Exploring the Mechanisms of Motion of Antibacterial Medicine: Unveiling Their Methods for Combating Bacterial Infections

Exploring the Mechanisms of Motion of Antibacterial Medicine: Unveiling Their Methods for Combating Bacterial Infections

 

ANTIMICROBIAL DRUG STEWARDSHIP

 

The invention of antimicrobials is likely one of the nice advances in

medication, and their use has considerably lowered morbidity and

mortality worldwide. Sadly, with widespread antibiotic

use, we now have witnessed the emergence of multidrug-resistant

pathogens and lowered efficacy of a lot of our most power-

ful antimicrobials. As well as, we now have additionally acknowledged many

antagonistic results of antimicrobials, most notably the rising charges

of Clostridium difficile colitis. Additional, the price of medical care

is enormously elevated as a consequence of overuse of antibiotics and treating

infections brought on by resistant organisms. It’s important that well being

occupation learners perceive the important thing ideas behind anti-

microbial stewardship on the time they find out about microbial

pathogens and antimicrobials.

The worldwide drawback of antibiotic resistance makes the

want for antimicrobial stewardship evident. The Facilities for

Illness Management and Prevention estimates that within the United

States over 2 million infections with multidrug-resistant patho-

gens happen every year, resulting in roughly 20,000 deaths.

These pathogens embody methicillin-resistant Staphylococcus

aureus and extended-spectrum β-lactamase–producing gram-

damaging rods (e.g., Escherichia coli and Klebsiella pneumoniae).

Hospital-associated infections, a lot of that are brought on by

antibiotic-resistant micro organism, are estimated to value billions of

{dollars} every year.

The essential ideas of fine stewardship are threefold:

(1) cut back inappropriate use of antibiotics, (2) encourage tar-

geted remedy with narrow-spectrum medication, and (3) restrict

antagonistic results (Desk 10–1). Inappropriate antibiotic use can

happen for a lot of causes, together with the suppliers’ want to stick

to affected person’s needs, even when it isn’t medically applicable.

The most typical instance of inappropriate antibiotic use is the

prescribing of antibiotics for a viral respiratory tract an infection. It

is estimated that half of all prescriptions given for higher respira-

tory infections (pharyngitis, sinusitis) are inappropriate.

The idea of focused remedy refers to creating a micro-

biologic analysis promptly and utilizing essentially the most particular anti-

biotic that has the very best security profile for the affected person. If a number of

broad-spectrum antibiotics are used as empiric remedy early

in an infection, then switching to a narrow-spectrum antibiotic as

quickly as doable ought to be finished. Cultures ought to be despatched prior

to beginning antibiotics in order that the medication is not going to cut back the like-

lihood of isolating the causative organism. Additional, switching

from intravenous antibiotics to oral dosing reduces the chance of

catheter-associated infections. The online results of focused treat-

ment is to cut back the flexibility of antibiotics to pick for resistant

mutants current within the bacterial inhabitants.

Limiting the incidence of antagonistic results brought on by antibi-

otics is one other main objective of antimicrobial stewardship. Mini-

mizing the length of antibiotic use to solely so long as clinically

indicated is a key intervention since length of publicity cor-

relates carefully with the chance of many kinds of antagonistic results.

Sufferers with lowered renal operate ought to have the dose of

some antibiotics adjusted based mostly on their estimated glomerular

filtration price.

Antibiotic allergy symptoms ought to be recognized and explored in

element. Though response to antibiotics could also be generally

reported, they could not at all times be of significance reminiscent of some

alleged hypersensitivity reactions. If optimum remedy requires

a drug reminiscent of penicillin to which the affected person says she or he is

allergic, then pores and skin testing might be employed to find out the

accuracy of that declare. As well as, sufferers ought to be warned

concerning the chance that sure medication could trigger antagonistic

results. For instance, sure photosensitizing antibiotics could

trigger a rash when the affected person is uncovered to daylight.

The explanations that inappropriate use of antibiotics happens are

diverse. In all probability, an important is the lack of understanding

or consciousness of the doctor. Danger avoidance on the a part of the

doctor can also be frequent. Insufficient microbiologic informa-

tion performs a job as effectively. Affected person expectation and direct calls for

for antibiotics contribute to the issue.

In abstract, antimicrobial stewardship refers back to the effort to

enhance the remedy of infectious illnesses by the suitable

use of antibiotics. That is important on this period of rising charges of

multidrug-resistant pathogens. Focused remedy with essentially the most

applicable single antibiotic will hopefully enhance scientific out-

comes and cut back the price of care.

 

PRINCIPLES OF ANTIMICROBIAL THERAPY

Crucial idea underlying antimicrobial remedy

is selective toxicity (i.e., selective inhibition of the expansion of the

microorganism with out injury to the host). Selective toxicity is

achieved by exploiting the variations between the metabolism

and construction of the microorganism and the corresponding

options of human cells. For instance, penicillins and cephalo-

sporins are efficient antibacterial brokers as a result of they forestall

the synthesis of peptidoglycan, thereby inhibiting the expansion of

bacterial however not human cells.

There are 4 main websites within the bacterial cell which can be suffi-

ciently totally different from the human cell that they function the idea

for the motion of clinically efficient medication: cell wall, ribosomes,

nucleic acids, and cell membrane (Desk 10–2 and Determine 10–1).

There are way more antibacterial medication than antiviral medication.

It is a consequence of the issue of designing a drug

that can selectively inhibit viral replication. As a result of viruses

use most of the regular mobile capabilities of the host of their

development, it isn’t simple to develop a drug that particularly inhibits

viral capabilities and doesn’t injury the host cell.

Broad-spectrum antibiotics are lively in opposition to a number of varieties

of microorganisms (e.g., tetracyclines are lively in opposition to many

gram-negative rods, chlamydiae, mycoplasmas, and rickettsiae).

Slim-spectrum antibiotics are lively in opposition to one or only a few

varieties (e.g., vancomycin is primarily used in opposition to sure gram-

constructive cocci, specifically, staphylococci and enterococci).

 

BACTERICIDAL & BACTERIOSTATIC ACTIVITY

 

In some scientific conditions, it’s important to make use of a bactericidal drug

slightly than a bacteriostatic one. A bactericidal drug kills micro organism,

whereas a bacteriostatic drug inhibits their development however doesn’t

kill them (Determine 10–2). The salient options of the conduct of

bacteriostatic medication are that (1) the micro organism can develop once more when

the drug is withdrawn, and (2) host protection mechanisms, reminiscent of

phagocytosis, are required to kill the micro organism. Bactericidal medication

are notably helpful in sure infections (e.g., these which can be

instantly life-threatening; these in sufferers whose polymor-

phonuclear leukocyte rely is under 500/μL; and endocarditis,

through which phagocytosis is restricted by the fibrinous community of the

vegetations and bacteriostatic medication don’t impact a treatment).

 

MECHANISMS OF ACTION

 

INHIBITION OF CELL WALL SYNTHESIS

1. Inhibition of Bacterial

Cell Wall Synthesis

Penicillins

Penicillins (and cephalosporins) act by inhibiting transpepti-

dases, the enzymes that catalyze the ultimate cross-linking step in

the synthesis of peptidoglycan (see Determine 2–5). For instance, in

S. aureus, transpeptidation happens between the amino group on

the tip of the pentaglycine cross-link and the terminal carboxyl

group of the d-alanine on the tetrapeptide aspect chain. As a result of

the stereochemistry of penicillin is just like that of a dipeptide,

d-alanyl-d-alanine, penicillin can bind to the lively web site of the

transpeptidase and inhibit its exercise.

Two further elements are concerned within the motion of penicillin:

(1) The primary is that penicillin binds to quite a lot of proteins

within the bacterial cell membrane and cell wall, referred to as penicillin-

binding proteins (PBPs). Some PBPs are transpeptidases; the

others operate within the synthesis of peptidoglycan. Modifications in

PBPs are partially liable for an organism’s turning into resis-

tant to penicillin.

 

FIGURE 10–2 Bactericidal and bacteriostatic exercise of antimi-

crobial medication. Both a bactericidal or a bacteriostatic drug is added

to the rising bacterial tradition on the time indicated by the arrow.

After a short lag time throughout which the drug enters the micro organism, the

bactericidal drug kills the micro organism, and a lower within the variety of

viable micro organism happens. The bacteriostatic drug causes the micro organism to

cease rising, but when the bacteriostatic drug is faraway from the

tradition, the micro organism resume rising.

(2) The second issue is that autolytic enzymes referred to as murein

hydrolases (murein is a synonym for peptidoglycan) are activated

in penicillin-treated cells and degrade the peptidoglycan. Some

micro organism (e.g., strains of S. aureus) are tolerant to the motion of

penicillin, as a result of these autolytic enzymes usually are not activated. A

tolerant organism is one that’s inhibited however not killed by a drug

that’s often bactericidal, reminiscent of penicillin. Penicillin-treated

R

A. 6-Aminopenicillanic acid

R N

c

H S

CH

C N

Web site of penicillinase motion

(break in β-lactam ring)

CH COOH

CH3

CH3

CH C

b a

Web site of acid hydrolysis

B. Penicillin G (benzylpenicillin)

R C CH C

O

C O

OC2H5

C. Nafcillin (ethoxynaphthamidopenicillin)

CC

O

cells die by rupture because of the inflow of water into the high-

osmotic-pressure inside of the bacterial cell.

Penicillin is bactericidal, but it surely kills cells solely when they’re

rising. When cells are rising, new peptidoglycan is being

synthesized, and transpeptidation happens. Nonetheless, in non-

rising cells, no new cross-linkages are required, and penicillin

is inactive. Penicillins are due to this fact extra lively in the course of the log

section of bacterial cell development than in the course of the stationary section

(see Chapter 3 for the bacterial cell development cycle).

Penicillins (and cephalosporins) are referred to as β-lactam medication

due to the significance of the β-lactam ring (Determine 10–3).

An intact ring construction is important for antibacterial exercise;

cleavage of the ring by penicillinases (β-lactamases) inactivates

the drug. Crucial naturally occurring compound

is benzylpenicillin (penicillin G), which consists of the

6-aminopenicillanic acid nucleus that every one penicillins have, plus a

benzyl aspect chain (see Determine 10–3). Penicillin G is accessible in

three predominant kinds:

(1) Aqueous penicillin G, which is metabolized most quickly.

(2) Procaine penicillin G, through which penicillin G is conjugated

to procaine. This kind is metabolized extra slowly and is much less

painful when injected intramuscularly as a result of the procaine acts

as an anesthetic.

(3) Benzathine penicillin G, through which penicillin G is conju-

gated to benzathine. This kind is metabolized very slowly and

is commonly referred to as a “depot” preparation.

Benzylpenicillin is likely one of the most generally used and efficient

antibiotics. Nonetheless, it has 4 disadvantages, three of which

have been efficiently overcome by chemical modification of

the aspect chain. The three disadvantages are (1) restricted effective-

ness in opposition to many gram-negative rods, (2) hydrolysis by gastric

acids, in order that it can’t be taken orally, and (3) inactivation by

β-lactamases. The restricted effectiveness of penicillin G in opposition to

gram-negative rods is because of the lack of ability of the drug to pen-

etrate the outer membrane of the organism. The fourth disad-

vantage frequent to all penicillins that has not been overcome

is hypersensitivity, particularly anaphylaxis, in some recipients of

the drug.

The effectiveness of penicillins in opposition to gram-negative rods

has been elevated by a collection of chemical modifications within the aspect

chain (Desk 10–3). It may be seen that ampicillin and amoxicil-

lin have exercise in opposition to a number of gram-negative rods that the ear-

lier penicillins should not have. Nonetheless, these medication usually are not helpful

in opposition to Pseudomonas aeruginosa and Okay. pneumoniae. Therefore,

different penicillins have been launched. Usually talking, because the

exercise in opposition to gram-negative micro organism will increase, the exercise

in opposition to gram-positive micro organism decreases.

The second essential drawback—acid hydrolysis within the

abdomen—additionally has been addressed by modification of the aspect

chain. The positioning of acid hydrolysis is the amide bond between

the aspect chain and penicillanic acid nucleus (see Determine 10–3).

Minor modifications of the aspect chain in that area, reminiscent of

addition of an oxygen (to provide penicillin V) or an amino

group (to provide ampicillin), forestall hydrolysis and permit the

drug to be taken orally.

The inactivation of penicillin G by β-lactamases is one other

essential drawback, particularly within the remedy of S. aureus

infections. Entry of the enzyme to the β-lactam ring is blocked

by modification of the aspect chain with the addition of enormous aro-

matic rings containing cumbersome methyl or ethyl teams (methicil-

lin, oxacillin, nafcillin, and so forth.; see Determine 10–3). One other protection

in opposition to β-lactamases is inhibitors reminiscent of clavulanic acid, tazo-

bactam, sulbactam, and avibactam. These are structural ana-

logues of penicillin which have little antibacterial exercise however bind

strongly to β-lactamases and thus defend the penicillin. Com-

binations, reminiscent of amoxicillin and clavulanic acid (Augmentin),

are in scientific use. Some micro organism resistant to those combos

have been remoted from affected person specimens.

Penicillins are often unhazardous at clinically efficient ranges.

The most important drawback of those compounds is hypersensitivity,

with a reported prevalence of 1% to 10% of sufferers. The immu-

noglobulin (Ig) E–mediated hypersensitivity reactions embody

anaphylactic shock, bronchospasm, and urticarial rash (see

Chapter 65). IgG and cell-mediated hypersensitivity reactions

embody nonurticarial pores and skin rashes, hemolytic anemia, nephritis,

and drug fever. A maculopapular drug-induced rash is kind of

frequent. Anaphylactic shock, essentially the most severe complication,

happens in 0.5% of sufferers. Dying because of anaphylaxis

happens in 0.002% of sufferers (1 in 50,000 sufferers).

Sufferers who say they’re allergic to penicillin might be handled

with one other equally efficient antibiotic, if accessible. To discourage-

mine whether or not the affected person’s allergy is clinically vital, a

pores and skin check utilizing penicilloyl-polylysine because the check reagent can

be carried out. A wheal and flare response happens on the web site of

injection in allergic people. If the affected person’s illness requires

remedy with penicillin, the affected person might be desensitized below

the supervision of a skilled allergist.

Cephalosporins

Cephalosporins are β-lactam medication that, like penicillins, additionally

inhibit the cross-linking of peptidoglycan. The buildings, how-

ever, are totally different: Cephalosporins have a six-membered ring

adjoining to the β-lactam ring and are substituted in two locations

on the 7-aminocephalosporanic acid nucleus (Determine 10–4),

whereas penicillins have a five-membered ring and are substi-

tuted in just one place.

The primary-generation cephalosporins are lively primarily

in opposition to gram-positive cocci (Desk 10–4). Much like the peni-

cillins, new cephalosporins have been synthesized with enlargement

of exercise in opposition to gram-negative rods because the objective. These new

cephalosporins have been categorized into second, third, and

fourth generations, with every era having expanded

protection in opposition to sure gram-negative rods. The fourth- and

fifth-generation cephalosporins have exercise in opposition to many

gram-positive cocci as effectively.

Cephalosporins are efficient in opposition to a broad vary of organ-

isms, are typically effectively tolerated, and produce fewer hypersen-

sitivity reactions than do the penicillins. Regardless of the structural

similarity, a affected person allergic to penicillin has solely a few 10%

likelihood of being hypersensitive to cephalosporins additionally. Most

cephalosporins are the merchandise of molds of the genus Cephalo-

sporium; a number of, reminiscent of cefoxitin, are made by the actinomycete

Streptomyces.

The inactivation of cephalosporins by β-lactamases (cepha-

losporinases) is a crucial scientific drawback. β-Lactamase

inhibitors reminiscent of tazobactam and avibactam are mixed with

sure cephalosporins to forestall inactivation of the cephalospo-

rin. For instance, the US Meals and Drug Administration (FDA)

has authorized the mix of ceftazidime/avibactam (Avycaz)

and ceftolozane/tazobactam (Zerbaxa) for the remedy of

intra-abdominal infections and complex urinary tract infec-

tions brought on by antibiotic-resistant gram-negative rods.

Carbapenems

Carbapenems are β-lactam medication which can be structurally totally different

from penicillins and cephalosporins. For instance, imipenem

CH3

CH3

C CH3

COOH

CONH

CO

O SO3

N

O

COOH

S

OH

N NHC

NH

H

N

S H2N

A B

N

FIGURE 10–5 A: Imipenem. B: Aztreonam.

(N-formimidoylthienamycin), a generally used carbapenem,

has a methylene group within the ring instead of the sulfur (Determine

10–5). Imipenem has one of many widest spectrums of exercise of

the β-lactam medication. It has glorious bactericidal exercise in opposition to

many gram-positive, gram-negative, and anaerobic micro organism. It

is efficient in opposition to most gram-positive cocci (e.g., streptococci

and staphylococci), most gram-negative cocci (e.g., Neisseria),

many gram-negative rods (e.g., Pseudomonas, Haemophilus, and

family members Enterobacteriaceae reminiscent of E. coli), and

numerous anaerobes (e.g., Bacteroides and Clostridium). Imipe-

nem is particularly helpful in treating infections brought on by gram-

damaging rods that produce extended-spectrum β-lactamases

that make them proof against all penicillins and cephalosporins.

Carbapenems are sometimes the “medication of final resort” in opposition to bac-

teria proof against a number of antibiotics and are thus reserved for

hospital settings.

Imipenem is prescribed together with cilastatin,

which is an inhibitor of dehydropeptidase, a kidney enzyme

that inactivates imipenem. Imipenem will not be inactivated by

most β-lactamases; nonetheless, carbapenemases produced by

Okay. pneumoniae that degrade imipenem and different carbapen-

emases have emerged. Different carbapenems, reminiscent of ertapenem

and meropenem, usually are not inactivated by dehydropeptidase and

usually are not prescribed together with cilastatin.

 

Monobactams

Monobactams are additionally β-lactam medication which can be structurally dif-

ferent from penicillins and cephalosporins. Monobactams are

characterised by a β-lactam ring with out an adjoining sulfur-

containing ring construction (i.e., they’re monocyclic) (see Determine

10–5). Aztreonam, at present essentially the most helpful monobactam,

has glorious exercise in opposition to many gram-negative rods, such

as Enterobacteriaceae and Pseudomonas, however is inactive in opposition to

gram-positive and anaerobic micro organism. It’s proof against most

β-lactamases. It is vitally helpful in sufferers who’re hypersensitive

to penicillin as a result of there isn’t any cross-reactivity.

Vancomycin

Vancomycin is a glycopeptide that inhibits cell wall pepti-

doglycan synthesis by blocking transpeptidation however by a

mechanism totally different from that of the β-lactam medication. Vanco-

mycin binds on to the d-alanyl-d-alanine portion of the

pentapeptide, which blocks the transpeptidase from binding,

whereas the β-lactam medication bind to the transpeptidase itself.

Vancomycin additionally inhibits a second enzyme, the bacterial trans-

glycosylase, which additionally capabilities in synthesizing the peptido-

glycan, however this seems to be much less essential than inhibition of

the transpeptidase.

Vancomycin is a bactericidal agent efficient in opposition to sure

gram-positive micro organism. Its most essential use is within the treat-

ment of infections brought on by S. aureus strains which can be resistant

to the penicillinase-resistant penicillins reminiscent of nafcillin and

methicillin (e.g., methicillin-resistant S. aureus [MRSA]). Word

that vancomycin will not be a β-lactam drug and, due to this fact, will not be

degraded by β-lactamase.

Vancomycin can also be used within the remedy of infections

brought on by Staphylococcus epidermidis, penicillin-resistant

Streptococcus pneumoniae, and enterococci. Strains of S. aureus,

S. epidermidis, and enterococci with partial or full resis-

tance to vancomycin have been recovered from sufferers.

A widely known antagonistic impact of vancomycin is “pink man”

syndrome. “Purple” refers back to the flushing brought on by vasodilation

induced by histamine launch from mast cells and basophils.

It is a direct impact of vancomycin on these cells and isn’t an

IgE-mediated response.

Telavancin is an artificial by-product of vancomycin that each

inhibits peptidoglycan synthesis and disrupts bacterial cell

membranes. It’s used for the remedy of pores and skin and tender tissue

infections, particularly these brought on by MRSA. Oritavancin and

dalbavancin are lipoglycopeptide derivatives of vancomycin and

teicoplanin, respectively. These medication inhibit the transpeptidases

and transglycosylases required to synthesize the peptidoglycan

of gram-positive micro organism. They’re efficient within the remedy of

infections brought on by S. aureus, together with MRSA, and Enterococcus,

together with vancomycin-resistant enterococci (VRE).

Cycloserine & Bacitracin

Cycloserine is a structural analogue of d-alanine that inhibits

the synthesis of the cell wall dipeptide d-alanyl-d-alanine. It

is used as a second-line drug within the remedy of tuberculosis.

Bacitracin is a cyclic polypeptide antibiotic that forestalls the

dephosphorylation of the phospholipid that carries the pep-

tidoglycan subunit throughout the cell membrane. This blocks the

regeneration of the lipid service and inhibits cell wall synthe-

sis. Bacitracin is a bactericidal drug helpful within the remedy of

superficial pores and skin infections however too poisonous for systemic use.

INHIBITION OF PROTEIN SYNTHESIS

A number of medication inhibit protein synthesis in micro organism with out sig-

nificantly interfering with protein synthesis in human cells. This

selectivity is because of the variations between bacterial and human

ribosomal proteins, RNAs, and related enzymes. Micro organism

have 70S1

ribosomes with 50S and 30S subunits, whereas human

cells have 80S ribosomes with 60S and 40S subunits.

Chloramphenicol, macrolides reminiscent of azithromycin and

erythromycin, clindamycin, and linezolid act on the 50S sub-

unit, whereas tetracyclines reminiscent of doxycycline and aminogly-

cosides reminiscent of gentamicin act on the 30S subunit. A abstract

of the modes of motion of those medication is introduced in Desk 10–5,

and a abstract of their clinically helpful exercise is introduced in

Desk 10–6.

1. Medicine That Act on the 30S Subunit

Aminoglycosides

Aminoglycosides are bactericidal medication particularly helpful in opposition to

many gram-negative rods. Sure aminoglycosides are used

in opposition to different organisms (e.g., streptomycin is used within the multi-

drug remedy of tuberculosis, and gentamicin is utilized in combi-

nation with penicillin G in opposition to enterococci). Aminoglycosides

are named for the amino sugar element of the molecule,

which is related by a glycosidic linkage to different sugar deriva-

tives (Determine 10–6).

The 2 essential modes of motion of aminoglycosides have

been documented greatest for streptomycin; different aminoglycosides

in all probability act equally. Each inhibition of the initiation com-

plex and misreading of messenger RNA (mRNA) happen; the

former might be extra essential for the bactericidal exercise

of the drug. An initiation advanced composed of a streptomycin-

handled 30S subunit, a 50S subunit, and mRNA is not going to func-

tion—that’s, no peptide bonds are fashioned, no polysomes are

made, and a frozen “streptomycin monosome” outcomes. Misinterpret-

ing of the triplet codon of mRNA in order that the incorrect amino acid

is inserted into the protein additionally happens in streptomycin-treated

micro organism. The positioning of motion on the 30S subunit consists of each a

ribosomal protein and the ribosomal RNA (rRNA). In consequence

of inhibition of initiation and misreading, membrane injury

happens and the bacterium dies. (In 1993, one other doable mode

of motion was described, specifically, that aminoglycosides inhibit

ribozyme-mediated self-splicing of rRNA.)

Aminoglycosides have sure limitations of their use: (1)

They’ve a poisonous impact each on the kidneys and on the auditory

and vestibular parts of the eighth cranial nerve. To keep away from

toxicity, serum ranges of the drug, blood urea nitrogen, and

creatinine ought to be measured. (2) They’re poorly absorbed

from the gastrointestinal tract and can’t be given orally. (3)

They penetrate the spinal fluid poorly and have to be given intra-

thecally within the remedy of meningitis. (4) They’re ineffective

in opposition to anaerobes, as a result of their transport into the bacterial cell

requires oxygen.

Tetracyclines

Tetracyclines are a household of antibiotics with bacteriostatic

exercise in opposition to quite a lot of gram-positive and gram-negative

micro organism, mycoplasmas, chlamydiae, and rickettsiae. They inhibit

protein synthesis by binding to the 30S ribosomal subunit and by

blocking the aminoacyl switch RNA (tRNA) from coming into

the acceptor web site on the ribosome. Nonetheless, the selective motion

of tetracycline on micro organism will not be on the stage of the ribosome,

as a result of tetracycline in vitro will inhibit protein synthesis equally

effectively in purified ribosomes from each bacterial and human cells.

Its selectivity relies on its enormously elevated uptake into suscep-

tible bacterial cells in contrast with human cells.

Tetracyclines, because the identify signifies, have 4 cyclic rings

with totally different substituents on the three R teams (Determine 10–7).

The assorted tetracyclines (e.g., doxycycline, minocycline, oxy-

tetracycline) have comparable antimicrobial exercise however totally different

pharmacologic properties. Basically, tetracyclines have low

toxicity however are related to some essential unwanted side effects. One

is suppression of the conventional flora of the intestinal tract, which

can result in diarrhea and overgrowth by drug-resistant micro organism

and fungi. Second is that suppression of Lactobacillus within the vag-

inal regular flora ends in an increase in pH, which permits Candida

albicans to develop and trigger vaginitis. Third is brown staining of

the enamel of fetuses and younger youngsters because of deposition

of the drug in creating enamel; tetracyclines are avid calcium

chelators. Because of this, tetracyclines are contraindicated for

use in pregnant girls and in youngsters youthful than 8 years

of age. Tetracyclines additionally chelate iron, and so merchandise contain-

ing iron, reminiscent of iron-containing nutritional vitamins, shouldn’t be taken

throughout remedy with tetracyclines. Photosensitivity (rash upon

publicity to daylight) can even happen throughout tetracycline remedy.

Tigecycline (Tygacil) is the primary clinically accessible member

of the glycylcycline class of antibiotics. They’ve a struc-

ture just like tetracyclines and have the identical mechanism

of motion as tetracyclines; specifically, they bind to the 30S ribo-

somal subunit and inhibit bacterial protein synthesis. They

have the same vary of antagonistic results. Tigecycline is used to

deal with pores and skin and pores and skin construction infections brought on by methicillin-

delicate and methicillin-resistant S. aureus, group A and group

B streptococci, vancomycin-resistant enterococci, E. coli, and

Bacteroides fragilis. Additionally it is used to deal with difficult intra-

stomach infections brought on by quite a lot of facultative and

anaerobic micro organism.

2. Medicine That Act on the 50S Subunit

Chloramphenicol

Chloramphenicol is lively in opposition to a broad vary of organisms,

together with gram-positive and gram-negative micro organism (together with

anaerobes). It’s bacteriostatic in opposition to sure organisms, such

as Salmonella typhi, however has bactericidal exercise in opposition to the

three essential encapsulated organisms that trigger meningitis:

Haemophilus influenzae, S. pneumoniae, and Neisseria meningitidis.

Chloramphenicol inhibits protein synthesis by binding to

the 50S ribosomal subunit and blocking the motion of peptid-

yltransferase; this prevents the synthesis of latest peptide bonds.

It inhibits bacterial protein synthesis selectively, as a result of it

binds to the catalytic web site of the transferase within the 50S bacterial

ribosomal subunit however to not the transferase within the 60S human

ribosomal subunit. Chloramphenicol inhibits protein synthesis

within the mitochondria of human cells to some extent, since mito-

chondria have a 50S subunit (mitochondria are thought to have

developed from micro organism). This inhibition could also be the reason for the

dose-dependent toxicity of chloramphenicol to bone marrow

(see subsequent paragraph).

Chloramphenicol is a relatively easy molecule with

a nitrobenzene nucleus (Determine 10–8). Nitrobenzene is a bone

marrow depressant and is more likely to be concerned within the hemato-

logic issues reported with this drug. Crucial

aspect impact of chloramphenicol is bone marrow toxicity, of which

there are two varieties. One is a dose-dependent suppression,

which is extra more likely to happen in sufferers receiving excessive doses for

lengthy intervals and which is reversible when administration of the

drug is stopped. The opposite is aplastic anemia, which is brought on by

an idiosyncratic response to the drug. This response will not be dose-

dependent, can happen weeks after administration of the drug has

been stopped, and isn’t reversible. Luckily, this response is

uncommon, occurring in about 1 in 30,000 sufferers.

One particular poisonous manifestation of chloramphenicol is “grey

child” syndrome, through which the toddler’s pores and skin seems grey and

vomiting and shock happen. This is because of lowered glucuronyl

transferase exercise in infants, leading to a poisonous concentra-

tion of chloramphenicol. Glucuronyl transferase is the enzyme

liable for cleansing of chloramphenicol.

Macrolides

Macrolides are a gaggle of bacteriostatic medication with a large spec-

trum of exercise. The identify macrolide refers to their giant (13–16

carbon) ring construction (Determine 10–9). Azithromycin, erythro-

mycin, and clarithromycin are the primary macrolides in scientific

use. Azithromycin is used to deal with genital tract infections precipitated

by Chlamydia trachomatis and respiratory tract infections

brought on by Legionella, Mycoplasma, Chlamydia pneumoniae, and

S. pneumoniae. Erythromycin has the same spectrum of exercise

however has a shorter half-life and so have to be taken extra often

and has extra antagonistic results, particularly on the gastrointestinal

tract. Clarithromycin is used primarily within the remedy of

Helicobacter infections and within the remedy and prevention of

Mycobacterium avium-intracellulare infections. An essential

antagonistic impact of clarithromycin is prolongation of the QT inter-

val, which can enhance the chance of cardiac dying.

Macrolides inhibit bacterial protein synthesis by binding to

the 50S ribosomal subunit and blocking translocation. They

forestall the discharge of the uncharged tRNA after it has trans-

ferred its amino acid to the rising peptide chain. The donor

web site stays occupied, a brand new tRNA can not connect, and protein

synthesis stops.

Clindamycin

Probably the most helpful scientific exercise of this bacteriostatic drug is

in opposition to anaerobes, each gram-positive micro organism reminiscent of Clostrid-

ium perfringens and gram-negative micro organism reminiscent of B. fragilis.

Clindamycin binds to the 50S subunit and blocks peptide

bond formation by an undetermined mechanism. Its specificity

for micro organism arises from its lack of ability to bind to the 60S subunit

of human ribosomes.

Crucial aspect impact of clindamycin is pseudo-

membranous colitis, which, actually, can happen with nearly

any antibiotic, whether or not taken orally or parenterally. The patho-

genesis of this doubtlessly extreme complication is suppression of

the conventional flora of the bowel by the drug and overgrowth of

a drug-resistant pressure of C. difficile. The organism secretes an

exotoxin that produces the pseudomembrane within the colon and

extreme, usually bloody diarrhea.

Linezolid

Linezolid is beneficial for the remedy of vancomycin-resistant

enterococci, methicillin-resistant S. aureus and S. epidermidis,

and penicillin-resistant pneumococci. It’s bacteriostatic

in opposition to enterococci and staphylococci however bactericidal in opposition to

pneumococci.

Linezolid binds to the 23S ribosomal RNA within the 50S sub-

unit and inhibits protein synthesis, however the exact mechanism

is unknown. It seems to dam some early step (initiation) in

ribosome formation. Tedizolid is a second-generation drug in

the identical class as linezolid however is roughly 10 instances extra

efficient. It’s used for the remedy of pores and skin and tender tissue infec-

tions brought on by the same vary of micro organism as linezolid and has a

comparable mechanism of motion.

Telithromycin

Telithromycin (Ketek) is the primary clinically helpful member of

the ketolide group of antibiotics. It’s just like the macrolides

basically construction and mode of motion however is sufficiently differ-

ent chemically such that organisms proof against macrolides could

be delicate to telithromycin. It has a large spectrum of exercise

in opposition to quite a lot of gram-positive and gram-negative micro organism

(together with macrolide-resistant pneumococci) and is used within the

remedy of community-acquired pneumonia, bronchitis, and

sinusitis.

Streptogramins

A mixture of two streptogramins, quinupristin and dal-

fopristin (Synercid), is used for the remedy of bloodstream

infections brought on by vancomycin-resistant Enterococcus faecium

(however not vancomycin-resistant Enterococcus faecalis). Additionally it is

authorized to be used in infections brought on by Streptococcus pyo-

genes, penicillin-resistant S. pneumoniae, methicillin-resistant

S. aureus, and methicillin-resistant S. epidermidis.

Streptogramins trigger untimely launch of the rising

peptide chain from the 50S ribosomal subunit. The construction

and mode of motion of streptogramins are totally different from all

different medication that inhibit protein synthesis, and there’s no cross-

resistance between streptogramins and these different medication.

Retapamulin

Retapamulin (Altabax) is the primary clinically accessible member

of a brand new class of antibiotics referred to as pleuromutilins. These medication

inhibit bacterial protein synthesis by binding to the 23S RNA of

the 50S subunit and blocking attachment of the donor tRNA.

Retapamulin is a topical antibiotic used within the remedy of

pores and skin infections, reminiscent of impetigo, brought on by S. pyogenes and

methicillin-sensitive S. aureus.

 

INHIBITION OF NUCLEIC ACID

SYNTHESIS

The mode of motion and clinically helpful exercise of the impor-

tant medication that act by inhibiting nucleic acid synthesis are sum-

marized in Desk 10–7.

1. Inhibition of Precursor Synthesis

Sulfonamides

Both alone or together with trimethoprim, sulfon-

amides are helpful in quite a lot of bacterial illnesses reminiscent of

urinary tract infections brought on by E. coli, otitis media precipitated

by S. pneumoniae or H. influenzae in youngsters, shigellosis,

nocardiosis, and chancroid. Together, they’re additionally the

medication of alternative for 2 further illnesses, toxoplasmosis and

Pneumocystis pneumonia. The sulfonamides are a big household

of bacteriostatic medication which can be produced by chemical synthesis.

In 1935, the mother or father compound, sulfanilamide, turned the primary

clinically efficient antimicrobial agent.

The mode of motion of sulfonamides is to dam the syn-

thesis of tetrahydrofolic acid, which is required as a methyl

donor within the synthesis of the nucleic acid precursors adenine,

guanine, and thymine. Sulfonamides are structural analogues

of p-aminobenzoic acid (PABA). PABA condenses with a

pteridine compound to type dihydropteroic acid, a precursor

of tetrahydrofolic acid (Determine 10–10). Sulfonamides compete

with PABA for the lively web site of the enzyme dihydropteroate

synthetase. This aggressive inhibition might be overcome by an

extra of PABA.

The premise of the selective motion of sulfonamides on micro organism

is that many micro organism synthesize their folic acid from PABA-

containing precursors, whereas human cells require preformed

folic acid as an exogenous nutrient as a result of they lack the

enzymes to synthesize it. Human cells due to this fact bypass the step

at which sulfonamides act. Micro organism that may use preformed folic

acid are equally proof against sulfonamides.

The p-amino group on the sulfonamide is important for its

exercise. Modifications are due to this fact made on the sulfonic acid

aspect chain. Sulfonamides are cheap and often trigger

unwanted side effects. Nonetheless, drug-related fever, rashes, photosensitiv-

ity (rash upon publicity to daylight), and bone marrow suppres-

sion can happen. They’re the most typical group of medication that

trigger erythema multiforme and its extra extreme kinds, Stevens-

Johnson syndrome and poisonous epidermal necrolysis.

Trimethoprim

Trimethoprim additionally inhibits the manufacturing of tetrahydrofolic

acid however by a mechanism totally different from that of the sulfonamides

(i.e., it inhibits the enzyme dihydrofolate reductase) (see Determine

10–10). Its specificity for micro organism relies on its a lot better

affinity for bacterial reductase than for the human enzyme.

Trimethoprim is used most often along with sulfa-

methoxazole. Word that each medication act on the identical pathway—

however at totally different websites—to inhibit the synthesis of tetrahydrofolate.

The benefits of the mix are that (1) bacterial mutants

resistant to 1 drug shall be inhibited by the opposite and (2) the

two medication can act synergistically (i.e., when used collectively, they

trigger considerably better inhibition than the sum of the inhibi-

tion brought on by every drug individually).

Trimethoprim-sulfamethoxazole is clinically helpful within the

remedy of urinary tract infections, Pneumocystis pneumonia,

and shigellosis. It is also used for prophylaxis in granulopenic

sufferers to forestall opportunistic infections.

2. Inhibition of DNA Synthesis

Fluoroquinolones

Fluoroquinolones are bactericidal medication that block bacterial

DNA synthesis by inhibiting DNA gyrase (topoisomerase).

Fluoroquinolones, reminiscent of ciprofloxacin (Determine 10–11), levo-

floxacin, norfloxacin, ofloxacin, and others, are lively in opposition to

a broad vary of organisms that trigger infections of the decrease

respiratory tract, intestinal tract, urinary tract, and skeletal

and tender tissues. Nalidixic acid, which is a quinolone however not

a fluoroquinolone, is far much less lively and is used just for the

remedy of urinary tract infections. Fluoroquinolones ought to

not be given to pregnant girls and kids below the age of

18 years as a result of they injury rising bone and cartilage.

The FDA has issued a warning concerning the potential for

Achilles tendonitis and tendon rupture related to fluoro-

quinolone use, particularly in these over 60 years of age and in

sufferers receiving corticosteroids, reminiscent of prednisone. In view

of this, the FDA recommends that fluoroquinolones not be used

within the remedy of acute sinusitis and uncomplicated urinary

tract infections. One other essential antagonistic impact of fluoro-

quinolones is peripheral neuropathy, the signs of which

embody ache, burning, numbness, or tingling within the arms or legs.

3. Inhibition of mRNA Synthesis

Rifampin is used primarily for the remedy of tuberculosis

together with different medication and for prophylaxis in shut

contacts of sufferers with meningitis brought on by both N. menin-

gitidis or H. influenzae. Additionally it is utilized in mixture with different

medication within the remedy of prosthetic-valve endocarditis precipitated

by S. epidermidis. Aside from the short-term prophy-

laxis of meningitis, rifampin is given together with different

medication as a result of resistant mutants seem at a excessive price when it’s

used alone.

The selective mode of motion of rifampin relies on

blocking mRNA synthesis by bacterial RNA polymerase with-

out affecting the RNA polymerase of human cells. Rifampin is

pink, and the urine, saliva, and sweat of sufferers taking rifampin

usually flip orange; that is disturbing however innocent. Rifampin is

excreted in excessive focus in saliva, which accounts for

its success within the prophylaxis of bacterial meningitis because the

organisms are carried within the throat.

Rifabutin, a rifampin by-product with the identical mode of

motion as rifampin, is beneficial within the prevention of illness precipitated

by Mycobacterium avium-intracellulare in sufferers with severely

lowered numbers of helper T cells (e.g., acquired immunodefi-

ciency syndrome [AIDS] sufferers). Word that rifabutin doesn’t

enhance cytochrome P450 as a lot as rifampin, so rifabutin is

utilized in human immunodeficiency virus (HIV)/AIDS sufferers

taking protease inhibitors or non-reverse transcriptase inhibi-

tors (NRTI).

Fidaxomicin (Dificid) inhibits the RNA polymerase of

C. difficile. It’s used within the remedy of pseudomembranous

colitis and in stopping relapses of this illness. It particularly

inhibits C. difficile and doesn’t have an effect on the gram-negative regular

flora of the colon.

 

ALTERATION OF CELL MEMBRANE

FUNCTION

There are few antimicrobial compounds that act on the cell

membrane as a result of the structural and chemical similarities of

bacterial and human cell membranes make it tough to supply

adequate selective toxicity.

Polymyxins are a household of polypeptide antibiotics of which

the clinically most helpful compound is polymyxin E (colistin).

Colistin is lively in opposition to gram-negative rods, particularly

P. aeruginosa, Acinetobacter baumannii, and carbapenemase-

producing Enterobacteriaceae. Most strains of those extremely

antibiotic-resistant micro organism are delicate to colistin, though

uncommon isolates from sufferers are resistant.

Polymyxins are cyclic peptides composed of 10 amino acids,

six of that are diaminobutyric acid. The positively charged

free amino teams act like a cationic detergent to disrupt the

phospholipid construction of the cell membrane.

Daptomycin is a cyclic lipopeptide that disrupts the cell

membranes of gram-positive cocci. It’s bactericidal for organisms

reminiscent of S. aureus, S. epidermidis, S. pyogenes, E. faecalis, and

E. faecium, together with methicillin-resistant strains of S. aureus

and S. epidermidis, vancomycin-resistant strains of S. aureus,

and vancomycin-resistant strains of E. faecalis and E. faecium. It

is authorized to be used in difficult pores and skin and tender tissue infections

brought on by these micro organism.

ADDITIONAL DRUG MECHANISMS

Isoniazid, or isonicotinic acid hydrazide (INH), is a bactericidal

drug extremely particular for Mycobacterium tuberculosis and different

mycobacteria. It’s utilized in mixture with different medication to deal with

tuberculosis and by itself to forestall tuberculosis in uncovered

individuals. As a result of it penetrates human cells effectively, it’s efficient

in opposition to the organisms residing inside macrophages. The struc-

ture of isoniazid is proven in Determine 10–12.

INH inhibits mycolic acid synthesis, which explains why it

is particular for mycobacteria and comparatively unhazardous for people.

The drug inhibits a reductase required for the synthesis of the

long-chain fatty acids referred to as mycolic acids which can be an important

constituent of mycobacterial cell partitions. The lively drug is prob-

ably a metabolite of INH fashioned by the motion of catalase per-

oxidase as a result of deletion of the gene for these enzymes outcomes

in resistance to the drug. Its predominant aspect impact is liver toxicity. It

is given with pyridoxine to forestall neurologic issues.

Metronidazole (Flagyl) is bactericidal in opposition to anaerobic

micro organism reminiscent of B. fragilis and C. difficile, and it’s used to deal with

bacterial vaginosis. (Additionally it is efficient in opposition to sure protozoa

reminiscent of Giardia and Trichomonas.) Metronidazole is a prodrug

FIGURE 10–12 A: Isoniazid. B: Metronidazole.

that’s activated to the lively compound inside anaerobic bacte-

ria by ferredoxin-mediated discount of its nitro group.

This drug has two doable mechanisms of motion, and it

is unclear which is extra essential. The primary, which explains

its specificity for anaerobes, is its potential to behave as an electron

sink. By accepting electrons, the drug deprives the organism

of required lowering energy. As well as, when electrons are

acquired, the drug ring is cleaved and a poisonous intermediate is

fashioned that damages DNA. The exact nature of the intermedi-

ate and its motion is unknown. The construction of metronidazole is

proven in Determine 10–12.

The second mode of motion of metronidazole pertains to its

potential to inhibit DNA synthesis. The drug binds to DNA and

causes strand breakage, which prevents its correct functioning

as a template for DNA polymerase.

Nitrofurantoin is a urinary tract antiseptic that’s helpful in

the remedy of uncomplicated decrease urinary tract infections. It

is concentrated within the urine to succeed in bactericidal ranges however does

not attain cidal ranges systemically so will not be helpful for infections

outdoors the urinary tract.

Nitrofurantoin acts by binding to DNA. Its selective toxicity

for micro organism relies upon the flexibility of micro organism to type

bigger quantities of the extremely reactive lowered type of the drug

in comparison with the quantity fashioned in human cells.

Ethambutol is a bacteriostatic drug used within the remedy of

infections brought on by M. tuberculosis and most of the atypical

mycobacteria. It acts by inhibiting the synthesis of arabinoga-

lactan, which capabilities as a hyperlink between the mycolic acids and

the peptidoglycan of the organism.

Pyrazinamide (PZA) is a bactericidal drug used within the treat-

ment of tuberculosis however not within the remedy of most atypical

mycobacterial infections. PZA is especially efficient in opposition to

semidormant organisms within the lesion, which aren’t affected by

INH or rifampin. The mechanism of motion of PZA is unsure,

however there’s proof that it acts by inhibiting a fatty acid synthe-

tase that forestalls the synthesis of mycolic acid. It’s transformed

to the lively intermediate, pyrazinoic acid, by an amidase within the

mycobacteria.