ANTI-MICROBIALS

Antimicrobials/ Antibiotics
Chemical substances, produced by microorganisms, which have
the capacity, in dilute solutions, to inhibit growth of bacteria and
other microorganisms
Exhibit selective toxicity
Selection of Antimicrobial Agents
- Requires knowledge of the organism's identity and its sensitivity
to a particular agent, the site of the infection, the safety of the
agent, patient factors and cost of therapy
Bacteriostatic Drugs- arrest growth and replication of bacteria
Bacteriocidal Drugs kills bacteria
- t is possible for one drug to be bacteriostatic for one organism
and cidal to another
Chemotherapeutic Spectra:
1. Narrow Spectrum
- Act on a single or limited group of microorganism
- Eg. soniazid Mycobacteria
2. Extended Spectrum
- Effective against Gram (+) and also against a significant number of
Gram (-) bacteria
- Eg. Ampicillin
3. Broad Spectrum
- Affect a wide variety of microbial species
- Eg. Tetracycline , Chloramphenicol
Advantages of Antimicrobial Drug Combinations
- Certain combinations show synergysms- more effective than either
drugs separately
Disadvantages - Toxicity, emergence of resistant organisms
Drug Resistance:
Bacteria are resistant if their growth is not halted by the maximal level of
antibiotic that is tolerated by the host
nherent (ex. Gram (-) to vancomycin) or develop resistance through
genetic alterations
1. Spontaneous mutations of DNA
2. DNA transfer of drug resistance
Or by altered expression of proteins in drug-resistant organisms
1. Modification of target sites
2. Decreased accumulation
3. Enzymatic nactivation
Prophylactic Antibiotics
- When antibiotics are used for the prevention rather than treatment of
infections
Complications of Antiobiotic Therapy
- hypersensitivity, direct toxicity, superinfections
Anti-Microbial Drug Action:
1. nhibition of Cell Wall Synthesis
2. nhibition of protein synthesis
3. nhibition of Nucleic Acid synthesis
4. nhibition of Metabolism
Inhibitors of CeII WaII Synthesis
(Bacitracin, Cephalosporins, Cycloserine, Penicillins, Vancomycin
Other Antibiotics
-Vancomycin
-Bacitracin
. Penicillins
.Cephalosporins
. Carbapenems
-Imipenem/
-Cilastatin
V. Monobactams
- Aztreonam
B- Lactamase nhibitors
-Clavulanic Acid
-Sulbactam
-Tazobacam
!NICILLINS
The most widely effective antibiotics and among the least toxic
Steps in Drug Action
1. Binding of the drug to PBP (Penicillin Binding Proteins) in the CM,
inactivating them, preventing cell wall synthesis
PBP- bacterial enzymes involved in the synthesis of the cell wall and
maintenance of the morphologic features of the bacterium
2. nhibition of Transpeptidase and peptidoglycan synthesis
- Hinders formation of crosslinks essential for cell wall integrity
- Some PBP's catalyze formation of the cross-linkages between
peptidoglycan chains
3. Autolysins
- some bacteria particularly Gram (+) cocci, produce degradative enzymes
that participate in normal remodeling of the bacterial cell wall
- Penicillins causes the degradative action to proceed in the absence of CW
synthesis
StructuraI and FunctionaI Characteristics affecting susceptibiIity
to - Iactams
1. Presence of an outer phospholipid membrane in gram (-) that may hinder
passage of the drugs
2. Low binding affinity of receptors to the drugs
3. Tolerance
4. Production of - lactamases which break the beta lactam ring
Adverse Effects
1. Hypersensitivity
2. Diarrhea
3. Nephritis
4. Neurotoxicity
5. Platelet Dysfunction
6. Cation toxicity
CEPHALO8PORN8
- lactam antibiotics that are closely related both structurally and
funcitonally to the penicillins
Antibiotic Spectrum
1. First Generation
2. Second Generation
3. Third Generation
4. Fourth Generation
Adverse Effects
1. Allergic Manifestations
2. Disulfiram-like effect due to accumulation of acetaldehyde
3. Bleeding treat with Vit K
CARBAPENEM8
Imipenem
Synthetic -lactam antibiotics that differ from penicillins in that
the sulfur atom of the thiazolidine ring has been externalized
and replaced by a carbon atom
Broadest spectrum -lactam antibiotic preparation currently
available
Resists hydrolysis by most -lactamases
V
Penetrates well into body tissues and fluids including CSF
Cilastatin dehydropeptidase inhibitor which protects the
parent drug from cleavage preventing formation of a toxic
metabolite
SE (mipenem/Cilastatin) N/V, Diarrhea, Eosinophilia,
Neutropenia, Seizzures
MONOBACTAM8
97eonam
- lactam ring is not fused to another ring
Also disrupts CW synthesis
Resistant to - lactamases
Narrow antimicrobial spectrum- Enterobacter/ Aerobic Gram
Negative rods
M/V
SE phlebitis, skin rash, abnormal LFTs
- Lactamase Inhibitors
avuanic acid
Su-ac9am
Tao-ac9am
- lactamase enzymes cause hydrolysis of the - lactam ring by
enzymatic cleavage,destroying antimicrobial activity
lactamase inhibitors contain a lactam ring but do not have
significant antimicrobial activity, instead, they bind to and inactivate
lactamases, thereby protecting the antibiotics
Protect Penicillins from enzymatic inactivation
OTHER AGENT8 AFFECTNG CW 8YNTHE88
VANCOMYCN
tricyclic glycopeptide
Effective against multiple drug resistant organisms (eg methicillin-
resistant staphylococci)
inhibits synthesis of bacterial CW phospholipids as well as
peptidoglycan polymerization
treatment of serious infections caused by lactam resistant Gram
(+) orgs or for px with gram (+) infections with serious allergy to
lactams
Acts synergistically with aminogllycosides
Resistance plasmid mediated changes due in permeability and
decreased binding of vancomycin to receptor molecules
Slow V
SE- fever, chills, phlebitis, shock (rapid infusion), flushing (red man
syndrome), dose related hearing loss
BACTRACN
Mixture of polypeptides that inhibits bacterial CW synthesis
Active against a wide variety of Gram (+) mcgs
Topical application
Nephrotoxic
PROTEN 8YNTHE88 NHBTOR8
TetracycIines
emecocycline
oxycycline
Minocycline
Tetracycline
MacroIides
Azithromycin
Clarithromycin
Erythromycin
AminogIycosides
Amikacin
Gentamycin
Neomycin
Netilmycin
Streptomycin
Tobramycin
ChIoramphenicoI
CIindamycin
TETRACYCLNE8
Compounds consisting of 4 fused rings with a system f conjugated
double bonds
Prototype broad spectrum antimicrobial
Bacteriostatric for many G(+) and (-) including some anaerobes for
richettsia, chlamydiae, mycoplasmas and protozoa eg. Amoebas
Binds to the 30S subunit of the bacterial ribosome blocking access of
the amino acyl-tRNA to the mRNA- ribosome complex preventing
addition of new amino acid to the growing peptide chain inhibiting
bacterial protein synthesis
Resistance due to lack of active transport mechanism across CM
Crosses the placenta and is also excreted in milk
As a result of chelation with calcium, tetracyclines are bound to growing
bone and teeth
Broad spectrum
- chlamydial infections (lymphogranuloma venereum)
- psittacosis
- Richettsia (rocky mountain spotted fever)
- Corynebacterium
- Mycoplasma pneumonia
- Borrelia burgdorferi ( lyme dis), Treponema pallidum
- H. influenzae
- Vibrio cholerae
Concentrate in liver, kidney, spleen, skin, and bind to tissues undergoing
calcification or to tumors with high calcium content
Clinical Uses
1. nfections with M. pneumoniae, Chlamydiae, rickettsia and some
spirochetes
2. Mixed bacterial infections related to respiratory tract sinusitis and
bronchitis
3. Gram (+) and (-) infection, including Vibrio
4. STDs
5. Acne, UT, relapsing fever, leptospirosis
6. Brucellosis, Tularemia
SE- G discomfort (N/V/D), discoloration and hypoplasia of teeth, stunting
of growth, hepatotoxicity- liver necrosis, phototoxicity , vestibular problems
dizziness, photosensitization , pseudotumor cerebri, superinfections
candida
C- renal dysfunction, pregnant , breast feeding women, children below 8yo
AMNOGLYCO8DE8
Mainstay treatment of serious infections due to aerobic Gram (-) bacilli
Mode of Action
Step attachment of aminoglycoside to a specific receptor protein on the
30's subunit of the microbial 70's ribosome
Step - Ag blocks the normal activity of the initiation complex of peptide
formation (mRNA+formylmethionine+tRNA)
Step mRNA message is misread on the recognition region of the
ribosome resulting to insertion of the wrong amino acid into the peptide
resulting in a non functional protein
Step V Ag attachment results in breakup of polysomes and their
separation into monosomes, incapable of protein synthesis
Aminoglycosides synergize with - lactam antibiotics because of the
latter's action on CW synthesis, which enhances diffusion of the
aminoglycosides into the bacterium
Pseudomonas, Vibrio, Yersinia, Francisella, Enterobacter, E. coli,
Klebsiella, Proteus, Serratia
Resistance
1. Plasmid dependent
- Plasmid associated synthesis of enzymes that modify and
inactivate aminoglycosides
2. Permeability defect
- Decreased uptake of the drug when the oxygen-dependent
transport system is absent
- Altered receptor
Parenteral route ( neomycin topical due to nephrotoxic)
Rapid excretion glomerular filtration
SE- ototoxicity, nephrotoxicity, neuromuscular paralysis, allergic
reactions
STR!TOMYCIN
- Now not usually given because of toxic reactions
- For advanced TB or miliary dissemination of tuberculous infections
- Used in combination treatment
- Allergy, vertibular dysfunction vertigo or loss of balance
KANAMYCIN and Neomycin
- Limited to topical or oral uses
AMIKACIN
- Semisynthetic derivative of kanamycin
- Less toxic
- Uses: severe infections caused by G(-) like in sepsis and pneumonia;
meningitis
GNTAMYCIN
- Effective against both G (+) and G(-)
- Sepsis, pneumonia, topical use for infected burns or wounds, meningitis
MACROLDE8
Group of antibiotics with a macrolytic lactone structure
Bind irreversibly to a site on the 50S subunit of the bacterial ribosome,
inhibiting the translocation steps of protein synthesis
Generally bacteriostatic, may be cidal in higher doses
Does not penetrate the CNS
797omcin used for px allergic to penicillin
a7i97omcin same antibacterial activity with erythromycin and also H.
influenzae. More effective activity against Chlamydia, Legionella,
Ureaplasma
i97omcin - more active against respiratory infections due to H.
influenzae, Moraxella catarrhalis
SE- epigastric distress, cholestatic jaundice, ototoxicity
C hepatic dysfunction
CHLORAMPHENCOL
Active against a wide range of Gram (+) and Gram (-) organisms but
because of its toxicity, use has been restricted to life-threatening
infections
nterferes with the binding of new amino acids to the peptide chain by
inhibiting peptidyl transferase
broad spectrum antibiotic also against rickettsiae; with excellent activity
agaist anaerobes
-cidal or static depending on organism
Resistance
presence of an R factor which codes for acetyl coenzyme A
transferase that inactivates chloramphenicol
- change in permeability
oral or V
SE- anemias, gray baby syndrome
nhibitors of Nucleic Acid Function or 8ynthesis
Fl0uR00ult0l0tFS
Ciprofloxacin
Enoxacin
Lomefloxacin
Norfloxacin
Ofloxacin
Trovafloxacin
0ult0l0tFS
Nalidixic acid
uRltARY TRACT
AtTlSFPTlCS
Methenamine
Nitrofurantoin
Block action of DNA gyrase
FLOUROOUNOLONE8
Enter the cell by passive diffusion through water-filled protein channels
(porins) in the outer membrane. They inhibit the replication of bacterial
DNA by interfering with the action of DNA gyrase (topoisomerase )
during bacterial growth and reproduction
Bactericidal
Not Given below 18 yo.
Clinical Uses UT, diarrhea, soft tissue, bone and joint infections,
STD, Respiratory infections
CiprofIoxacin
most potent
- Pseudomonas infections, Enterobacteraceae, Gram (- )bacilli; MRSA
resistant
- alternative to more toxic drugs
NorfIoxacin
- Gram (-) and Gram (+) organisms
- complicated and uncomplicated UT and prostatitis, but not systemic
infections
OfIoxacin
- treatment of prostatitis and STD with the exception of syphilis
- skin and lower respiratory infections
SE- CNS problems, nephrotoxicity, phototoxicity
C pregnancy, nursing mothers, and children 18 years of age
articular cartilage erosion (arthropathy)
OUNOLONE8
- nhibitors of DNA synthesis by forming complexes (DNA Actinomycin
complex) by binding to the deoxyguqnosine residues
NALIDIXIC ACID
- Effective against most Gram (-) bacteria than common cause UT
- Most Gram (+) are resistant
- Widespread resistance
- SE- N/V, Abdominal pain, photosensitivity, urticaria, fever, HA, malaise
- Liver dysfunction (therapy > 2 weeks)
NITROFURANTOIN
- Narrow antimicrobial spectrum and toxicity
NHBTOR8 OF METABOL8M -
Folate Antagonists
nhibitors of
FOLATE SYNTHESS
Silver Sulfadiazine
Sulfamethoxazole
Sulfasalazine
nhibitors of FOLATE
REDUCTON
Pyrimethamine
Trimethoprim
nhibitors of
Folate Synthesis
and Reduction
Co-trimoxazole
Folic acid required for synthesis of purines and pyrimidines ( precursors
of RNA and DNA) and other compounds required for cellular growth
and replication
SULFONAMIDS
- Can inhibit both G(+) and G(-) bacteria, Chlamydia, and some
protozoa
- DOC in previously untreated UT
- Structure analogue of PABA (p-aminobenzoac acid)
- Bacteriostatic
- inhibitors of folic acid synthesis; low cost and effective
- Bacteria are impermeable to folic acid and rely on their ability to
synthesize folate from PABA, Pteridine, and glutamate. Because of
structural similarity to PABA, sulfonamides compete with PABA for the
enzyme dihydropteroate synthetase, preventing synthesis
Trimethoprim, Pyrimethamine when given with sulfonamides produce
sequential blocking resulting in a marked enhancement (synergism) of
activity of both drugs
Resistance
- mutation causing overproduction of PABA
- structural change in the folic-acid synthesizing enzyme with a lowered
affinity for sulfonamides
- loss of permeability
Most are given orally, rapidly absorbed from the stomach and small
intestine and distributed widely to tissues ; increased in CSF and CNS;
placenta and fetus
Uses: topical use as prevention of colonization of burns and wounds;
trachoma; Nocardiosis ( an actinomycete that causes peumonia and
brain abscess); UT (E.coli and P. mirabilis)
SE Nephrotoxicity due to crystalluria (need adequate hydration)
- Hypersensitivity
- Hemopoietic disturbances Granulocytopenia, Thrombocytopenia
- Kernicterus in newborns
- Drug potentiation
C Newborns, nfants <2 months, pregnant women, px receiving
methenamine for UT

CO- TRIMOXAZOL
- Combination shows greater antimicrobial activity than equivalent quantities
of either drug
- Synergystic activity results from inhibition of two sequential steps in the
synthesis of tetrahydrofolic facid
1. Sulfamethoxazole inhibits incorporation of PABA into folic acid
2. TMP prevents reduction of dihydrofolate to tetrahydrofolate
- Broader spectrum of action than either drug
- P.carinii pneumonia, Genital infections, Respiratory infections, Prostate
and UT, G infections
- Resistance is less frequent
- SE hypersensitivity
G N/V/ Glossitis, stomatitis
Hematologic megaloblastic anemia, leukopenia, thromocytopenia
n HV patients drug induced fever, rashes, diarrhea, pancytopenia
M!IRIC ANTIMICROBIAL THRA!Y
1. Formulate a clinical dx of microbial infection
2. Obtain sample for lab exam
3. Formulate a microbial dx
4. Determine the necessity for empiric tx
5. nstitude tx
- Need a good clinical hx and good physical examination
COMMON CAUSS OF FAILUR OF ANTIMICROBIAL
TRATMNT
. DRUG
1. nappropriate drug
2. nadequate drug (underdose)
3. mproper route of administration
4. Malabsorption
5. Accelerated Drug Excretion or nactivation
6. Poor Drug Penetration into site of infection
. HOST
1. Poor Host Defences
2. Undrained Pus
3. Retained nfected Foreign Body
4. Dead Tissue