Antimicrobial chemotherapy

Prof. Beata M. Sobieszczańska

Department of Microbiology

University of Medicine

Antimicrobials

• Antibiotic is a low molecular substance produced by

microorganisms (molds, bacteria) that at a low

concentration inhibits or kills other microorganisms

• Antimicrobial is any substance of natural, semisynthetic

or synthetic origin that kills or inhibits the growth of

microorganisms but causes little or no damage to the

host

Antimicrobials

• Bacteriostatic = agent that inhibits bacterial growth but

generally do not kill the bacteria

e.g. protein synthesis inhibitors (macrolides,

tetracyclines, streptogramins, lincozamides,

oxazolidinones, chloramphenicol)

• Bactericidal = agent that kills the target bacteria (β-

lactams, glycopeptides, bacitracin, polymyxin,

fluoroquinolones, metronidazole, rifampin)

Drug’s spectrum of activity

Depending on the range of bacterial species

susceptible to antimicrobials – they are classified as:

Narrow spectrum - have limited activity to some bacteria

e.g. GP or GN (e.g. natural penicillins, glycopeptides)

Broad spectrum – are active against both GP and GN

(e.g. amoxycillin, carbapenems, fluoroquinolones)

PAE = post-antibiotic effectIt is a persistence of antibiotic effect observed long after the serum concentration has fallen below the MIC

Strong PAE:

aminoglycosides, clindamycin, macrolides, tetracyclines, rifamycins, streptogramins

Benefit for large, intermittent doses

Weak/absent PAE:

β-lactams; carbapenems –moderate

Benefit from continuous infusion

Sites of action of different antimicrobial agents

Bactericidal - without cell wall osmotic

pressure causes bacteria to burst

Examples:

• All β-lactams

• Glycopeptides

• Bacitracin

• Fosfomycin

Inhibitors of cell wall synthesis

PBP=penicillin binding proteins

(enzymes transpeptidases)

GP susceptible groups of streptococci (except enterococci),

pneumococci, T. pallidum, Actinomyces

Treatment e.g. strep throat, syphilis, pneumonia

Narrow spectrum

GP cocci + penicillinase-producing staphylococci

Treatment e.g. infections caused by MSSA (methicillin sensitive S.

aureus)

Narrow spectrum

Addition of BLIs extends activity to cover β-lactamase-producing

GN rods/bacilli, boarder activity than penicillinase-resistant

penicillins, and activity against anaerobes

Treatment e.g. empiric treatment of polymicrobial infections

Broad spectrum

GP bacteria but limited activity against GN

Treatment e.g. skin/soft tissue infections or surgical prophylaxis

GP + more activity against GN (some β-lactamase-producing Klebsiella

and H. influenzae strains); variable activity against anaerobes

Treatment e.g. mild community-acquired pneumonia (CAP), sinusitis, etc.

GP + expanded GN coverage, but not active against ESBL+ or AmpC+

Treatment e.g. severe infections requiring IV treatment, hospital-acquired

pneumonia (HAP), meningitis etc.

Similar to 3rd generation, but better activity against P. aeruginosa and

Enterobacteriaceae family

Similar to 3rd generation, but activity against MRSA (methicillin-resistant

S. aureus), but not against P. aeruginosa

Restored activity vs GN pathogens that produce β-lactamases

Broadest spectrum of activity

Narrow spectrum of activity vs GN including some P. aeruginosa strains (but

not ESBL– and AmpC-producers)

Monobactams are NOT active against Stenotrophomonas maltophilia

Safe for use in penicillin allergic patients

Broadest spectrum of activity including many GP and GN, and anaerobes

Ertapenem is NOT active vs P. aeruginosa and Acinetobacter spp.

Carbapenems are reserved for severe infections that are polymicrobial and

caused by multidrug resistant pathogens

Cilastatin inhibits renal dehydropeptidases that deactivate imipenem

Bacitracin

Polypeptide antibiotic (mixture of cyclic peptides)

Narrow spectrum; bactericidal

• Inhibits cell wall synthesis of GP bacteria – mostly staphylococci,

streptococci, Corynebacterium, Clostridium

• Used as a topical preparations e.g. ointments

(too toxic to be used parenterally)

• Used to prevent infection from minor abrasions, wounds, bites,

burns etc.

Glycopeptides

Vancomycin, teicoplanin, telavancin, ramoplanin, dalbavancin

Effective against GP bacteria only – but active vs resistant bacteria e.g.

MRSA, HLAR

Narrow spectrum of activity; bactericidal

Inhibit cell wall synthesis

Poor absorption from GIT – orally to treat AAD

Used IV in serious infections caused by GP cocci and other GP bacteria

Fosfomycin

Inhibits bacterial cell wall synthesis by interfering with the enzymes involved

in the formation of peptidoglycan precursors - bactericidal

Effective against many GP and GN bacteria (broad spectrum of activity),

including enterococci irrespective of vancomycin resistance, staphylococci

(irrespective of methicillin resistance), Enterobacteriaceae family, Listeria

monocytogenes, N. gonorrhoea and anaerobes

Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia,

S. saprophyticus, M. tuberculosis are intrinsically resistant to fosfomycin

Fosfomycin has an immunomodulatory effects – supress synthesis of

proinflammatory cytokines, enhances bactericidal activity of neutrophils

Penetrates into biofilms

Antimicrobial agents that alter/disrupt the cytoplasmic membrane

bactericidal

Colistin (polymyxin E) used in severe infections caused by MDR GN rods: Pseudomonas, Klebsiella, Acinetobacter, Stenotrophomonas maltophilia, M. tuberculosis, M. intracellulare

BUT: Proteus, Burkholderia, Neisseria, Brucella exhibit intrinsic resistance

Daptomycin (lipopeptide antibiotic) disrupts membrane potential

(depolarization)

Spectrum: GP pathogens (VRE, MRSA etc.), S. pyogenes, S. agalactiae

Used to treat complicated skin/soft tissue infections

Antimicrobial agents that inhibit protein synthesis

These agents prevent bacteria from synthesizing structural proteins and enzymes: alter bacterial ribosome, block translation & cause

faulty protein synthesis

These antibiotics are bacteriostatic or bactericidal depending on concentration

Macrolides Glycylcyclines

Tetracyclines Ketolides

Aminoglycosides Fusidic acid

Spectinomycin Mupirocin

Streptogramins Oxazolidinones

Lincozamides Chloramphenicol

Tetracyclines

• Broad-spectrum: GP & GN bacteria, Rickettsia, Chlamydia, Mycoplasma, spirochetes, some protozoa (malaria)

tetracycline, oxytetracycline, doxycycline, minocycline

• Resistance common

• Primarily used to treat: atypical pneumonia, syphilis, brucellosis, Lyme disease, acne, plague, leptospirosis, anthrax, cholera

Glycylcyclines

Tigecycline – derived from minocycline

Broad-spectrum: GP+GN bacteria including MDR pathogens

GP cocci: staphylococci, enterococci, streptococci - including resistant strains

GN intestinal rods – except Proteus

GN nonfermentive rods e.g. Acinetobacter spp. except Pseudomonas

Obligatory anaerobic – Bacteroides fragilis

Atypical bacteria

Advantage over tetracyclines: active against bacteria resistant to tetracyclines, higher binding affinity, broader spectrum

AminoglycosidesBactericidal – except for staphylococci = static

Active against most GN aerobic bacilli but lack activity against anaerobic & most GP bacteria - except for staphylococci

streptomycin, kanamycin, tobramycin, amikacin, gentamycin

Spectinomycin

Bacteriostatic antibiotic chemically related to aminoglycosides

Its activity is restricted to gonococci

Spectinomycin is given for gonococcal urethritis, cervicitis, proctitis

Macrolideserythromycin, roxithromycin, clarithromycin, azithromycin

mainly affects GP cocci (streptococci, staphylococci, but NOT enterococci) and intracellular pathogens (Mycoplasma, Chlamydia, Legionella); other: Campylobacter, Helicobacter, Borrelia, Treponema, Corynebacterium sp., and some anaerobes (Propionibacterium)

Ketolides (derived from erythromycin)

Bacteriostatic (bactericidal at higher concentrations)

Telithromycin, cethromycin, solithromycin

Active against bacterial strains resistant to macrolides

Lincozamides narrow spectrum

lincomycin, clindamycin

active against GP bacteria (but NOT GN aerobic), and most obligatory anaerobic bacteria, including Bacteroides – but they can induce AAD

Principal therapeutic indications are staphylococcal infections of bones and joints, and anaerobic infections

They are static or cidal depending on concentration, bacterial inoculum and species

StreptograminsA combination of quinupristin & dalfopristin (Synercid) – exhibit dose-dependent cidal activity

Work synergistically to inhibit protein synthesis

Active against: GP cocci (also multi-resistant: VRSA, VRE), modest activity: common respiratory pathogens (Moraxella, Str. pneumoniae,

Mycoplasma, Legionella, Chlamydophila) & anaerobes

OxazolidinonesLinezolid - narrow spectrum of activity: GP bacteria

(staphylococci, streptococci, enterococci, pneumococci –

resistant strains, Listeria, corynebacteria), and certain GN bacteria:

Moraxella, Pasteurella, Bacteroides, also Legionella, M. tuberculosis

but other GN are resistant

Fusidic acidNarrow spectrum of activity: staphylococci (MSSA, MRSA) -treatment skin, eye infections, bone, joints infections – as cream, ointment, eye drops

Activity against other GP (streptococci, enterococci) cocci is poor

Other: anaerobes (Bacteroides fragilis, Clostridium spp.), Neisseria, Bordetella, Corynebacterium

Moderate activity against mycobacteria: M. leprae and certain protozoa (Giardia lamblia, Plasmodium falciparum)

Mupirocin

Bactericidal or static activity depends on concentration

Narrow spectrum of activity: staphylococci + resistant strains, streptococci

Used for topical treatment of superficial skin infections e.g. furuncles, impetigo and eradication of nasal carriage of MRSA (intra-nasally)

Chloramphenicol

GP bacteria: streptococci, staphylococci, enterococci, B. anthracis, Listeria

GN bacteria: H. influenzae, Moraxella, Neisseria, E. coli, Proteus mirabilis, Salmonella, Shigella, Stenotrophomonas matlophilia

Many anaerobic bacteria

Penetrates to CSF

Side effects: fatal aplastic anemia, dose-dependent leucopenia, bone marrow suppression etc. – limit its use

Antimicrobial that interfere with DNA synthesis

bactericidal

Rifampins Fluoroquinolones

Metronidazole Fidaxomicin

Rifamycin (Rifampicin, Rifampin)

Prevent the synthesis of mRNA by inhibiting the RNA polymerase

Effective against some GP & GN bacteria, M. tuberculosis, M. leprae,

Legionella pneumophila

Prophylaxis in e.g. meningococcal meningitis

FluoroquinolonesSynthetic chemicals broad spectrum of activity

Inhibit topoisomerases (DNA gyrases) involved in bacterial nucleic

acid synthesis

Generations:

I – nalidixic acid (GN bacteria) – UTI

II – ciprofloxacin, norfloxacin, ofloxacin

(GN including P. aeruginosa, and S. aureus, some atypical) – UTI,

STD, skin, soft tissue infections, GITI

III – levofloxacin, gatifloxacin, temafloxacin, grepafloxacin, (GP especially pneumococci, GN, atypical) – RTI, GITI

IV – trovafloxacin, moxifloxacin, gemifloxacin (GP, GN, atypical, anaerobes)

Fidaxomicin

Macrocyclic lactone

Inhibits RNA polymerase

Minimally absorbed – active only locally in GTI

Minimal or no activity vs GN bacteria

Bactericidal against C. difficile – better option than vancomycin to treat AAD

Nitroimidazoles

metronidazole, tinidazole

Converted into metabolites that impede bacterial DNA synthesis

An antibiotics active against anaerobic bacteria & certain parasites (Entamoeba histolytica, Trichomonas, Giardia – treatment of bacterial vaginosis)

Competitive antagonistic antibiotics

Synthetic chemicalsInhibitors of metabolic pathways via competitive antagonism include:• Sulphonamides• Trimethoprim• IsoniazidThese all inhibit folic acid biosynthesis

Competitive antagonism - a drug chemically resembles a substrate in a metabolic pathway

Because of their similarity, either the drug or the substrate can bind to the enzyme

While the enzyme is bound to the drug, it is unable to bind to its natural substrate and blocks that step in the metabolic pathway

Sulfonamides & trimethoprim

(TMP-SMX)

Co-trimoxazole is a combination of trimethoprim + sulfamethoxazole (TMP-SMX)

Both of these drugs block enzymes in the bacterial pathway required for the synthesis of tetrahydrofolic acid - a cofactor needed for bacteria to produce nucleic acids

Spectrum - broad:

GP: staphylo, strepto, Listeria, Nocardia,

GN: enteric rods, Stenotrophomonas maltophilia, H. influenzae, Pasteurella, Brucella, Bordetella, Neisseria

Pneumocystis pneumonia

Lipophilic antibiotics Hydrophilic antibiotics

macrolides

tetracyclines

fluoroquinolones

chloramphenicol

rifampin

tigecycline

β-lactams

glycopeptides

aminoglycosides

colistin

daptomycin

● Free diffuse through cytoplasmic

membranes

● Active vs intracellulare pathogens

● Eliminated by hepatic metabolism

● Unable to diffuse through cytoplasmic

membranes

● Inactive vs intracellulare pathogens

● Eliminated renally as unchanged drugs

Thank you for your attention