
174
Carbapenems
* Broadest spectrum of antibacterial drugs available
* Reserved for life threatening or multi-resistant infections
* Structurally related to other β-lactam antibiotics
* All given intravenously
175
Broadest spectrum of antibacterial drugs available
Carbapenems
176
Imipenem-cilistatin
* Carbapenem
* Cilistatin inhibits enzyme that hydrolyzes imipenem in kidney – helps increase T ½, but still give every 8 hrs
177
Examples of carbapenems
* Doripenem (Doribax) – now preferred agent
* Imipenem-cilistatin (Primaxin)
* Meropenem (Merrem)
* Ertapenem (Invanz)
178
Doripenem
* Carbapenem
* Now preferred agent
* More active against Pseudomonas than others
179
Uses for Carbapenems
* Serious polymicrobial and nosocomial infections due to highly resistant bacteria
* Imipenem, doripenem, and meropenem (but not ertapenem) also have activity against Pseudomonas
180
Side Effects of Carbapenems
* Can be neurotoxic at higher doses (seizures)
* Greater chance of superinfections
* High cost
* Some cross sensitivity in penicillin-allergic patients
181
Bacitracin
* Cell Wall Synthesis Inhibitor
* Active only against gram(+)
* Only used topically to treat Strep and Staph skin infections
* Systemic: Highly nephrotoxic
* Oral: Poorly absorbed
182
Fosfomycin
* phosphonic antibiotic
* Cell Wall Synthesis Inhibitor
* bactericidal in urine – inhibits peptidoglycan synthesis
* Oral agent now ecommended for gram(-) UTIs if pt suspected/known resistance to sulfa and fluoroquinolones
183
Nitrofurantoin (Macrodantin)
* Cell Wall Synthesis Inhibitor
* Only used for lower UTIs (bactericidal against E. coli, Enterococcus, and other common UTI orgs)
* Commonly causes GI irritation, nausea, and vomiting
* Avoid in elderly b/c increased risk of pneumonitis and neuropathy
* Contraindicated in renal failure
184
Vancomycin
* Glycopeptide molecule with high molecular weight
* inhibits cell wall synthesis by blocking peptoglycan elongation
185
Bacterial Susceptibility to Vancomycin
* Bactericidal against most gram(+) including those resistant to β-lactams
* No activity against gram(-)
* Some enterococci have become resistant (VRE)
* Big worry that this mutant gene can be transferred to Staph
186
Vancomycin Administration
* Usually given IV
* Not absorbed orally.
* Oral vancomycin remains in GI tract, only used to treat C. difficile colitis
187
Vancomycin Pharmacokinetics
* Renal elimination directly proportion to creatinine clearance
* Narrow therapeutic index – must monitor peak and trough levels
188
Important adverse reactions to Vancomycin
Red Man Syndrome
* infusion reaction due to massive histamine release if given too fast or in too high a dose
* treat with antihistamine
Ototoxicity at higher doses
189
Red Man Syndrome
* reaction to Vancomycin
* infusion rxn due to massive histamine release if given too fast or in too high a dose
* treat with antihistamine
190
Vancomycin uses
* Reserved for known or suspected MRSA
* used in combination with aminoglycoside for serious Enterococcus infections
* Oral vanc only used to treat pseudomembranous colitis secondary to C. difficile
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Bacterial Cell Membrane Synthesis Inhibitors
* Daptomycin (Cubicin)
* Colistin
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Daptomycin
* Cell Membrane Synthesis Inhibitor
* Unique cyclic lipopeptide active against gram(+)
* only available in IV form
* Old drug making comeback for treating vancomycin-resistant bacteria
* Concentration-dependent activity
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Colistin
* Cell Membrane Synthesis Inhibitor
* Also known as polymyxin E that was used in 1920’s
* Intravenous
* Starting to be used for MDR-resistant bacteria such CRE (carbapenemase-resistant Enetrobacteriaceae)
* Nephrotoxic like aminoglycosides
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Bacterial Protein Synthesis Inhibitors
* Macrolides
* Tetracyclines
* Aminoglycosides
* Clindamycin
* Linezolid
* Mupirocin
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Examples of Macrolides
* Erythromycin
* Clarithromycin
* Azithromycin
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Examples of Tetracyclines
* Tetracycline
* Doxycycline
* Tigecycline
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Examples of Aminoglycosides
* Gentamicin
* Tobramycin
* Amikacin
* Streptomycin
* Neomycin
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Miscellaneous Bacterial Protein Synthesis Inhibitors
* Clindamycin
* Linezolid
* Mupirocin
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Macrolide Antibiotics Mechanism of Action
reversibly bind to 50s ribosomal subunit
200
Bacterial Susceptibility to Macrolides
* Usually bacteriostatic
* Streptococcus sp and Staphylococcus
* Resistance gradually increasing
* Some activity against H. influenzae and Bordetella
* Activity against atypical bacteria (Mycoplasma, Legionella, Chlamydophyla) that cause pneumonia
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Macrolide Uses
* For upper and lower respiratory infections potentially due to atypical bacteria
* IV azithromycin used extensively in hospitals for pneumonia
* For penicillin-allergic patients
* For Chlamydia trachomatis STD infections
* Clarithromycin for Mycobacterium Avian Complex (MAC)
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Clarithromycin
* Macrolide
* Used for Mycobacterium Avian Complex (MAC)
* better absorbed than erythromycin
* Higher serum levels and lower GI levels
* fewer GI adverse effects
* Not available in IV
* Can give 2x/day
* Same drug interactions as erythromycin but stronger
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Azithromycin
* Macrolide
* Given IV and orally
* IV used extensively in hospitals for pneumonia
* Most popular and safest macrolide antibiotic
* T ½ = 60 hrs, requires loading dose and 1x/day dosing (Z-Pack)
* Only have to give for 3 to 5 days
* Minimal adverse reactions
* No drug interactions
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Erythromycin
* IV form rarely used anymore
* Available orally
* Must give 3-4x/day
* Adverse effects
* Oral form: dose-dependent effect on peristalsis (motilin) --\> abd pain, diarrhea
* High IV doses: ototoxicity
* Inhibits CYP 450 3A4 (metabolizes 50% of drugs)
* Increases serum levels of statins, benzodiazepines, Ca channel blockers, cyclosporine, etc
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Most popular and safest macrolide antibiotic
Azithromycin
206
Tetracyclines Mechanism of Action
reversibly bind to bacterial 30s ribosomal subunit
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Bacterial Susceptibility to Tetracyclines
* Usually bacteriostatic effect
* Activity against many gram(+) and gram(-) bacteria
* Activity against rickettsiae, chlamydiae, mycoplasma, and some protozoa
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Important adverse reactions of Tetracyclines
* GI irritation
* Photosensitivity
* Can cause skeletal deformities in developing fetus and discoloration of tooth enamel in children and fetus
* (tetracycline loves calcium! Will bind to it and interfere w/bone and tooth development)
* Hepatotoxicity possible with extended use
* One of the most common causes of superinfection
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One of the most common causes of superinfection
Tetracyclines
210
Important drug interactions with Tetracyclines
* Cations such as calcium will bind and prevent absorption
* Avoid giving with dairy products or antacids
211
Uses for Tetracyclines
* Lyme Disease
* Erlichiosis
* Rocky Mountain Spotted Fever
* Atypical pneumonia
* Pelvic inflammatory disease
* Tetracycline and minocycline for acne
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Tetracycline
Rarely used now because of lower bioavailability and short T½ - have to give 4x/day
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Doxycycline
* Most popular tetracycline
* Give both IV and oral (good bioequivalence)
* Long T½
* Can be given 1-2x/day depending on infection
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Minocycline
* Popular for acne due to high distribution in skin
* Very expensive
* Long-term can cause anemias
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Tigecycline
* Derivative of minocycline approved in 2005
* IV (not oral) approved for complicated skin and intra-abdominal infections
* Not affected by 2 major mechanisms of tetracycline resistance, but still only bacteriostatic activity
* Active against gram(+) (including MRSA), gram(-), and anaerobic bacteria
* Not active against Pseudomonas or Proteus species
* Reserve for antibiotic-resistant infections
* Adverse effects: frequent nausea and vomiting
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Aminoglycoside Antibiotics Mechanism of Action
irreversibly bind to bacterial 30s ribosomal subunit
217
Bacterial Susceptibility to Aminoglycoside Antibiotics
* Bactericidal activity against most gram(-), including Pseudomonas
* Streptococci are resistant to agents when used alone
* Synergistic activity combined with β-lactams
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Uses for Aminoglycoside Antibiotics
Bacteremia, pneumonia, intra-abdominal infections, and other serious infections from gram(-)s
219
Pharmacokinetics of Aminoglycoside Antibiotics
* Only available IV or IM (not absorbed orally)
* Short T½ -- 2-3 hrs
* Concentration-dependent killing -- high dose 1x/day
* Eliminated renally; accumulate in renal failure
* Monitor peak and trough levels -- **narrow therapeutic index**
220
Important adverse reactions of Aminoglycoside Antibiotics
* Very nephrotoxic – can accumulate in renal tubules and cause acute renal failure
* Also ototoxic at high doses for extended periods of use
* Block NM junctions -- implications for anesthesia
221
Streptomycin
* First aminoglycoside
* Used IV or IM as 2nd-line therapy for active TB
222
Neomycin
* Most toxic aminoglycoside -- never used IV
* Used in topical formulas in combination with other antibiotics
* Oral form sometimes used for prophylaxis before elective bowel surgery
223
Tobramycin
Given IV, IM, or inhaled for cystic fibrosis patients with Pseudomonas pneumomniae
224
Clindamycin Mechanism of Action
binds to same 50s ribosomal subunit as macrolides
225
Bacterial Susceptibility to Clindamycin
* Bacteriostatic activity
* Inhibits Streptococci, Staphylococci, and Pneumococci
* Inhibits anaerobic bacteria such as Bacteroides fragilis and Clostridium perfringies
226
Uses for Clindamycin
* Anaerobic infections: intra-abdominal wounds, gynecologic infections, abscesses, aspiration pneumonia
* Gram(+) infections in penicillin-allergic patients
* Newly discovered community-acquired MRSA
227
Clindamycin Pharmacokinetics
* Can be given IV or orally
* Metabolized by liver
228
Important adverse reactions of Clindamycin
* GI upset: nausea, diarrhea
* Primary cause of antibiotic-associated pseudomembranous colitis
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Primary cause of antibiotic-associated pseudomembranous colitis
Clindamycin
230
Linezolid Mechanism of Action
oxazolidinedione with unique activity against bacterial 50s ribosomal subunit
231
Bacterial Susceptibility to Linezolid
* Bacteriostatic activity
* Active against most gram(+)s, including most strains resistant to other antibiotics
* Resistance may occur with overuse
232
Uses for Linezolid
Should be reserved for infections caused by multidrug-resistant bacteria such as VRE and MRSA
233
Pharmacokinetics of Linezolid
* Given oral or IV with 100% bioavailability
* Metabolized by the liver with T ½ of 4-6 hrs
234
Important adverse reactions of Linezolid
Hematologic toxicity – can cause thrombocytopenia and neutropenia with extended use
235
Cost of Linezolid
$2700 for 10 days of oral therapy
236
Mupirocin (Bactroban)
* Unrelated to other antibiotics
* Used in topical preps for treating Staph infections
* Should be reserved for suspected/definite MRSA to avoid resistance
* Special nasal formulation available to eliminate MRSA carriage
* Also used for impetigo caused by Strep or Staph
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Nucleic Acid Synthesis Inhibitors
* Usually bactericidal
* Inhibition of bacterial DNA gyrase (Fluroquinolones)
* Inhibition of bacterial folic acid synthesis (Trimethoprim & sulfamethoxazole)
* Disruption of bacterial DNA helix (Nitroimidazoles such as metronidazole)
238
Fluoroquinolone Antibiotics
* Bacterial DNA Gyrase Inhibitors
* 3 generations
239
1st Gen Fluoroquinolones
Nalidixic acid
240
2nd Gen Fluoroquinolones
* Norfloxacin
* Ciprofloxacin
* Ofloxacin
* Lomefloxacin
* Enoxacin
241
3rd Gen Fluoroquinolones
* Levofloxacin (Levaquin)
* Moxifloxacin (Avelox)
* Gemifloxacin (Factive)
242
Fluoroquinolones Mechanism of Action
inhibit DNA gyrase and topoisomerase that are essential for maintaining bacterial DNA structure and function
243
Bacterial Susceptibility to Fluoroquinolones
* Bactericidal activity against most gram(-)s
* Active against atypical bacteria
* 3rd gen agents also have good activity against gram(+)s (except staph)
244
Uses for Fluoroquinolones
* Complicated UTIs and prostatitis
* Serious infections secondary to gram(-)s -- bacteremia, intra-abdominal infections
* 3rd gen agents used for severe pneumonia
* Infectious diarrhea secondary to Salmonella and Shigella
* Penicillin-resistant anthrax
245
Pharmacokinetics of Fluoroquinolones
* Most available as both IV and oral forms
* Distribute very well into most tissues
* Most excreted renally
246
Important adverse reactions of fluoroquinolones
* Causes arthropathy in developing animals - avoid in children less than 18 years old and during pregnancy
* Achilles tendon rupture
* Neurotoxic in high doses (irritability, seizures)
247
Important drug interactions w/fluoroquinolones
* Absorption of oral forms inhibited by cations such as calcium, magnesium, iron, and zinc (multivitamins and antacids)
* Inhibit metabolism of caffeine and theophylline
248
Ciprofloxacin
* Most commonly used 2nd gen fluoroquinolone
* Advantage: only quinolone w/activity against Pseudomonas aeruginosa
* Disadvantages:
* Poor activity against gram(+)s
* Shorter T½ requires IV or oral dose *bid*
249
Norfloxacin
* 1st fluoroquinolone
* Still used for UTIs
* does not achieve high enough serum levels for systemic infections
250
Uses for 3rd Gen Fluoroquinolones
* Aka the “respiratory fluoroquinolones”
* Active against gram(-)s
* Active against most bacteria responsible for respiratory infections (atypical bacteria, MDR Strep pneumoniae)
251
Levofloxacin
* L-isomer of ofloxacin
* Most common fluoroquinolone used for variety of serious infections
* Renal elimination with normal T ½ = 7 hrs
* Given once daily IV or oral
252
Moxifloxacin
* 3rd gen Fluoroquinolone w/better activity against anaerobics than levofloxacin
* Metabolized by liver, so should not be used for UTIs
* Given once daily IV or oral
253
Gemifloxacin
* Newest fluoroqunolone
* Only available as oral dose
* Hepatic metabolism
* Greater incidence of rash
* 2x as expensive as other 2nd gen agents
254
these antibiotics can cause tendon rupture
fluoroquinolones like ciprofloxacin
255
Antifolate Drugs Mechanism of action
Sequential blockade of DNA synth pathway
256
Trimethoprim-Sulfamethoxazole (Bactrim)
* Antifolate
* Sulfamethoxazole is only oral sulfonamide still used as an antibacterial agent
* Only available in combination w/trimethoprim (TMP-SMX)
* For maximal synergy, dosed in ratio 5 SMX :: 1 TMP
257
Bacterial Susceptibility to Trimethoprim-Sulfamethoxazole
* Bactericidal activity against most gram(+)s and gram(-)s incl CA-MRSA
* Active against nocardia, Pneumocystis jiroveci,
* No activity against enetrococci, atypical bacteria, anaerobic bacteria, or Pseudomonas aeruginosa
258
Uses for Trimethoprim-Sulfamethoxazole
* Primary drug for UTIs
* 2ary drug for upper and lower respiratory tract infections, sepsis, meningitis, travelers diarrhea, typhoid, cholera
259
Pharmacokinetics of Trimethoprim-Sulfamethoxazole
* Can be given both oral and IV
* Well distributed in tissues including CSF
* 50% excreted by kidneys
* T½ = 12 hrs, so can be dosed *bid*
260
Important adverse reactions to Trimethoprim-Sulfamethoxazole
* Hypersensitivity rxn to SMX -- can use TMP alone for UTIs
* Severe hypersensitivity reactions include exfoliative dermatitis and Stevens-Johnson syndrome
* High doses for P. jiroveci infections in AIDS: can cause thrombocytopenia, neutropenia, high incidence of allergic reactions, hyperkalemia
261
Important drug interactions for Trimethoprim-Sulfamethoxazole
Can increase serum levels and toxicity of warfain, phenytoin, and oral sulfonylureas (for diabetes)
262
Metronidazole (Flagyl)
* antibacterial and antiprotozoal
* Nitroimidazole that is readily taken up only by anaerobics, then reduced to toxic metabolite
* Disrupts DNA helix only in anaerobics
* Best single agent to treat anaerobic infections, incl intra-abdominal infections and C. difficile colitis
* Available oral and IV
* Avoid alcohol while taking: disulfiram-like effect
263
Best single agent to treat anaerobic infections
Metronidazole
264
FDA Categories for Drug Use in Pregnancy
* CatA – controlled trials show no risk to human fetus
* CatB – animal studies do not indicate risk, or animal studies indicate risk but controlled trials in pregnant women do not
* CatC – no available studies or animal studies indicate risk but no controlled trials in women
* CatD – positive evidence of fetal risk but may be situations where benefit outweighs risk
* CatX – definite fetal risk clearly outweighs benefit
265
Examples of Category B antibiotics
* β-lactams
* Azithromycin
* Clindamycin
* Metronidazole
266
Examples of Category C antibiotics
* Clarithromycin
* Fluroquinolones
* TMP-SMX (1st & 2nd)
* Nitrofurantoin (1st & 2nd)
* Vancomycin
267
Examples of Category D antibiotics
* Aminoglycosides
* Tetracyclines
* TMP-SMX (3rd)
* Nitrofurantoin (3rd)
