ANTIBACTERIAL

AGENTS
J MANGOYI
DEPARTMENT OF CLINICAL PHARMACOLOGY

1
Lecture objectives
To classify antibacterials by mechanism of action
To discuss clinical uses of different antibacterials

2
Antibacterials

HOW ARE THEY CLASSIFIED?

3
Based on biological activity
Bactericidal: Act primarily by killing the bacteria
e.g penicillins, cephalosporins, aminoglycosides, isoniazid, rifambicin
Bacteriostatic: Act primarily by preventing bacterial multiplication (i.e keeps them at the
stationery phase of growth)
e.g macrolides, tetracyclines, sulphonamides, chloramphenicol
Antimicrobials generally have selective toxicity: The success of antibacterial agents owes much
to the fact that they can act selectively against bacterial cells rather than animal cells

4
Antibacterial agents classifaction
Inhibition of cell wall synthesis Inhibition of bacteria protein synthesis
- Penicillins - Aminoglycosides
- Cephalosporins - Chloramphenicol
- Carbapenems - Macrolides
- Monobactams - Tetracyclines
- vancomycin - linezolid

Antibacterials
Inhibition of folic acid synthesis
Inhibition of nucleic acid synthesis - Sulfonamides
- Fluoroquinolones - Trimethoprim
- rifampicin - Pyrimethamine

5
Penicillins/ β lactams
Shared features of chemistry, mechanism of action, pharmacology, and immunologic
characteristics between penicillins, cephalosporins, monobactams, carbapenems and β-
lactamase inhibitors

Have greatest activity against gram-positive organisms, gram-negative cocci and non- β-
lactamase producing anaerobes

Mechanism of action: inhibit bacterial growth by interfering with the transpeptidation reaction
of bacterial cell wall synthesis…..bactericidal

β-lactam kill bacterial cells only when they are actively growing and synthesizing cell wall

6
Penicillins/β lactams - MOA
Covalently binds to penicillin binding proteins
This inhibits the transpeptidation reaction, halting peptidoglycan synthesis, and the cell dies due
to osmotic pressure

7
Narrow spectrum Broad spectrum
beta lactamase beta lactamase
sensitive sensitive

Penicillins

Beta lactamase Extended spectrum

resistant

8
Narrow-spectrum beta-lactamase
Phenoxymethylpenicillin (penicillin V) – oral, minor infections because of its relatively poor
bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum.
Amoxicillin is often used instead
Benzyl penicillin (x-pen, penicillin G) – highly active against gram positive cocci (streptococci,
meningococci, enterococci), non-β-lactamase producing staphylococci
Benzathine and procaine penicillin: intramuscular injection yield low but prolonged drug levels,
benzathine (used for syphyllis as a once weekly dose for 1-3 weeks, used also for hemolytic
streptococcal pharyngitis; given intramuscularly once every 3–4 weeks)

9
Broad spectrum, β lactamase sensitive
Amoxycillin, ampicillin
Spectrum similar to benzyl pecillin + greater activity against gram negative
Less active than benzylpenicillin against gram+ cocci
Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the
drugs should be administered at least 1–2 hours before or after a meal

β-lactams can be combined with β-lactamase inhibitors e.g co-amoxiclav (amoxicillin + clavulanic
acid),

10
β lactamase resistant penicillins
Use should be limited to staphylococci infections

e.g nafcillin, oxacillin, flucloxacillin, cloxacillin

However, cases of methicillin resistant staph aureus (MRSA) are increasing worldwide

11
Extended-spectrum penicillins
e.g tircacillin, piperacillin, cabernicillin, azlocillin
Also called antipseudomonas penicillins
These drugs have greater activity against gram-negative bacteria because of their enhanced
ability to penetrate the gram-negative outer membrane compared to broad spectrum

Active against gram +ve cocci plus gram –ve cocci plus gram +ve rods plus gram –ve anaerobic
rods

However, they are β-lactamase sensitive

12
Adverse effects
The penicillins are remarkably nontoxic
Hypersensitivity: all penicillins are cross-sensitizing and cross-reacting
Ampicillin has been associated with pseudomembranous colitis
Secondary infections such as vaginal candidiasis may occur with all penicillins
Nafcillin is associated with neutropenia
Oxacillin can cause hepatitis
Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature

13
Cephalosporins
Similar to penicillins, but more stable to many bacterial β-lactamases and therefore have a broader
spectrum of activity
1st generation: cefazolin, cefadroxil, cephalexin, cephalothin, cephapirin, and cephradine
- very active against gram +ve cocci, gram –ve (E coli, K pneumoniae, and Proteus mirabilis)
2nd generation: cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef
- H influenza + those covered by 1st generation
3rd generation: ceftriaxone, ceftazidime, ceftizoxime
- expanded gram –ve coverage
4th generation: Cefepime, good activity against P aeruginosa, Enterobacteriaceae, S aureus, and S
pneumoniae. It is highly active against haemophilus and neisseria. It penetrates well into
cerebrospinal fluid

14
Adverse effects
Hypersensitivity reactions: similar to those seen with penicillins
- cross – sensitivity with penicillins (5-10%)
Nephrotoxicity (cefradine)
Diarrhea
Secondary infections such as vaginal candidiasis may occur

15
Resistance to penicillins and
cephalosporins

16
Inhibition of protein synthesis

17
Inhibition of protein synthesis

18
Aminoglycosides
Kanamycin, gentamycin, streptomycin, neomycin, amikacin, tobramycin, netilmicin, framycetin
Bactericidal: irreversible inhibition of protein synthesis
MOA: Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins (S12 in
the case of streptomycin). Protein synthesis is inhibited by aminoglycosides in at least three
ways
(1) interference with the initiation complex of peptide formation
(2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide
and results in a nonfunctional or toxic protein
(3) breakup of polysomes into nonfunctional monosomes.
These activities occur more or less simultaneously, and the overall effect is irreversible and lethal
for the cell

19
Pharmacokinetics of aminoglycosides
Water soluble, highly polar, poorly absorbed from the GIT therefore normally administered iv or
im or as eye drops
Aminoglycosides have concentration-dependent killing; that is, increasing concentrations kill an
increasing proportion of bacteria and at a more rapid rate
They also have a significant post-antibiotic effect, such that the antibacterial activity persists
beyond the time during which measurable drug is present
The post-antibiotic effect of aminoglycosides can last several hours. Because of these properties,
a given total amount of aminoglycoside may have better efficacy when administered as a single
large dose than when administered as multiple smaller doses.
Elimination is by glomerular filtration, may need therapeutic drug monitoring because of possible
renal cortex accumulation

20
Aminoglycosides: indications
Widely used for gram-negative enteric bacteria and aerobic gram +ve bacteria
Bacterial endocarditis in combination with penicillin or vancomycin for enhanced transportation
into bacterial cells
Tuberculosis

Conjuctivitis: neomycin, tobramycin

21
Aminoglycosides uses + AE

Other AE
Rashes, bone marrow
suspension

22
Aminoglycosides resistance

23
Tetracyclines
Doxycycline, oxytetracycline, tetracycline, minoxyline
MOA: bind to 30S ribosomal subunit thereby blocking the binding of aminoacyl-tRNA to the acceptor site
on the mRNA-ribosome complex.
This prevents addition of new amino acids
Bacteriostatic
Broad spectrum, active against most gram +ve and gram –ve bacteria but incidences of resistance is now
limiting use
Rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa (eg, amebas).
Doxycycline for malaria
Skin infections (oxytetracycline)
Eradication of Helicobacter pylori (gastric and duodenal ulcers) in combination

24
Pharmacokinetics of tetracyclines
Absorption after oral administration is approximately 30% for chlortetracycline; 60–70% for
tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline
and minocycline
Absorption occurs mainly in the upper small intestine and is impaired by food (except
doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and
antacids, which contain multivalent cations; and by alkaline pH
Tetracyclines cross the placenta to reach the fetus and are also excreted in milk
As a result of chelation with calcium, tetracyclines are bound to and damage growing bones and
teeth
Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life
of doxycycline 50% by induction of hepatic enzymes that metabolize the drug

25
Tetracyclines use

26
Tetracycline adverse effects
GI : Nausea, vomiting, and diarrhea
Bony structures and teeth: When a tetracycline is given during pregnancy, it can be deposited in
the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia
Hepatotoxicity
Kidney toxicity
Photosensitization
Vestibular reactions: dizziness, vertigo, headaches and visual disturbances
Vitamin b complex deficiency

27
Resistance to tetracyclines

28
Macrolides
Azithromycin, erythromycin, roxithromycin, clarithromycin, rovamycine, spiramycin
Bind to 50s ribosomal subunit
Inhibiting aminoacyl translocation reactions and the formation of initiation complexes
Primarily bacteriostatic but may be bactericidal at very high conc esp erythromycin
Spectrum is similar to penicillins hence are good alternatives to penicillins in patients allergic to
penicillins
Gram +ve cocci but not effective against most gram -ve

29
 Macrolides clinical use
Erythromycin: Diptheria,
prophylaxis against
endocarditis during dental
procedures, community
acquired pneumonia

Clarithromycin spectrum
similar to erythromycin,
choice hugely depend on
cost and tolerability

30
Resistance to macrolides

The major mechanism

may be production (by
Enterobacteriaceae)
of esterases
(methylase) that
hydrolyze macrolides

modification of the
ribosomal binding site
(so-called ribosomal
protection) by
chromosomal mutation

31
Clindamycin
Mechanism similar to macrolides
Antibacterial action: similar to macrolides (partial cross resistance)
Effective against anaerobes eg bacteriodes fragilis
Uses: bone and joint infections, dental infections, serious abdominal sepsis
Can be used in malaria in combination with quinine
Adverse effects: diarrhea, nausea, and skin rashes, pseudomembranous colitis (treat with
vancomycin)

32
33
Chloramphenicol
Binds reversibly to the 50S subunit of the bacterial ribosome and inhibits the peptidyl
transferase step of protein synthesis
Also inhibits mitochondrial protein synthesis in mammalian bone marrow cells
Broad spectrum
Bacteriostatic, active against both aerobic and anaerobic gram-positive and gram-negative
organisms, rickettsiae but not chlamydiae
Bactericidal: H influenzae, N meningitidis

34
Chloramphenicol - Pharmacokinetics
It is inactivated by glucuronidation in the liver
Dosage need not to be adjusted in renal insufficieny
Penetrates well into all tissues, including the CSF and brain even in the absence of meningeal
inflammation
The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield
free chloramphenicol, giving blood levels somewhat lower than those achieved with orally
administered drug

35
Chloramphenicol adverse effects
Hypersensitivity
Irritation effects (nausea and vomiting)
Gray baby syndrome (lack of glucuronic acid conjugation mechanisms especially in children)-
circulatory collapse – skin develops cyanotic grey colour, 40% mortality
Bone marrow suppression (appears in the form of aplastic anaemia)
Superinfection
Inhibits liver enzymes (hence drug interactions with warfarin, phenytoin, tolbutamide,
chlorpropamide)

36
Inhibition of nucleic acid synthesis
Quinolones
Sulphonamides
Azoles – metronidazole, tinidazole

37
Quinolones
Broad spectrum: Ciprofloxacin, norfloxacin, ofloxacin, levofloxacin (gram +ve and gram –ve)
Nalidixic acid: narrow spectrum, no systemic antibacterial activity, used in UTI and diarrhea
treatment
Moxifloxacin, catifloxacin and gemifloxacin have strong activity against gram +ve bacteria
Mechanism of action
inhibit DNA gyrase (topoisomerase ll) thereby blocking bacterial DNA synthesis
Inhibits topoisomerase lV thereby interfering with separation of replicated chromosomal DNA
into the respective cells during cell division

Bactericidal

38
Quinolones use and adverse effects

39
Sulphonamides and trimethoprim
sulphamethoxazole, sulphadiazine, sulphamethizole, sulphadoxine, sulphapyridine,
sulphasalazine
Inhibit both gram +ve and gram –ve, Chlamydia trachomatis, Escherichia coli, klebsiella,
salmonella, shigella, and enterobacter
Sulphonamides are structural analogues of PABA
Bacteriostatic in monotherapy
Bactericidal in combination
Activity is poor against anaerobes

40
Sulfonamides: Mechanism of action

Trimethoprim

41
Sulfonamides – adverse effects
Urinary tract disturbances: may crystallize in urine (crystalluria, hematuria or even obstruction
Allergic reactions: fever, skin rashes, photosensitivity, urticarial, nausea, vomiting and diarrhea,
Stevens Johnson syndrome
Hematopoietic disturbances: hemolytic or aplastic anemia, granulocytopenia,
thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in
patients with glucose-6-phosphate dehydrogenase deficiency.
Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.

42
Sulfonamides: Resistance
Exogenous sources of folic acid
Over production of PABA
Structural change in the folic acid synthesizing enzyme (low affinity for sulfonamides)
Low permeability
Overproduction of dihydrofolate reductase

43
How bad do you want it
When you want to succeed as
bad as you want to breathe
then you will be successful

44