4. Ribosomal Inhibiting Antibacterial Agents

What is the mechanism of action for tetracyclines? Is this reversible or irreversible? Does this make them bacteriostatic or bacteriocidal?

inhibitors of the bacterial 30S ribosome; reversible; bacteriostatic

What is the spectrum? What tetracycline is the exception?

very limited because of resistance; doxycycline

What microbes are always sensitive to any tetracycline?

B
R
C
S

• brucella

• rickettsia

• chlamydia

• spirochetes

True or false: Some mycoplasma are also sensitive to some tetracyclines.

true

Tetracyclines are very good versus what form bacteria?

L-form bacteria

L-form bacteria are resistant to what? Why? What does this allow for with the tetracyclines?

B-lactams; the L forms lack PTDGs; good penetration for tetracyclines

L-form bacteria are not ________ to tetracylines because the tetracycline efflux pumps are often ________ to the cell membrane and thus are lost when the ________ shell is lost.

resistant; exterior; outer

Where are L-form bacteria sometimes present?

in abscesses

What is the resistance of tetracyclines? Except for which?

widespread; doxycycline and tigecycline

What is not resistant to tetracyclines?

L-form bacteria

What is the main resistance mechanism when it comes to tetracyclines?

efflux

What are some toxicities associated with tetracyclines?

M
E
I
P

• mildly nephrotoxic

• esophageal strictures following an oral dose

• injection site irritant

• photosensitivity

Which tetracyclines are not mildly nephrotoxic?

doxycycline or minocycline

In what species and what tetracycline are esophageal strictures following an oral dose common?

cats and doxycycline

What is toxic effect of oral tetracyclines in horses?

will cause intestinal dysbiosis in horses (disruption of the good bacteria in the intestinal microbiome), so avoid in this species

What are tetracyclines chelated by? What is the effect of this? What will this lead to?

Ca2+ and Mg2+; poorly absorbed in the presence of milk; tetracyclines will deposit in the bone and teeth

What is the effect of tetracyclines in fetuses, neonates, and juveniles?

yellow teeth

Which tetracycline does not cause yellow teeth? What does it cause instead?

minocycline; leaves black deposits in the thyroid

Which tetracycline is neuroprotective? How?

doxycycline; inhibits apoptosis in neurons

Which tetracycline is helpful against CNS infections?

doxycycline

What tetracycline is a good, safe choice if a nephropathy is present? Why?

doxycycline; not eliminated via the kidneys

True or false: Most antibiotics are eliminated via the kidneys and thus dosages are determined assuming that the kidneys are functionally normal. Thus, the PK profile of doxycycline is not altered if a nephropathy is present.

true

Elimination of Drugs via the Kidney:

1. most drugs ________ move from the ________ arteriole into the ________ ________ and then stays in the ________ filtrate

2. some drugs, such as ________, can move through the tubule cells and enter a peritubular capillary

3. once in the peritubular capillary, the ________ will return to the ________ circulation

4. the majority of antibiotics do not cross the tubule cell and thus do not re-enter the ________ circulation

5. kidney disease will lead to drug retention and potential toxicity, but not for ________

1. passively; afferent; glomerular filtrate; urinary

2. doxycycline

3. doxycycline; systemic

4. systemic

5. doxycycline

What are the clinical applications of tetracyclines, especially doxycyclines?

N
C
C
L

• non-responsiveness abscesses (L-form bacteria)

• chlamydia infections

• contracted tendons in foals

• lyme disease

Why are tetracyclines, especially doxycycline, used to treat contracted tendons in foals?

inhibit collagen contraction of myofibroblasts

What can be a negative effect of chronic oral use of doxycycline to treat lyme disease? What can this worsen? What is the solution to this problem?

can have a deleterious impact on the gut microbiome (dysbiosis); the clinical signs associated with lyme disease; spirochete-specific bacteriocidal antibiotics (those that spare the gut microbiome)

Describe the bovine respiratory disease (BRD) treatment.

oxytetracycline is FDA-approved but useless because of resistance, so it is combined with the NSAID flunixin

What is oxytetracycline no longer available as a feed additive for?

preventing (metaphylaxis) for BRD

What tetracycline is still available for preventing liver abscesses in feedlot cattle but only by prescription?

chlortetracycline

What is the mechanism of action of the aminoglycosides and the aminocyclitols?

inhibitors of the 30S ribosomal subunit

Do the aminoglycosides irreversibly or reversibly fuse to the 30S ribosome? Therefore, are they bacteriocidal or bacteriostatic?

irreversibly; bacteriocidal

Do the aminocyclitols reversibly or irreversibly bind? Are they bacteriocidal or bacteriostatic?

reversibly; bacteriostatic

True or false: The bacteria that are exposed to aminocyclitols, which are bacteriostatic, have a chance to survive once the antibiotic is gone if the immune system has not cleared the bacteria.

true

What is the spectrum of aminoglycosides and the aminocyclitols?

gram negative aerobes and gram positive cocci

What are aminoglycosides and the aminocyclitols useless against? Why?

anaerobes; transport of these drugs into bacteria is oxygen-dependent

What does streptomycin have activity against?

mycobacterium tuberculosis

What do both tobramycin and amikacin have activity against?

pseudomonas

What is resistance to aminoglycosides and the aminocyclitols attributed to?

bacterial enzymes that modify and inactivate the drugs and there is also some cross resistance between aminoglycosides and the aminocyclitols

What are toxicities associated with aminoglycosides and the aminocyclitols?

N
O
N
P

• nephrotoxicity

• ototoxicity

• neuromuscular blockade

• physical incompatibility with other drugs

Nephrotoxicity (Reversible Acute Tubular Necrosis):

Aminoglycosides and the aminocyclitols are ________ and have a tropism for binding to the ________ phospholipids on the renal tubule epithelial cell. These drugs are then absorbed into the renal tubule via ________. The drugs than rupture the ________, killing the tubule cell.

cationic; anionic; lysosomes; lysosomes

Which aminoglycosides and the aminocyclitols is the most nephrotoxic?

neomycin

Which aminoglycosides and the aminocyclitols are the least nephrotoxic?

streptomycin and tobramycin

How can the nephrotoxicity of aminoglycosides and the aminocyclitols be minimized?

by increasing the dose interval (trough)

How is the nephrotoxicity of aminoglycosides and the aminocyclitols accentuated?

by diuretics and calcium supplementation

How is nephrotoxicity due to aminoglycosides and the aminocyclitols diagnosed?

elevated (2-3 fold) urine GGT:urine creatinine and proteinuria

What are the general ototoxicities associated with aminoglycosides and the aminocyclitols?

vestibular (balance) and cochlear (hearing)

What is the mechanism of ototoxicity with the aminoglycosides and the aminocyclitols?

damages ear cells by binding to and harming the 12S ribosome present in the mitochondria of ear cells

What are the two main types of ototoxicities associated with aminoglycosides and the aminocyclitols?

C
V

• cochlear toxicity (can be reversible)

• vestibulopathies (reversible)

Cochlear toxicity is seen more frequently with the use of what drugs?

K
A
N

• kanamycin

• amikacin

• neomycin

Cochlear toxicity is mostly observed in what species?

dogs

Cochlear toxicity is not observed with what drug class?

aminocyclitols

Vestibulopathies are seen more frequently with the use of what drugs?

S
G
T

• streptomycin

• gentamicin

• tobramycin

Vestibulopathies are mostly observed in what species?

cats

With what drug class are vestibulopathies not observed with?

aminocyclitols

How does the neuromuscular blockade occur with aminoglycosides and the aminocyclitols?

inhibition of nAChR

Neuromuscular blockade seen with aminoglycosides and the aminocyclitols mostly occurs in conjunction with what?

anaesthetic agents

In what patients is the neuromuscular blockade due to aminoglycosides and the aminocyclitols worse?

myasthenia gravis

What is the treatment for the neuromuscular blockade seen with aminoglycosides and the aminocyclitols?

calcium gluconate or neostigmine

The aminoglycosides and the aminocyclitols are most incompatible with what drugs? However, how are they clinically? What needs to be done if administering these drugs?

beta-lactams; synergistic; flush the IV line between administration of these drugs

Aminoglycosides are ________ and very ________ with other drugs so do not mix in an ________.

polar; reactive; IV

True or false: Even momentary exposure of bacteria to aminoglycosides and the aminocyclitols can have a lasting effect upon bacteria. An elevated short-term dose kills bacteria for long periods of time.

true

With aminoglycosides and the aminocyclitols, is the time above the MIC more important or the concentration above the MIC?

concentration above MIC

Since the aminoglycosides and the aminocyclitols are polar drugs, how do you reach therapeutic blood levels?

injectable

What is the Vd of the aminoglycosides and the aminocyclitols? Where do the aminoglycosides tend to remain? Therefore, what is the association with aminoglycosides and the BBB?

low; in the blood which is mostly water; rarely will cross the BBB (lipid barrier)

What are the clinical uses for the aminoglycosides and the aminocyclitols?

O
U

• otitis

• UTI

How are the aminoglycosides and the aminocyclitols used against otitis? What is important to ensure prior to treating? Why?

topically; make sure the ear drum is not patent; ototoxicity will ensue if the ear drum is ruptured

Why are the aminoglycosides and the aminocyclitols useful against UTIs?

not metabolized by the patient

Why are aminoglycosides a good choice for use against UTIs? What does this mean?

they are already water soluble so the liver does not need to metabolize the aminoglycosides for the kidneys to eliminate them; aminoglycosides are lost in the urinary filtrate in the active bacteriocidal form

In what form do aminoglycosides reach the bladder?

in an active state ready to kill any bacteria present

What are the clinical limitations of aminoglycosides and the aminocyclitols?

R
T
A
F
E

• resistance

• toxicities

• aminoglycosides are not available in pill form for dispensing (no treatment continuity)

• fluoroquinolones have clinically supplanted aminoglycosides

• extended withdrawal times in food animals (no systemic extralabel use)

What are the exeptions to resistance with the aminoglycosides and the aminocyclitols?

A
A

• amikacin

• apramycin

What are the exceptions to toxicities with the aminoglycosides and the aminocyclitols?

plazomicin, which is a new drug with minimal toxicity

Aminoglycosides and the aminocyclitols are still used in a number of what type of preps? What are specific examples of uses? Why are these used?

E
S
E
I
I

topical

• eye

• skin

• ear

• intrauterine

• intestinal (oral)

minimal side effects since these applications are not systemically absorbed

aminoglycoside that has a lot of topical applications, especially in companion animals

gentamicin

What is gentamicin used for in equine?

M
G

• metritis (intrauterine)

• gram negative sepsis (injectable)

What is gentamicin used for in swine?

colibacillosis (injectable)

Overall, what is the most relevant use of gentamicin? What is another widely used topical aminoglycosides?

small animal topical; neomycin

What bacteria seem to be mostly incapable, at this point, of mounting resistance to amikacin?

gram negative enteric bacteria

What is the main use for amikacin in companion animals and equine?

IV for limb joints

When do you know if amikacin is warranted?

when dictated by the antibiogram (but remember the toxicities)

What is the use for paromomycin?

cryptosporidium

Since aminoglycosides are polar and not biotransformed (excreted unchanged), when injected, they can be used to treat what type (location) of infection?

UTI (near 100% renal elimination in the bacteriocidal form)

What is the only feed grade aminoglycoside and will remain available but restricted (prescription needed)?

neomycin

What is the clinical applications of gentamicin?

injectable in swine and equine and topical in companion animals

What is the clinical application of amikacin?

when dictated by the antibiogram

Which aminoglycoside does not cause nephrotoxicity but may cause ototoxicity? What can be said about the resistance of this drug?

plazomicin; less likely to occur since it has fewer hydroxyl groups than other aminoglycosides

Why might plazomicin be a replacement for doxycycline in treating chronic/recurring infections like brucella and borrelia? Is it approved yet in veterinary medicine?

the bacteriocidal activity will be more useful for treating these infections since doxycyline is bacteriostatic; no

What is the most expensive beef cattle diseases in the US, costing about $1 billion per year?

bovine respiratory disease (BRD)

When does BRD occur?

when calves are stressed during the transportation from the cow-calf site to the feedlot

What drug class is used metaphylactically no most transported calves as they arrive at the feedlot?

macrolides

What is the mechanism of action of the macrolides? Are they bacteriocidal or bacteriostatic?

reversible 50S inhibitors; bacteriostatic

What is the spectrum of the macrolides?

all gram positive aerobes and all anaerobes

Which macrolide has an enhanced spectrum that includes gram negative aerobes, but does not include pseudomonas?

azithromycin

What macrolide has good efficacy against mycoplasma? But what are superior?

tylosin; long-acting BRD metaphylactic drugs

What leads to resistance to the macrolides? What else does this confer?

methylation of the ribosome; cross-resistance to most other 50S inhibitors

What are the side effects and toxicities of macrolides?

D
C
G

• drug interactions are very common with erythromycin

• cause sterile abscesses

• GI distress (motilinR agonist → hyperperistalsis)

Which macrolides more commonly cause sterile abscesses? What do they cause in swine?

tylosin and erythromycin; edema and rectal prolapses

Macrolides have what type of side effect? What is it?

beneficial; anti-inflammatory by inducing neutrophil apoptosis

What is an important consideration when it comes to tilmicosin?

the fatal IV dose is fairly low in cattle (5 mg/kg)

What is significant about tilmicosin in humans? What does it cause specifically?

accidental injection in humans can be fatal (cardiotoxic); prolonged Q-T interval