Antibacterial drugs Flashcards
(192 cards)
1
Q
Define
Post-antibiotic effect (PAE)
A
The persistent suppression of microbial growth that occurs even after levels of antibiotic have fallen below the MIC
2
Q
Define
Minimum inhibitory concentration (MIC)
A
The lowest concentration of an antibiotic that prevents visible microbial growth
3
Q
Define
Minimum bactericidal concentration (MBC)
A
The lowest concentration of an antibiotic that reduces the number of viable cells by at least 1000-fold
4
Q
What is the factor by which a bactericidal antibiotic at its MBC reduces the number of viable cells?
A
1000-fold
5
Q
Define
Attainable antibiotic level (AAL)
A
The concentration of an antibiotic that can be reached in target tissues without causing toxic or side effects
6
Q
How does the MBC of a truly bactericidal drug compare to its MIC?
A
The MBC is equal to or slightly greater than the MIC
7
Q
What are examples of antibacterials that have a long PAE?
A
- Aminoglycosides
- Fluoroquinolones
8
Q
Fluoroquinolones are antibacterials with long PAEs. How does this affect their dosage?
A
They require only one dose per day
9
Q
For some antibacterial drugs, the trough level is lower than the MIC. However, these drugs are still therapeutically useful. How is this?
A
- The drugs have a notable post-antibiotic effect (PAE)
- There is synergism between host defenses and sub-MIC levels of the antibiotic
10
Q
What is a negative implication of an antibacterial having low trough levels?
A
Development of drug-resistant strains of bacteria
11
Q
At which trough concentrations of antibacterial is the likelihood of developing antibiotic resistance greatly increased?
A
- Levels below the MIC
- Levels at the MIC
- Levels slightly above the MIC
(depending on the drug)
12
Q
Where are common sites of action of antibacterials in bacterial cells?
A
- Cell wall
- Plasma membrane
- DNA
- RNA
- Ribosomes (protein synthesis)
13
Q
How do antibacterials targeting the cell wall function?
A
Inhibiting the formation of peptidoglycans that are essential in cell wall formation. This disruption of the cell wall causes death of the bacterium
14
Q
How do antimicrobials targeting the plasma membrane function?
A
Interfering with the permeability or function of the plasma membrane
15
Q
How do antibacterials targeting the DNA function?
A
Inhibiting DNA synthesis and replication
16
Q
How do antibacterials targeting RNA function?
A
Inhibiting RNA synthesis
17
Q
How do antibacterials targeting protein synthesis function?
A
Inhibiting the 30S and/or 50S subunits of ribosomes
18
Q
What are examples of antibacterials that interfere with bacterial metabolism?
A
- Sulfonamides
- Trimethoprim
19
Q
What is the pathway that sulfonamides and trimethoprim act on?
A
para-aminobenzoic acid → dihydrofolate (DHFA) → tetrahydrofolate (THFA)
- Sulfonamides inhibit the synthase forming DHFA
- Trimethoprim inhibits the reductase forming THFA
20
Q
How are antimicrobials classified?
A
- Mechanism of action
- Chemical structure
- Spectrum of antimicrobial activity
21
Q
What are the types of narrow-spectrum drugs?
A
- Those effective in Gram-positive cocci and bacilli
- Those effective in Gram-negative bacilli (e.g. aminoglycosides)
- Those only effective in specific infections (e.g. isoniazid is only effective against Mycobacterium tuberculosis)
22
Q
What is an example of a drug with narrow-spectrum action against Gram-negative bacilli?
A
Aminoglycosides
23
Q
What is an example of a drug effective only against TB?
A
Isoniazid
24
Q
What are broad-spectrum drugs?
A
Those effective against Gram-positive and Gram-negative cocci and bacilli
25
What is a negative implication of using broad-spectrum antibacterials?
These drugs can alter the nature of the normal flora and precipitate a superinfection
26
What are extended-spectrum drugs?
Agents that are effective against Gram-positive organisms **and** against a significant number of Gram-negative bacteria, or against a specific microorganism
27
What is an example of an extended-spectrum antibiotic?
Antipseudomonal penicillins
28
What is the major consideration in the use of antibacterial drugs?
The identification of the causative microorganism and the use of the proper drug for an adequate duration
29
What are the factors affecting the choice of antimicrobial agent?
* The causative microorganism and its susceptibility
* Pharmacokinetic factors
* Toxicity and side effects
* Interactions with other drugs
* Cost
* Host factors
* Genetic factors
* Pregnancy
* Lactation
* Local factors at the site of infection
30
How can the causative organism of an infection be determined?
* Clinical picture
* Culture and sensitivity
* Serology
* PCR
31
What are some of the pharmacokinetic factors affecting choice of antimicrobial agent?
* The site of infection (e.g. if in the CNS, the drug must cross the blood–brain barrier)
* The presence of renal disease that affects clearance
* The presence of liver disease that affects metabolism and elimination
* The route of administration
32
What are examples of host factors?
* Age
* Allergic reaction to a given antimicrobial agent
* Host defense mechanisms (e.g. immunodeficiency or immune suppression)
33
What is an example of genetic factors affecting selection of an antimicrobial drug?
Those with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk of severe hemolysis if they take sulfonamides, chloramphenicol, or nitrofurantoin
34
What are the concerns of using antimicrobial drugs in pregnancy?
They may be teratogenic
35
What is an example of a local factor at the site of infection that affects chemotherapy?
The presence of an abscess means use of chemotherapeutic drugs will not be effective
36
Under which conditions does bacterial resistance occur?
* The clinical condition of the host is impaired
* The normal flora has been suppressed
* Interrupted or inadequate chemotherapy
* Widespread use of broad spectrum antibiotics
* Poor environmental setting of the host
* More frequent in certain types of bacteria (e.g. Gram-negative bacteria)
37
What are the mechanisms of bacterial resistance?
* Natural resistance
* Acquired resistance
38
What are the types of natural bacterial resistance?
* Absence of a metabolic process, enzyme, or protein in the bacterium that is required for the action of the antimicrobial
* Absence or tough cell wall, making it difficult for the antimicrobial to penetrate and enter the cell
* Low concentration (subtherapeutic) of the antimicrobial drug at the site of action, compared to its plasma concentration (overcome by highering the dose, which also leads to adverse effects)
39
What are the types of acquired bacterial resistance?
* Mutation or genetic change
* Adaptation, e.g. production of β-lactamases
* Infectious or multiple drug resistance, acquired through
* transduction via a phage,
* transformation using exogenous DNA, or
* conjugation with another bacterium
40
# Define
Acquired bacterial resistance
Development of resistance in a previously sensitive microorganism population
41
What is the most common reason for acquired bacterial resistance?
Misuse or abuse of antibiotics, e.g.
* Improper dose and duration of action
* Prescribing antibiotics for suppurative diseases (with abscesses)
* Prescribing antibacterials for viral infections
42
What are some specific examples of antibacterial resistance?
| (how the cell is resistant, not how it *acquires* the resistance)
* Generating enzymes that inactivate the antibiotic (e.g. β-lactamase)
* Changing the structure of a target effector (e.g. penicillin-binding protein for β-lactam drugs and aminoglycosides)
* Membrane proteins or efflux pumps that prevent cellular accumulation of the antibiotic (prominent in Gram-negative bacteria, usually an issue for tetracyclins)
* Changing the metabolic pathway that is being blocked (e.g. the DHFA synthase blocked by sulfonamides)
* Overproducing the target enzyme/protein to overpower the effect of the drug
* Mycoplasmas lack a cell wall, making them resistant to penicillins
* Circumventing the targeted metabolic process (e.g. sulfonamides don't affect bacteria that obtain reduced folate from the environment)
43
What are the indications of combined antibacterial therapy?
* Obtaining synergism, or being able to reduce the dose of a toxic drug
* Reducing the emergence of resistance
* Treating mixed infections with microorganisms of different sensitivities
* Treating infections at different, privileged anatomical sites (e.g. bile, cerebrospinal fluid)
* Treating infections of unknown etiology, especially in patients at high risk of developing infection (e.g. AIDS patients)
44
What are the outcomes of combined chemotherapy?
* Indifference (the most common outcome)
* Antagonism (e.g. when using a cidal and a static, the static inhibits division of cells, so the cidal's function is impaired)
* Synergism (e.g. with penicillins and aminoglycosides, the penicillin increases permeability of the cell wall allowing for aminoglycoside entry, and the aminoglycoside inhibits protein synthesis, thus decreasing synthesis of cell wall)
45
What are the disadvantages of combined chemotherapy?
* Increased toxicity
* Increased cost
46
What are the indications of prophylactic antibacterial therapy?
* Protection of healthy individuals at risk of highly contagious diseases or infections (e.g. syphilis, gonorrhea, TB, meningococcal meningitis)
* Preventing secondary or opportunistic infections in very ill patients (e.g. AIDS patients, before major surgeries, before labor and delivery, organ transplantations, recurrent UTIs)
47
When is prophylactic use of antibacterials successful?
* A single antibacterial drug is used
* The dose needed for prophylaxis is lower than the therapeutic dose
* The drug is needed for a brief period (chronic therapy can lead to resistance)
48
What are complications of antibacterial therapy?
* Hypersensitivity (allergy or otherwise; the most frequent and serious adverse effect)
* Direct toxicity (to the liver, kidney, or other)
* Superinfections, precipitated by alterations to the normal flora, allowing for overgrowth of normally opportunistic pathogens, especially fungi and resistant bacteria (e.g. *C. difficile*)
49
What are the classes included in the β-lactam drugs?
* Penicillins
* Cephalosporins
* Carbapenems
* Carbacephems
* Monobactams
50
What is the unifying characteristic of the β-lactam drugs?
An intact β-lactam ring (a four-membered ring containing [at least] a nitrogen atom in the ring and an oxygen doubly bonded to the ring)
51
The β-lactam drugs have, as part of their general structure, a highly substituted R group linked by an amide to the β-lactam ring. What is the significance of this R group?
The precise structure of the R group determines the characteristics of the the specific antimicrobial drug, e.g.
* Narrow or broad spectrum
* Route of administration
* Sensitivity of target organisms
* Resistance to β-lactamases
52
What are the agents that degrade the β-lactam ring?
* Gastric acid
* β-lactamases
53
What is the general mechanism of action of the β-lactam drugs?
* Inhibit synthesis of bacterial cell wall by binding to proteins in the cell membrane, e.g. penicillin-binding proteins
* Binding produces a defective cell wall that allows the intracellular contents to leak out (lysis)
* Most effective when bacterial cells are dividing (as they produce new cell wall during this time)
54
What are examples of species that produce β-lactamase?
* *Staphylococcus aureus*
* *Moraxella catarrhlis*
* *Neisseria gonorrhoeae*
* Enterobacteriaceae spp.
* *Hemophilus influenzae*
* *Bacteroides* spp.
55
What are the general characteristics of penicillins (PCNs)?
* Most widely used antibiotics
* Most effective
* Least toxic
* Cheap
* Derivatives of 6-aminopenicillanic acid
* Derived from a fungus
* The prototype drug is penicillin G
* Widely distributed in the body, except in the CSF (unless inflammation is present) and the intraocular fluid
* Complications include hypersensitivity, seizures, and nephropathy
56
What are the natural penicillins?
* Penicillin G (benzylpenicillin)
* Penicillin V (phenoxymethylpenicillin)
None of the other natural penicillins are currently used therapeutically
57
How is benzylpenicillin (penicillin G) administered?
* Acid labile and short acting, so it is not effective orally
* Penicillin G procaine is given IM twice daily
* **Seriously contraindicated** IV as it leads to lowered blood pressure and convulsions
* Penicillin G benzathine is given IM once monthly for rheumatic fever prophylaxis
58
How is phenoxymethylpenicillin (penicillin V) administered?
Orally
59
What are the therapeutic characteristics of the natural penicillins?
* Narrow spectrum
* Sensitive to penicillinase (a type of β-lactamase)
* Drugs of choice to treat infections with β-hemolytic type A streptococci
* Little effect, if any, against Gram-negative bacteria
| (penicillins G and V)
60
What are the narrow-spectrum, penicillinase-resistant (anti-Staph) penicillins?
* Nafcillin
* Oxacillin
* Cloxacillin
* Dicloxacillin
* Flucloxacillin
61
What are the broad-spectrum, penicillinase-sensitive (aminopenicillin) penicillins?
* Ampicillin
* Amoxicillin: given orally; more potent, better bioavailability, and longer DOA than ampicillin
62
What are the therapeutic characteristics of the aminopenicillins?
* Have little effect, if any against:
* penicillinase-producing bacteria, e.g. *Hemophilus influenzae*
* Gram-negative bacteria, e.g. *E. coli*, *Proteus* spp.
* No effect against pseudomonas
* Widely used in tonsillitis, otitis media, gonorrhea, respiratory infections, shigella infections, and UTIs
* Amoxicillin has good activity against *H. pylori* in peptic ulcers (with PPIs, with or without clarithromycin and metronidazole)
| (ampicillin, amoxicillin)
63
What are the diseases treated using aminopenicillins?
* Otitis media
* Tonsilitis
* Gonorrhea
* Respiratory infections
* Shigella infections
* UTIs
* *H. pylori*-related peptic ulcers
| (ampicillin, amoxicillin)
64
What are the antipseudomonal penicillins?
* Piperacillin >
* Mezlocillin =
* Ticarcillin >
* Carbenicillin
| (relative potencies given)
65
What are the amidinopenicillins?
* Mecillinam
* Pivmecillinam
66
What are the therapeutic characteristics of the amidinopenicillins?
* Most potent PCNs against enterobacteria (*Salmonella* , *Shigella*, *Klebsiella*, *E. coli*, etc)
* Little or no activity against Gram-positive cocci and pseudomonas
* Synergistic with other β-lactams but not with aminoglycosides
| (mecillinam, pivmecillinam)
67
What are the most potent penicillins against enterobacteria?
The amidinopenicillins (mecillinam, pivmecillinam)
68
What are the penicillins suitable for use against pseudomonas?
* Piperacillin
* Mezlocillin
* Ticarcillin
* Cabernicillin
69
What is the mechanism of action of penicillins?
* Inhibit transpeptidases, the enzymes that catalyze the final cross-linking step in the synthesis of peptidoglycan
* Disruption of the cell wall causes death of the bacterial cell, thus all PCNs are **bactericidal**
70
Are the penicillins bactericidal or bacteriostatic?
Bactericidal
71
What are the general pharmacokinetic properties of the penicillins?
* **Absorption**: many have poor oral bioavailability, while others are suitable orally
* **Distribution**:
* bind plasma proteins, are widely distributed;
* have low concentrations in the ocular fluid, joints, and CSF (do not cross the BBB unless the meninges are inflamed);
* do not cross the placenta
* **Metabolism**: by the liver
* **Excretion**: usually in the kidney by glomerular filtration and tubular secretion
* probenecid (a drug used for gout and hyperuricemia) inhibits tubular secretion of PCNs, increasing their half-life
* naficillin and oxacillin are mainly excreted _by the liver_
72
What are the indications for the penicillins?
* More effective in treating Gram-positive infections (the outer membrane of the Gram-negative organisms decreases efficacy)
* Used to treat infections of the skin, genitourinary system, GI tract, respiratory tract, and soft tissues
* Selection of the specific PCN depends on the organism and severity of the infection
* Combination of PCNs with a potent inhibitor of lactamases broadens the spectrum
73
What are the β-lactamase inhibitors?
* Clavulanic acid
* Sulbactam
* Tazobactam
74
What is the action of the β-lactamase inhibitors?
* Have no intrinsic antibacterial activity
* Inhibit bacterial β-lactamases to potentiate and broaden the spectrum of β-lactam drugs
75
What are common combinations of penicillins with β-lactamase inhibitors?
* Augmentin: amoxicillin/clavulanate
* Unasyn: ampicillin/sulbactam
* Zosyn: piperacillin/tazobactam
## Footnote
Note: using β-lactamase inhibitors means the dose of the PCN can be lowered
76
What are the mechansisms of resistance to PCNs specifically?
* Altered penicillin-binding proteins
* Production of β-lactamases (e.g. penicillinases)
* Decreased penetration
* In pseudomonas, increased efflux pumps
77
What are the available preparations of PCNs?
* Oral
* Parenteral (mostly IM and IV)
* Intrathecal
* Topical
* Intra-articular
78
What are the common side effects to PCNs?
**Hypersensitivity** (most frequent and dangerous)
* Type I (immediate): early onset (IgE-mediated)
* Type II: may manifest as eosinophilia, hemolytic anemia, interstitial anemia, serum sickness (fever, arthralgia, malaise)
* Nonallergic ampicillin rash: usually only occurs once (more common in patients with mononucleosis, lymphomas, cytomegalovirus infection)
**Other**
* Neurotoxicity (especially for oxacillin and IV benzylpenicillin)
* Hepatotoxicity (espeically for IV oxacillin)
* Reversible bone marrow depression (especially for IV naficillin)
* Nephrotoxicity (especially for methicillin, which has been mostly withdrawn from the market)
79
What are the contraindications of PCNs?
* Hypertension or heart failure (only for preparations with sodium)
* Renal failure (only for preparations with potassium)
* Absolute contraindication to all PCNs in patients with history of β-lactam or penicillin allergy
80
What are the general characteristics of cephalosporins?
* Derivatives of 7-aminocephalosporanic acid
* Semisynthetic
* Broad spectrum
* Inhibitors of cell wall synthesis
* Differ in pharmacokinetic properties and spectrum of activity
* Classified into 5 generations, mostly based on history of discovery and somewhat on spectrum of activity
81
What are the first-generation cephalosporins?
* Cefadorxil
* **Cefalexin**: oral
* **Cefazolin**: IM, IV
* Cefapirin
* Cefradine
* Cefaloridine
82
What are the second-generation cephalosporins?
* **Cefaclor**: oral
* **Cefamandole**: IM, IV
* Cefmetazole
* Cefonicid
* **Cefotetan**
* **Cefoxitin**
* Cefprozil
* **Cefuroxime**
* Cefuroxime axetil (prodrug of cefuroxime)
* Loracarbef (technically a carbacephem)
83
What are the third-generation cephalosporins?
* **Cefixime**: oral
* Cefoperazone
* **Cefdinir**
* Cefotaxime
* **Ceftriaxone**
* Cefpoxodime
* Ceftazidime
* Ceftibuten
* Ceftizoxime
84
What are the fourth-generation cephalosporins?
* Cefepime: IM, IV
85
What are the fifth-generation cephalosporins?
* Ceftaroline: IV
86
How do the generations of the cephalopsorins compare by distribution of spectrum of activity?
* First generation have the best activity against Gram-positives and are less resistant to β-lactamases
* Second, third, and fourth generations cross the BBB more readily
87
What are the therapeutic uses of cephalosporins?
* Never the first line therapy for any infection
* Highly effective in:
* Upper and lower respiratory infections
* *Hemophilus influenzae*
* UTIs
* Dental infections
* Severe systemic infections
88
Which cephalosporin has the best activity against *Bacteroides fragilis*
Cefoxitin (2nd gen)
89
Which cephalosporin has the best activity against *H. influenzae*?
Cefamandole (2nd gen)
90
Which cephalosporins have the best activity against *Pseudomonas aeruginosa*?
* Cefoperazone (3rd gen)
* Ceftazidine (3rd gen)
* Cefepime (4th gen)
91
Which cephalosporin has the broadest Gram-positive spectrum of activity?
Ceftaroline:
* Active against MRSA
* Has some activity against Gram-negatives
92
What are the adverse effects to cephalosporins?
* Allergy: 10% of patients with penicillin allergy have cross-reactivity with cephalosporins
* Hepatotoxicity
* Nephrotoxicity: especially with cephaloridine (1st gen), risk increases with concomitant aminoglycoside use
* Disulfiram-like reaction (severe nausea and vomiting): cefamandole, cefoperazone, ceftriaxone, cefmetazole
* Hemolytic anemia
93
How are cephalosporins excreted?
All by the kidney **except** ceftriaxone (3rd gen), by the liver
94
What are the carbapenems?
* Imipenem
* Meropenem
95
What are the therapeutic characteristics of imipenem?
* Broadest spectrum of activity of all β-lactam drugs: effective against most Gram-positive and Gram-negative bacteria and anaerobes
* β-lactamase resistant
* More potent against *E. faecalis*, *B. fragilis* and *Pseudomonas aeruginosa* than 3rd gen. cephalosporins
* Considered by some the drug of choice in the management of polymicrobial pulmonary, intra-abdominal, and tissue infections
96
What are the pharmacokinetic properites of imipenem?
* **Administration**: IV or IM
* **Metabolism**: in the kidney by the enzyme dehydropeptidase I, so it is combined with cilastatin (an inhibitor of the enzyme)
* **Excretion**: kidney
97
What are the adverse effects of imipenem?
* Seizures
98
What are the properties of meropenem?
* Similar activity to imipenem
* Resistant to dehydropeptidase I, so cilastatin is not used concomitantly
* Lower incidence of seizures
99
What are the carbacephems?
Loracarbef (also considered a second generation cephalosporin)
100
What are the properties of the carbacephems?
* Similar to 2nd gen. cephalosporins (especially cefaclor and cefprozil)
* Effective orally
* Excreted by the kidney
101
What are the monobactams?
* Aztreonam
102
What are the properties of monobactams?
* Excellent activity against Gram-negatives
* Little to no effect on Gram-positives
* β-lactamase resistant
* Considered a substitute to aminoglycosides in treating Gram-negative infections (less toxic)
* Rarely, cause allergic reactions in patients with type I hypersensitivity to other β-lactam drugs
103
What are the glycopeptides?
* Vancomycin
* Teicoplanin
104
What are the therapeutic properties of glycopeptides?
* Narrow spectrum of activity
* Effective against Gram-positive bacteria, especially against MRSA
* Used as alternatives to penicillins
* Considered the drug of choice to treat pseudomembranous colitis and antibiotic-associated diarrhea (from *C. dificile* or *Staph. enterocolitis*), with or without metronidazole
105
What are the pharmacokinetic properties of glycopeptides?
* **Administration**:
* Vancomycin: given IV as oral absorption is poor; but can be given orally in pseudomembranous colitis
* Teicoplanin: IM
106
What are the adverse effects of glycopeptides?
* Rapid IV administration: flushing, tachycardia, lowered blood pressure, erythroderma (red man syndrome)
* Thrombophlebitis (inflammation of the wall of a vain associated with thrombosis)
* Ototoxicity
* Circumoral paresthesia (pins and needles)
107
What is the mechanism of action of glycopeptides?
* Prevent the cross-linking of peptidoglycans
* Thus, **bactericidal**
108
What are the aminoglycosides?
* Streptomycin
* Gentamicin
* Netilmicin
* Kanamycin
* Tobramycin
* Amikacin
* Neomycin
* Paromomycin
109
What are the common properties of aminoglycosides?
* They all contain amino sugars and a cyclohexane ring
* They have a similar spectrum of activity: highly effective against Gram-negative bacteria (some are broader but are still most used for Gram-negatives)
* Bactericidal
* Ineffective orally
* Interfere with the bacterial membrane and inhibit bacterial protein synthesis by binding the 30S subunit
* Do not bind plasma or tissue proteins
* Have a small AVD (25% of body weight) and do not penetrate the BBB or the eye
* Rapidly excrete unchanged by the kidney (they are not secreted or resorbed)
* Are highly toxic and have a narrow therapeutic window
110
What are the general toxic effects of aminoglycosides?
* Ototoxicity: hearing and balance issues due to toxicity to the cranial nerve VIII. Reversible but severe toxicity may lead to deafness
* Nephrotoxicity: acute tubular necrosis
* Curare-like effect (muscle paralysis due to neuromuscular blockade)
* Allergy
111
Which aminoglycoside is most toxic?
Neomycin—it is only used topically and orally (for local GI tract infections)
112
Which aminoglycoside is the drug of choice for neonatal Gram-negative meningitis?
Gentamicin. It is administered intrathecally as it does not cross the BBB
113
Which aminoglycoside is the drug of choice for brucellosis and TB?
Streptomycin
114
In which groups is dose adjustment necessary when administering aminoglycosides?
* Children and old patients
* Patients with renal disease
* Patients with hypotension
* Patients on diuretics
115
What are the clinical uses of gentamicin, netilmicin, tobramycin, and amikacin?
* Very potent against Gram-negative bacilli (e.g. *E. coli*, *Klebsiella*, *Proteus*, *Pseudomonas*)
* Synergistic effects with the antipseudomonal PCNs
* Strains of bacteria resistant to gentamicin could be sensitive to amikacin and vice versa
116
What are the clinical uses of netilmicin?
Similar to gentamicin but less ototoxic. Effective against infections resistance to gentamicin
117
What are the clinical uses of kanamycin?
Similar to netilmicin but with no antipseudomonal activity
118
What are the clinical uses of neomycin?
* Used to sterilize the bowel before abdominal surgeries (alongside erythromycin) as prophylaxis
* Also used locally on the skin and the eye
* Highly nephrotoxic, so it is never administered systemically
119
What are the clinical uses of streptomycin?
* Highly effective against TB
* Used alongside PCNs to treat endocarditis due to streptococci
* Highly effective against brucellosis
* Administered IM, which leads to generalized muscle weakness
120
What are the clinical uses of paromomycin?
* Effective only in treating tapeworm infestation and intestinal amebiasis
* It is a first-line treatment for amebiasis or giardiasis during pregnancy
121
Which aminoglycosides are particularly ototoxic?
Kanamycin > amikacin >> gentamicin = tobramycin
122
Which aminoglycosides are particularly nephrotoxic?
Neomycin >>> gentamicin = amikacin > tobramycin
123
What are the macrolide antibiotics?
* Erythromycin
* Clarithromycin
* Azithromycin
* Oleandomycin
* Telithromycin
* Roxithromycin
* Spiramycin
124
What are the general properties of macrolides?
* Bacteriostatic
* Contain a lactone ring and sugars (a 12–22 carbon lactone ring linked to sugars)
* Inhibits with the translocation process of protein synthesis
* Given orally
* Distribute well but cross well-inflamed meninges
125
What is the mechanism of action of aminoglycosides?
* Interfere with the bacterial membrane
* Inhibit bacterial protein synthesis by binding the 30S subunit
126
What is the mechanism of action of macrolides?
Inhibit with the translocation process of protein synthesis
127
What are the clinical uses of erythromycin?
* High activity against Gram-positive bacteria
* Little effect against Gram-negative bacteria
128
What are the clinical uses of clarithromycin and azithromycin?
* More effective than erythromycin against several Gram-negatives, as well as against *Mycoplasma pneumoniae*, *Helicobacter pylori*, *Toxoplasma gondii*, cryptosporidia, and sever atypical mycobacteria
* Clarithromycin is a second-line drug to PCNs in treating streptococcal and staphylococcal infections, e.g. tonsillitis in patients with PCN allergy
129
What are the clinical uses of macrolides?
* Drugs of choice in treating *Corynebacterium diphtheriae* and *Mycoplasma pneumoniae* (alongside tetracyclines)
* Considered alternatives to PCNs in treating streptococcal and staphylococcal infections, e.g. tonsillitis in patients with PCN allergy (especially clarithromycin)
* Considered second-line therapy for treatment of dental infections
130
Why are macrolides never given as first-line therapy in treating dental infections?
* They are bacteriostatic
* Resistance to them develops easily
* Less effective than PCNs in orodental infections and more toxic
131
What are the side effects to macrolides?
* GI irritation: major side effect and most frequent
* Allergy
* Cholestatic hepatitis: occurs due to direct toxicity or as a hypersensitivity reaction. Reversible, more common in adults, and more common with the estolate (gastric acid–resistant) form of erythromycin
132
What is the mechanism of chloramphenicol?
Inhibits protein synthesis by inhibiting transpeptidation
133
What are the properties of chloramphenicol?
* Bacteriostatic
* Broad spectrum: Gram-positive and Gram-negative bacteria as well as anaerobes
* Highly lipid soluble—effective orally and widely used as local application on the eye
* The best antibiotic in crossing the BBB
* Metabolized to inactive metabolites by conjugation with glucuronide
134
Which antibiotic crosses the BBB best?
Chloramphenicol
135
What are the clinical uses of chloramphenicol?
* Treating *H. influenzae* meningitis and epiglottitis
* Treating brain abscesses
* Treating salmonellosis (typhoid and paratyphoid fever)—use has recently been restricted due to its toxicity
136
What are the adverse effects of chloramphenicol?
* Reversible, dose-related bone marrow depression
* Aplastic anemia: allergic in nature. Fatal. Non–dose-related
* Gray-baby syndrome: a fatal toxic reaction. Causes abdominal distension, severe vomiting, cyanosis, hypothermia, respiratory collapse
* Optic neuritis
* Nausea
* Vomiting
* Diarrhea
137
What is the mechanism of action of spectinomycin?
Inhibits protein synthesis
138
What are the features of spectinomycin?
* Bacteriostatic
* Chemically related to the aminoglycosides
* Used as an alternative to PCNs and cephalosporins in treating uncomplicated gonococcal infection in patients allergic to those drugs
* A single IM injection is sufficient
139
What are the tetracyclines?
* Tetracycline
* Chlortetracycline
* Oxytetracycline
* Demeclocycline
* Doxycycline
* Minocycline
* Methacycline
140
What are the properties of tetracyclines?
* Bacteriostatic
* Have a broad spectrum: antibacterial **and** antiparasitic
* Inhibit protein synthesis
* Somewhat selective since they penetrate the bacterial plasma membrane by an energy-dependent mechanism (which is absent in human cells)
141
How does bacterial resistance to tetracyclines develop?
* Altered bacterial permeability to tetracylcine
* Increased efflux of tetracyclines by bacterial energy-dependent mechanisms, leading to lower intracellular concentrations
* Altered structure of bacterial proteins
142
What is the mechanism of action of tetracyclines?
Inhibit protein synthesis
143
What are the clinical uses of tetracyclines?
* Effective against Gram-positive and Gram-negative bacteria
* Considered the drugs of choice in treating *Rickettsia*, *Mycoplasma pneumoniae*, and chlamydia
144
What are the pharmacokinetic properties of tetracyclines?
* Doxycycline has the longest duration of action
* **Administration**: can be given orally and parentally (as IV)
* **Absorption**: food, Mg2+, Al3+, and Ca2+ (especially from milk) form complexes with the drugs and decrease their absorption
* **Distribution**: good but do not cross the BBB
* **Excretion**: in feces (mino-, oxy-, and chlortetracycline) or urine (the others)
145
What are the adverse effects of tetracyclines?
* Irreversible dental staining (yellowish–brown)
* Incorporate into growing teeth and bones and are thus contraindicated in pregnant women and children <8 years
* Nausea, vomiting, diarrhea
* Hepatotoxicity
* Photosensitivity (increased sensitivity to sunlight): especially demeclocycline and doxycycline
* Nephrotoxicity: least with doxycycline and minocycline
* Increased ICP
* Superinfection with *Candida albicans* and *Clostridium difficile*
146
What are the features of lincomycin and clindamycin?
* Bacteriostatic
* Inhibitors of bacterial protein synthesis by binding to the 50S subunit and preventing formation of the 70S complex
* Have good activity against Gram-positive cocci (staphylococci, streptococci), Enterobacteriaceae (*Salmonella*, *Shigella*, *Klebsiella*, *Escherichia*, *Proteus*), Vibroaceae (*Vibrio cholerae*), Pasteurellaceae (*Pasteurella*, *Haemophilus*)
* Have good effect against bone and teeth infections, as well as *Corynebacterium* acne
147
What are the indications of lincomycin and clindamycin?
* Gram-positive cocci (staphylococci, streptococci)
* Enterobacteriaceae (*Salmonella*, *Shigella*, *Klebsiella*, *Escherichia*, *Proteus*)
* Vibroaceae (*Vibrio cholerae*)
* Pasteurellaceae (*Pasteurella*, *Haemophilus*)
* Bone and teeth infections
* *Corynebacterium* acne
148
What are the adverse effects of lincomycin and clindamycin?
* Skin rashes
* Hepatotoxicity
* Pseudomembranous colitis (*C. difficile*)—drug must be stopped and vancomycin ± metronidazole administered
* Contraindicated in patients with hepatic impairment and a history of pseudomembranous colitis
149
Which antimicrobials are typically administered locally?
Polymyxins:
* Polymixin B
* Polymixin E (colistin)
150
What are the features of polymyxins?
* Bactericidal
* Interfere with function or permeability of plasma membrane
* Effective against Gram-negative bacteria and highly effective against *Pseudomonas*
151
What are the adverse effects of polymyxins?
* Highly nephrotoxic (even more than the aminoglycosides)
* Their use is restricted to topical preparations, typically in combination with bacitracin (a cell wall inhibitor) or neomycin, in creams, ointments, eye drops, and ear drops
152
What is the mechanism of action of lincomycin and clindamycin
Inhibitors of bacterial protein synthesis by binding to the 50S subunit and preventing formation of the 70S complex
153
What is the mechanism of action of polymyxins
Interfere with function or permeability of plasma membrane
154
What are the polymyxins?
* Polymyxin B
* Polymyxin E (colistin)
155
What are the microbial DNA synthesis inhibitors?
* Quinolones
* Fluoroquinolones
156
What is the mechanism of action of the quinolones and fluoroquinolones?
Inhibition of bacterial DNA gyrase, a type II topoisomerase
157
What are the features of quinolones and fluoroquinolones?
* Inhibitors of bacterial DNA gyrase
* Bactericidal
* Chemotherapeutic agents
* Broad spectrum (effective against pseudomonas)
158
What are the first generation quinolones?
* Nalidixic acid
* Pipemidic acid
* Oxolinic acid
159
What are the second generation quinolones?
* Ciprofloxacin
* Ofloxacin
* Norfloxacin
* Enoxacin
* Lomefloxcin
* Nadifloxacin
160
What are the third generation quinolones?
* Levofloxacin
* Sparfloxacin
* Gatifloxacin
161
What are the fourth generation quinolones?
* Moxifloxacin
* Prulifloxacin
* Gemifloxacin
162
What are the clinical uses of the first generation quinolones?
* Most effect in Gram-negative infections and only in UTIs
* Has little activity against Enterbacteriaceae
* No effect against pseudomonas
163
What are the clinical uses of the second generation quinolones?
More activity against Gram-negative bacteria
164
What are the clinical uses of the third generation quinolones?
Good activity against pseudomonas and anaerobic microorganisms
165
Which quinolones are the most widely used?
* Ciprofloxacin (2nd gen)
* Levofloxacin (3rd gen)
* Moxifloxacin (4th gen)
166
What are the clinical uses of the quinolones?
* Mainly in complicated UTIs
* Respiratory infections
* Invasive external otitis
* Bacterial prostatitis and cervicitis
* Bacterial diarrhea caused by *Shigella*, *Salmonella*, or *E. coli*
167
What are the pharmacokinetic properties of the quinolones?
**Absorption**: orally effective and well absorbed but affected by food containing calcium and iron
168
What are the mechanisms of bacterial resistance to quinolones?
* Bacterial efflux pumps decrease intracellular concentrations
* Some bacteria (especially Gram-negatives) produce proteins that bind to DNA gyrase, protecting it from the action of quinolones
* Mutations in DNA gyrase/topoisomerase could lead to a decrease in quinolone binding affinity
169
What are the adverse effects of quinolones?
* GI irritation
* Photosensitivity
* Cardiac toxicity (many may prolong the QT interval)
* Some are not recommended in children and during pregnancy as they interfere with cartilage development
* Some have been reported to be carcinogens
170
What is the mechanism of action of nitrofurantoin?
It is converted by bacterial reductases to reactive intermediates that directly damage the bacterial DNA, disrupt RNA transcription and protein synthesis, and interfere with metabolic processes
171
What are the features of nitrofurantoin?
* Synthetic
* Bactericidal
* Orally effective
* Effective against Gram-positive and Gram-negative bacteria (particularly *E. coli*)
* Highly effective in UTIs (cystitis), it is known as a UT antiseptic
* Resistance rarely develops as it has many sites of action
172
What are the adverse effects of nitrofurantoin?
* Pulmonary fibrosis
* Contraindicated in patients with G6PD deficiency
173
What are the features of fosfomycin?
* A broad-spectrum bactericidal drug
* Used primarily to treat lower UTIs and occasionally for prostate infections
* Effective against Gram-positive and Gram-negative organisms and many antibiotic-resistant organisms
174
What is the mechanism of action of fosfomycin?
Dirsupts cell wall synthesis by inhibiting phosphoenolpyruvate synthetase, an enzyme in the pathway of peptidoglycan synthesis
175
What are the adverse effects of fosfomycin?
* Restricted to a single dose as resistance builds rapidly
* Metallic tase
* Stomach upset
* Dizziness
* Stuffy nose
* Back pain
* Vaginal itching or discharge
176
What are the features of sulfonamides?
* Broad-spectrum bacteriostatic drugs
* Structural analogs of PABA used to synthesize dihydrofolate
* Effective against many Gram-positive and Gram-negative bacteria, nocardia, lymphogranuloma, trachoma, blastomycosis, and many protozoal infections
177
What is the mechanism of action of sulfonamides?
Structural analogs of PABA used to synthesize dihydrofolate
178
What are the clinical uses of sulfonamides?
* Upper respiratory tract infections
* UTIs (sulfamethoxazole, sulfisoxazole)
* Toxoplasmosis
* Chlamydia infections
* Protozoal infections
* Infected burns
* Eye infection (sulfacetamide, sufadiazine)
* Sterilization of the bowel before surgery
* Sulfasalazine (sulfapyridine salicylate) is used in IBD
179
What are the sulfonamides?
* Sulfamerazine
* Sulfamethazine
* Sulfisoxazole
* Sulfadiazine
* Sulfacetamide
* Sulfamethoxazole
* Phthalylsulfathiazole (sulfathalidine)
* Sulfasalazine
180
Which sulfonamides are used locally?
* Sulfadiazine
* Sulfacetamide
181
Which sulfonamides are well absorbed?
* Sulfamerazine
* Sulfamethazine
* Sulfisoxazole
* Sulfadiazine
* Sulfacetamide
* Sulfamethoxazole
182
What are the features of sulfamethoxazole?
* The most widely used sulfonamide
* Well-absorbed
* Intermediate-acting
183
What are the features of phthalylsuflathiazole?
* Long-acting
* Orally effective
184
What are the features of sulfasalazine?
* Poorly absorbed from the GI tract
* Long-acting
185
What are the mechanisms of bacterial resistance to sulfonamides?
* Reduced permeability to the drugs
* Increased production of PABA
* Altered dihydropteroate synthase
* Obtaining reduced folate from the environment
186
What are the pharmacokinetic properties of sulfonamides?
* **Distribution**: bind plasma proteins (and lead to elevated bilirubin levels in the blood, leading to kernicterus); distributes well, including in the CSF
* **Metabolism**: acetylated (metabolites are toxic but inactive)
* **Excretion**: renal. They may precipitate in the urine, forming stones, so there must be good fluid intake
187
What are the strategies to avoid precipitation of sulfonamides in the urine?
* Good fluid intake
* Using sulfisoxazole, which has high urine solubility
* Using combined sulfa drugs at lower total doses (due to synergism)
* Alkalization of the urine
188
What are the features of trimethoprim?
* Bacteriostatic
* A structural analog of folic acid
* Inhibits dihydrofolate reductase
* Effective against *E. coli*, *H. influenzae*, *K. pneumoniae*
* Ineffective against pseudomonas and *Proteus*
* Used in the treatment and prophylaxis of UTIs
189
How do the pharmacokinetic properties of trimethoprim compare to those of the sulfonamides?
* Faster onset of action
* Well absorbed orally, like the sulfonamides
* Has a similar half-life to sulfamethoxazole
* Crosses the BBB to a lesser extent
* Excreted unchanged in the kidney
* Associated with fewer side effects
190
Which sulfonamide is commonly combined with trimethoprim?
Sulfamethoxazole (co-trimoxazole)
191
What are the properties of combined sulfamethoxazole–trimethoprim (co-trimoxazole)?
* Acts sequentially in preventing nucleic acid synthesis in some bacteria
* Synergistic activity
* Broader spectrum but still not effective against pseudomonas
* More bactericidal
* Resistance is less likely
192
What are the adverse effects of sulfonamides?
* Allergic reactions (frequent)
* Kernicterus
* Renal damage (toxic nephrosis, allergic nephritis, drug crystals)
* Liver damage (rare)
* Nausea
* Vomiting
* Blood dyscrasia, hemolysis in G6PD deficient patients
* Steven-Johnson syndrome (uncommon): inflammatory condition of the skin and mucosal membranes
