Chemotherapy began with Paul Ehrlich.

Bactericidal drugs kill organisms and more effective during logarithmic growth, since the increased metabolic activity provides maximum susceptibility. Bacteriostatic antimicrobials only prevent bacterial growth.

The use of antibiotics in fixed dosage combinations is to be avoided. However, the simultaneous administration of two or more antibiotics may be justified in certain situations.

Natural resistance depends on the absence of a metabolic process affected by the antibiotic in question.

Due to three mechanisms:

1. non-susceptible metabolism;

2. ability of the organism to destroy the drug (penicillinase);

3. inability of the drug to penetrate to an appropriate location in the parasite.

Acquired resistance can arise through mutation, adaptation, or through development of infectious (multiple) drug resistance. Many gram-negative bacilli have genetic material (R factors) what is separate from the chromosomes but that mediates resistance to many different antibiotics. The R factors can be transferred from one bacterium to another (conjugation). Bacteriophages can transfer DNA via transduction to impart resistance to penicillin, erythromycin, tetracycline, and chloramphenicol. Transposition can also occur.

In general, the selection of an antibiotic should be based upon an etiologic diagnosis. Although sensitivity determinations are desirable in infections caused by E. coli, Proteus, P. aeruginosa, and Staphylococcus, they are not absolutely necessary in infections caused by some organisms that are usually sensitive to penicillin.

An antibacterial drug usually causes significant clinical improvement within 12-24 hrs. If no clinical improvement is obvious after 48-72 hrs of full therapy, it can usually be concluded that the organisms are resistant or an abscess exists.

Chemotherapeutic agents should be measured using viability.

Bacteriologic diagnosis: Disk diffusion method provides quick, basic information as to whether an organism is susceptible or resistant to a particular antibiotic. Tube dilution method provides exact concentration of antibiotic needed to kill bacteria.

In general, there is no place for prophylaxis unless it is directed against one particular organism, or a small group of organisms.

Adverse drug effects: Superinfection is the appearance of both microbiological and clinical evidence of a new infection with pathogenic microorganisms or fungi; caused by inappropriate drug use, drug resistance, inadequate dosing, or possibly catheterization. Hypersensitivity reactions can develop to most antibacterial drugs, particularly in atopic individuals.

1. Ancient History  In ancient Peru the Indians used bark from the cinchona tree to treat malaria. 2500 years ago, the Chinese were using moldy soybean curd for infections. Hippocrates wrote about the antibacterial properties of wine and salts.

2. 20^th Century 

   1. 1909  Paul Erlich discovered Salvarsan and arsen could be used to treat syphilis. He was the first to define the selective toxicity (magic bullet) concept, which is that a drug can be toxic to the parasite but will not harm the host.

   2. 1930’s  Domagk discovered the first sulfonamide (prontosil).

   3. 1929  the famous accidental discovery of penicillin G by Alexander Fleming.

   4. WWII Florey and Chain use penicillin to treat people and get the Noble prize.

   5. 1944  Walkman discovers streptomycin, 1947 saw chloramphenicol, 1948 tetracycline, 1952 erythromycin.

   6. 1960’s  able to synthesize new antibodies by molecular modification of existing drugs

   7. 1980’s  quinolones

   8. 2000  antifungals such as voriconazole and caspofungin are at the forefront of medicine.

Definition

The original definition of antibiotics was material derived from microorganisms that suppress growth and sometimes kill the microorganism. Synthetic material was added later, when they were able to make synthetic antibiotics.


Classification

1. Bactericidal drugs kill the target bacterium or fungus and are more effective. You would use these types of drugs to treat endocarditis, meningitis, osteomyelitis, and other invasive bacterial infections. Hosts with low immune systems should also be treated with bactericidal drugs. These drugs include β- Lactams, aminoglycosides, and fluoroquinolones.
2. Bacteriostatic drugs inhibit growth and can be helpful cuz they let the normal host defenses to destroy the microorganisms. You would use these to treat infections such as cystitis. These drugs include tetracycline, sulfonamides, clindamycin, and chloramphenicol. Some organisms require 2 agents for killing such as entercocci.

We can classify antibiotics by their mode of action.

1. Cell Wall Inhibitors: These include the Glycopeptides (ex vancomycin), Bacitracin, Cycloserin, Fosfomycin, and the β–lactams (penicillins, cephalosporines, monobactams, carbapenems) that are important to know because if someone is allergic to penicillin you can’t give them a different β-lactam.

Antibiotic agents usually diffuse easily through Gram +ve cell walls, but in Gram –ve they need to go through narrow walls and it’s harder. Peptidoglycan is the critical attack site in cell wall inhibition because it is not found in eukaryotes, and it’s loss = cell death. It is a cross-linked complex of polysaccharides and peptides, which has been discussed, in earlier lectures (see bacteriology). The cross linked structure is the reason for it’s great strength. It is synthesized in 3 stages:

Precursor formation UDP-NAM-pentapeptide and UDP-NAG are synthesized in the cytosol {inhibitors here = fosfomycin and cycloserine – this is not used because it is also toxic to the nervous system)

Polymer formation precursor molecules are transferred to phosphorylated undecaprenyl alcohol (a lipid carrier in the cytoplasmic membrane) and are transported to the outside surface. Bacitracin interacts with the carrier and so prevents precursor transport.Transglycosylases and transpeptidases reticulate the peptidoglycan units. β–lactams inactivate transpeptidases because they bind them so D-ala-D-ala can’t. Glycopeptides inhibit both transglycosylases and transpeptidases by binding to the D-ala-D-ala termini, preventing anything else from binding there.

Cross Linkinglinking the new peptidoglycan strand into the existing molecule. These enzymes are called Penicillin –Binding Proteins (PBP) because they were discovered by labeling with radioactive penicillin G. They are membrane bound and structurally resemble serine proteases. Bacteria make 4 types of PBP numbered according to molecular weight; letters are used to differentiate PBPs of similar weight (so you can PBP 2a, PBP 2b etc.)

PBPs differ in affinities for β–lactams, amounts and function in cell walls, and enzymes are different in Gram + vs. Gram – vs. anaerobic bacteria. Which PBP a β–lactam binds to affects how the bacteria will look, for example binding to PBP 3 causes bacteria to grow into long filaments and die, while binding to PBP 1 results in bulgeing and bursting of the cell wall. With PBP’s inhibited, the autolysins are unopposed which can also contribute to the antibacterial effect. β–lactamases are PBPs that inactivate the drug by catalyzing hydrolyses of the β–lactam ring.

2. 
   
   Cell Membrane Inhibitors : These cause disorganization of the membrane. Antibacterials – polymyxin, Antifungals – Polyenes (amphotericin), Imidazoles (fluconazole , itraconazole , and vorconazole). We can divide these into cationic, anionic, and neutral agents.
   1. 
      
      Polymyxin B and colistin (polymyxin E) : these are low molecular weight octapeptides that inhibit Gram – ve bacteria with –vely charged lipids on the surface. Allow nucleic acid and cations to leak out of the cell so the cell dies. Can’t be used systemically because they are toxic to the kidney and nervous system (except in cases of extreme need), but are used topically.
      
      
   2. 
      
      Polyene antibiotics  fungal membranes have sterols while bacterial membranes don’t. Polyene antibiotics bind to the sterols and make a pore in the membrane and the contents leak out. This does not work in prokaryotes.
      
      
   3. 
      
      Imidazoles : inhibit ergosterol synthesis.
      
      
   
   

3. 
   
   Nucleic Acid Synthesis Inhibitors
   1. 
      
      Inhibitors of DNA replication: Quinolones and Nitroimidazoles. Fluoroquinolones block the action of DNA gyrase and DNA topoisomerase IV that control and modify the topological states of DNA in cells. They do this by relieving supercoils, which can form during the unwinding of DNA for replication or transcription. Positive supercoils are when the front segment of DNA crosses over the back from left to right. There are a few types of topoisomerases:
      1. 
         
         Type 1: makes transient single stranded breaks in DNA and removes supercoils one at a time. In eukaryotes both topo 1 and 2 can remove both + and – supercoils. In bacteria topo 1 can only remove – supercoils.
         
         
      2. 
         
         Type 2: makes transient double stranded breaks and removes supercoils 2 at a time, and is more efficient but requires energy from ATP hydrolysis. Bacterial topo II is also called DNA gyrase and has 2 functions (a) to remove +ve supercoils during DNA replication, and, (b) to introduce –ve supercoils so the DNA molecule can be packed into the cell. It is made of two A and two B subunits. Bacterial Topo IV can only relax supercoils, it can’t make supercoils. Topo IV has 2 subunits, ParC and ParE.
         
         
      
      
   
   

2. 
   
   Inhibitors of RNA polymerase  Rifamycins. Rifampin binds to a β-subunit of RNA polymerases and prevents initiation of DNA transcription. Mammalian mitochondrial RNA synthesis is not impaired significantly.
   
   
3. 
   
   Inhibitors of nucleotide metabolism  Acyclovir  inhibits viruses by being converted to a tiphosphate and inhibiting the thymidine kinase and DNA polymerase of the herpes viruses, AZT (viruses)  inhibits the incorporation of DATP into DNA, Flucytosine (fungi)  inhibits yeast by being converted to 5-fluorouracil which inhibits thymidylate synthetase so there are not enough thymine nucleotides to replicate DNA.
   
   

4. 
   
   Protein Synthesis Inhibitors  I am sure you all know the steps of protein synthesis so I won’t go into the long explanation she gave. Instead I’ll just name the steps  formation of the initiation complex  elongation of the polypeptide chain  termination.
   1. 
      
      Inhibitors of 30S subunit  Aminoglycosides  bind to specific ribosomal proteins and to a major deep grove in the rRNA. Streptomycin was the first studied and it has a different mechanism from other aminoglycosides. It binds to the S12 protein and causes the ribosome to misread the genetic code. Others also bind the L6 protein of the 50S ribosome. Eukaryotes are relatively unaffected but ribosomes in the mitochondria are sensitive to their effects.
      
      
   
   

2. 
   
   Inhibitors of 50S subunit 
   1. 
      
      Macrolides, Ketolides, Lincinoids  have large lactone rings, bind to the peptidyl side of the 50S subunit. Impair peptidyltransferase and interferes with the translocation of the peptide chain from A to P site, and promotes dissociation of peptidyl-tRNA from the ribosomes.
      
      
   2. 
      
      Chloramphenicol  bacteriostatic, binds to a peptidyltransferase enzyme on the 50S ribosome.
      
      
   3. 
      
      Fusidic acid
      
      
   4. 
      
      Streptogramin  relatives of macrolides, binds to 50S
      
      
   5. 
      
      Oxazolidinones  binds to 50S near the 30S interface which prevents the 30S initiation complex from forming the 70S complex, blocking initiation of protein synthesis. Bacteriostatic
      
      
   
   

5. 
   
   Metabolic Inhibitors  Folate inhibitors  bacteria make folic acid while humans take it in from their diet. Sulfonamides and trimethoprim block the biosynthesis of tetrahydrofolate, which is a carrier of 1C fragments and is necessary for DNA, RNA, and cell wall synthesis.
   
   

Penicillin was a huge breakthorugh that saved millions of lives, but a few years after it was put on the market, penicillin resistant S. aureus was found. In the 70’s resistant strains of H. influenza, gonorrhea, and shigella emerged. Antimicrobial resistance is now a worldwide problem. There has been a dramatic increase in antimicrobial resistant community acquired and nosocomial pathogens. Major risk factors include antimicrobial misuse and noncompliance. Currently there is MDR-TB, penicillin resistant pneumococci, malaria, cholera, MDR-gonorrhea, VRE and MRSA in the community, 60% of vsceral leishmaniasis are resistant along with 60% of hospital acquired infections.

Consequently there has been an increased mortality because usually the people who get these diseases are the ones in hospitals. There is also an increase in morbidity because the illness takes longer to be resloved and there is a greater chance for resistant organisms to spread to other people. Resistance means increased costs of care due to newer and more expensive drugs. The future is bleak as there are few new drugs on the horizon.

MOLECULAR GENETICS OF ANTIBIOTIC RESISTANCE

DEFINITIONS:

1. Plasmids  y’all already know about plasmids, plasmids can encode antibiotic resistance and virulence factors.

2. Bacteriophages  viral nucleic acid can be injected into the host cell

3. Transposable Elements  DNA segments that can insert themsleves into DNA molecules and leave. They can’t replicate by themselves and so must be on a replicon like a chromsome, bacteriophage, or plasmid. Can be trabsferred along a chromosme. There are 2 kinds: insertion sequences (IS elements) which have minimal genetic information for transposition and Transposons (Tn) which also have other genes such as antibiotic-resistance marker.

4. 4 Modes of introducing DNA into bacteria  these are transformation, transduction, conjugation, and transposition and have already been covered in previous lectures.

Genetic Mechanisms of Antiobiotic Resistance

1. Inherent (natural) resistance  pseudomonas are always resistant to penicillin.

2. Point mutations in the chromosomes  can alter target site of an antimicrobial agent.

3. Rearrangements  by all the methods we learned about

4. Foreign DNA  carried by all the methods mentioned above, this is the main mechanism for antibiotic resistance, especially plasmid mediated resistance. It is easily transmissable, highly stable, confers resistance to lots of classes of antibiotics at the same time. And is also associated with other virulence factors. An example of this is the spread of β-lactamase from enterobacteriaceae to H. influenza and N. gonorrhea.

Antibiotics have a strong selective pressure on the development of resistance by destroying the susceptible bacteria but allowing the resistant ones to proliferate.

BIOCHEMICAL MECHANISMS OF ANTIBIOTIC RESISTANCE

1. Drug Inactivation 

   1. β-lactamases  inactivate β-lactams by splitting the amide bond if the ring.

   • There are over 340 different types that can be inducible (level of production varies with the induction potential of specific agents, strong inducers are imipenem, ampicillin, cefoxitin, and clavulanate; modate inducers include sulbactam, and weak inducers are ceftriaxone, ureidopenicillins, and tazobactam) or Constitutive (constant level of production).
     

   • In Gram +ve bacteria they are excreted into the environment; all hospital isolated staph and 50-80% of community aquired staph can make these enzymes.
     

   • In Gram –ve they are excreted into the periplasm, these are found mainly in the Enterobacter species.
     

   • They are classified by genetic or biochemical properties. TEM1 accounts for 75-80% of plasmid-mediated resistance worldwide and is found mainly in influenza, Slamonella, Shigella, and Gonorrhea.
     

   • ESBL give resistance to all penicillins and cephalosporines and is a problem in lots of hospitals.

2. Β-lactamases can be classified into 4 groups:

1. Group A has serine at the active site, constitutive, usually found on plasmids. Preferred hydrolysis of penicillin, the group includes TEM-1, SHV-1, penicillinase.

2. Group B are metalloenzymes with Zn at the active site, hydrolyze carbapenems, include IMP-1

3. Group C has serine at the active site and is found on the ampC gene. It is inducible and includes enzymes such as MIR-1.

4. Group D has serine at the active site, hydrolyze Oxacillin, OXA-1.

Another way of classifying β-lactams is the Bush-Jacoby-Medeiros functional classification scheme. Each group has 20-80 different enzymes.

2. Aminoglycoside modifying enzymes  there are more than 24 and are coded for on plasmids or the chromsome. There are 3 reactions – N-acetylation, O-nucleotidylation, and O-phosphorylation.

3. Chloramphenicol acetyltransferase

4. Erythromycin esterase

2. Reduced Target Affinity 

1. Alteration of target enzymes  altered PBP give a decreased affinity for β-lactams. Methicillin resistance S. aureus (MRSA) and MRSE (S. epidermidis) are formed by a PBP2a encoded by mecA gene. It is capable of cell wall synthesis in the absence of other PBPs has low affinity for all β-lactams. Altered DNA gyrase gives resistant to quinolones. Altered synthetase gives resistance to sulfonamides.

2. Alteration of ribosomal targets  MLS resistance is conferred by genes that encode 8 classes of enzymes that demethylate adenine residue on 23S rRNA of the 50S subunit. Conformational changes in the ribosome results in a decreased affinity and leads to coresistance to all MLS antibiotics. They are plasmid or chromosomal encoded. Aminoglycoside resistance is caused by mutations of S12 protein of the 30S subunit.

3. Alterations of cell wall precursor targets  Glycopeptides bind to D-ala-D-ala at the end of the peptidoglycan precursors and prevent further transglycosilation. Resistance happens when they turn it into D-ala-D-lac. The vancomycin don’t fit anymore.

4. Reduced permiability  Penicillin is effective against gram+, but not gram _ due to the outer membrane. LPS impedes the entry of hydrophobic antibiotics. Some bacteria can change their production of porins. The bigger the antibiotic molecule, the more negative charges, the greater the degree of hydrophobicity, the less likely it is to penetrate through the OM. Mutations in porins can lead to increased resistance to β-lactams, aminoglycosides, quinolones.

1. Antibiotic Efflux  There can be active efflux of antibiotics by the inner membrane. This is the major mechanism of resistance in Gram- bacteria to tetracycline. This is found in E.coli, shigella, and pseudomonas.

2. Bypass of Antibiotic  Folate auxotrophs can use their own folates so they’re not susceptible to sulfonamides and trimethoprim.

We can test for susceptible bacteria by the MIC (Minimal Inhibitory Concentration)  the lowest concentration of a specific antimicrobial agent that inhibits the test organism. The MBC (Minimal Bactericidal Concentration) is the lowest concentration of a specific antimicrobial agent that kills the test organism.

Disk diffusion susceptibility testing  a disk with antibiotics is put on an agar plate after the test organism has been put on it. The diameter of the zone of inhibition after incubation for 16-18 hours. The zone diameter interpretive breakpoints are based on the inverse correlation of zone diameter with MIC.

Agar dilution testing is cost effective if a large number of isolates are tested at the same time. Many different organisms can be tested simultaneously on each plate.

E test is a new procedure that uses a strip impregnated with antimicrobial agent and applies it to a plate. The plate is examined for growth.

Antibiotic combinations are used for life-threatening infections, prevention of emergence of bacterial resistance, polymicrobial infections, decreased toxicity, and enhanced antibacterial activity. Synergy is when the combined drugs are greater than their individual activities. Indifference is when the combined action is equal to the sum of their independent activity. Antagonism is when the sum is less than the parts.

PK/PD

Absorption can be from the GI tract after oral, rectal, or tube administration. It can also be from IM, subcutaneous, or topical administration.

Bioavailability is the fraction of dose that is absorbed intact. IV antibiotics have 100% bioavailability. Fluroquinolones, flucanazole, cotrimoxazole, nitrofurantoin all have 100% bioavailability.

Apparent volume of distribution reflects the ability of the drug to enter inflammatory cells and tissues.

Rapidly metabolized antibiotics excreted by the kidneys are not a good choice for urinary tract infections.

Drugs with short half lives need more frequent administration. Drugs with longer half lives can be given in a single daily dose and are more convenient. Drugs primarily excreted via the hepatic or biliary system need dose adjustment in renal insufficiency and might accumulate inappropriately in patients with hepatic failure.

Peak/MIC ratio, Cmax/MIC ratio is the ratio of the maximum serum concentration to the MIC. AUC/MIC is the ratio of the area under the concentration-time curve to the MIC. Both predict activity of concentration dependant bactericidal antibiotics.

Concentration-dependant killing agents such as fluroquinolones and aminoglycosides eliminate bacteria when their concentrations are above the MIC of the organism. As the ratio of drug concentration to MIC increases, bacterial killing increases. Cmax/MIC can also be helpful in seeing the development of bacterial resistance for aminoglycosides and quinolones.

t>MIC is the duration of time during the dose interval that serum concentration stays above MIC. This predicts activity of time dependent bactericidal antibiotics. These include β-lactams, macrolides, and clindamycin. Any dosing strategy requires clinical investigations in human studies before they can be used in clinical practice.

Postantibiotic effect (PAE) is growth inhibition that continues for a varying period after the concentration of the antibiotic is below the MIC. Aminoglycosides and fluoroquinones have in vitro PAEs against gram – of about 2-6 hrs. β-lactam antibiotics have little to no PAE against gram-, but 2 hours vs. gram+. There is in vivo PAE against gram - for aminoglycosides, fluorquinolones, erythromycin, clindamycin, and tetracycline. PAE is important cuz theoretically a drug with long PAE can be used less frequently. A drug with no PAE might be most effective if given as a continuous infusion.

INDICATIONS AND CLINICAL SELECTION

β-LACTAMS

1. Mechanism of action  binds and inhibits PBPs. Different antibiotics can inhibit certain PBPs more than others. Inhibition of cell wall synthesis leads to activation of the autolytic system. Bacteria deficient in autolytic enzymes have tolerance to this class of antibiotic.

2. Resistance  decreased penetration to target site by changes in the porin proteins. This is why P. aeruginosa is resistant. Alteration of PBPs might influence binding of the antibiotic. This is resistance in pneumococci, and oxacillin resistance. β-lactamases is the major mech of resistance to β-lactam antibiotics. They can cleave either penicillins, cephalosporins or both. They can be synthesized constitutively or inducible.

3. Side effects 

1. There can be allergic reactions – immmediate (w/in 60 min, anaphylaxis), accelerated (1-72 hrs, urticaria), or late (>72 hrs, skin rash, serum sickness, drug fever). Penicillin G causes anaphylaxis in .01% people. People at risk can be id’d by skin testing with penicilloyl, penicilloate, or penilloate metabolic products. 40-73% of + will have a reaction. Patients with a + skin test can be desensitized with increased doses of drug.

2. Neurologic reactions like encephalopathy, changes in consciousness, seizures. This happens in high dose penicillin therapy particularly renal disease

3. Pulmonary infiltrate with eosonophilia syndrome.

4. Diarrhea (C. difficile colitis)

5. Hypersensitivity hepatitis (oxacillin and nafcillin) Ceftrixone can cause biliary sludge and pseudolithiasis in kids.

6. Renal reactions  methicillin—allergic interstitial nephritis. Glomerulonephritis in association with serum sickness. Ticarcillin can cause sodium overload and hypokalemia.

7. Neutropenias, hemolytic anemia, thrombocytopenia.

8. Vitamin K deficiency

Penicillins

There are two natural penicillins: penicillin G and V. You can also have semisynthetic penicillins which are natural products modified in the lab. Completely synthetic products include the sulfa drugs. Penicillins are sodium or potassium salts. The side chain determines the antibacterial spectrum and properties of each penicillin. All IV penicillins have short t1/2. They penetrate CSF poorly in the absence of inflammation. Nafcillin, oxacillin, doxacillin, and didoxacilin have non-renal routes of clearance so don’t need dose modifications. Ampicillin, mezlocillin, and pineracillin need dose modification when the GFR is <10ml/min.

1. Natural penicillins  work against gram + cocci like streptococci, gram + rods like Listeria, gram – cocci like Neisseria, most anaerobes, treponemal infections. Penicillin G isn’t active against gram – bacilli. Gram + bacteria inhibited by natural penicillins are more susceptible than to semisynthetic.

   1. Penicillin G can’t be given orally. When given in IV it’s cleared every 4-6 hours. Procaine penicillin delays the peak of activity and provides serum and tissue levels for at least 12 hours. Benzathine penicillin is a repository lat can last for 15-30 days.

   2. Penicillin V is given orally in suspension or tablets. Should be given every 6-8 hours. Less active than Penicillin G against Haemophilus, Neisseria, and enteric organisms.

2. Penicillinase-resistant penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria. They are the drugs of choice for penicillin-resistant S. aureus and S. epidermidis.

   1. Methicillin is least active, most likely to cause interstitial nephritis and is not used anymore.

   2. Nafcillin is highly protein bound, given by IV, and is excreted by the liver and kidney.

   3. Isoxazolyl penicillins (cloxacillin, dicloxacin, flucloxacillin, oxacillin) are absorbed orally on an empty tummy. Dicloxacillin has better absorption. Bound to serum proteins and is excreted mostly by the kidney.

3. Aminopenicillins (ampicillin and amoxicillin) have the same spectrum as penicillin G, but are more active against enterococci and listeria. It’s not stable to β-lactamases of gram + or gram – bacteria. They both have the same spectrum, but amoxicillin is better absorbed when given orally and is preferred to ampicillin for oral use, except in shigella.

4. Carboxy penicillins (carbenicillin, ticarcillin) are like aminopenicillins but they can also penetrate the porin channel of gram – bacteria. They are more resistant to β lactamases like enterobacter, pseudomonas, proteus.

5. Extended-spectrum ureidopenicillins  mezlocillin and pineracillin are derivatives of ampicillin and cover the same spectrum as carboxypenicillins. They are more active against klebsiella, enterococci, and bacteroides fragilis. These drugs are all basically the same so choices are made by cost considerations.

6. Β-lactam and β lactamase inhibitor  clavulonic acid and penicillanic sulfone derivatives like sulbactam and tazobactam are β-lactamase inhibitors. They basically make the enzyme inactive so the β-lactam they’re administered with can do its work. They are most efficient against plasmid encoded β-lactamses made by S. aureus, influenza, B. catarrhalis, bacteroides, serratia. They do not work against chromosomal lactamases of serratia, c. freunsii, enetreobacter, P. aeruginosa, and enterobacteriaceae.

   1. Amoxicillin-clavulanate  works against S. aureus, H. influenza, enterobacteriaceae, and anaerobes

   2. Ampicillin-sulbactam works against enterobacteriaceae and acinetobacter. It’s broader spectrum but less potent than clavulanic acid.

   3. Timentib, Zosyn has a spectrum like sulbactam but a potency like calvulonic acid. Works against S. areus, inflenza, gonorrhoeae, enterobactericaea, and anaerobes.

Cephalosporins

Active against gram+ and – bacteria and are not destroyed by penicillinase. Most forms are semi-synthetic derivatives of cephalosporin C. There are 4 gnerations based on spectrum of activity against aerobic and facultative gram – bacilli. First and second generation don’t penetrate the CSF barrier well and shouldn’t be used for meningitis. Third generation ones should be used.

1. 1^st Generation  cefazolin, cephapirin they are active against gram + cocci, anaerobes. They are not active against gram -.

2. 2^nd 

   1. activity vs. H. influenza – cefruxime and cefamandole

   2. activity vs. bacteroides – cefotoxin and cefotetan

3. 3^rd  1) bad vs. P aeruginosa – cefotaxime, ceftriaxone, ceftizocime 2) good vs. p. aeruginos ceftazidime and cefoperazone

4. 4^th  cefepime

Carbapenems

Imipenem, Meropenem, Entapenem. Resistant to plasmid and chromosomal β-lactamases. Work against gram +, gram -, and anaerobic bacteria. They are not active against s. maltophelia, B. cepacia, E. faecilium, oxacillin resistant staphylococcci, and JK diphtheroids. They are effective against P. aeruginosa through a different channel than normal. It causes resistance easily when the drug is used as a single agent. Imipenem-cilastatin has been associated with CNS toxicity. Meropenem has a lower risk of producing seizures. Ertapenem has a longer half-life and can be administered once daily, but it has a narrower spectrum of activity.

Monobactams

Aztreonam has good activity against most gram – aerobic and facultative bacteria. There is no cross-allergenicity with other β-lactams.

GLYCOPEPTIDES

Vancomycin, teicoplanin, and daptoomycin. Should be given IV over 1hr. absorbed poorly from GI. Eliminated by glomerular filtration. T1/2 is 6-8 hours.

1. Mechanism of action  bind to D-ala-D-ala and prevent further gylcosylation.

2. Resistance  There at least 3 genes reesponsible )called van A, B, and C). A is the most common and is induced by vancomycin or teiciplanin and can be plasma encoded. It makes the code D-ala-D-lactate so vancomycin doesn’t fit anymore. B is inducible by vancomycin, but bacteria with this are still susceptible to teicoplanin. C is on the genome and is constitutive. VISA (S. aureus) resistance is due to excessive production of cell wall material , and these bacteria are usually also resistant to teicoplanin.

3. Side effects most common are fever, chill, and phlebitis. There can also be hearing loss, reversible nephrotoxicity, rashes, leukopenia, thrombocytopenia, eosonophilia, and lacrimation.

Gram-Positive Antibiotics – Macrolides

Erythromycin

MOA: Drug binds exclusively to the 50S subunit where it blocks the translocation step in which the peptidyl tRNA is shifted from the acceptor (A) site back to the peptide (P) site. Bacteriostatic.

Spectrum: Used primarily against G(+) infections in patients sensitive to penicillin. Also effective against G(-) N. gonorrhea, N. meningitidis, H. influenzae, B. pertussis.

Resistance: 1. Genetically altered ribosomal protein; 2. Decreased permeability to drug; 3. Induced resistance (unique to erythromycin, due to low dose). Resistance to one macrolide induces resistance to all.

Pharmacokinetics: Administered as an ester to reduce acid lability. Metabolized by liver, with high concentrations found in bile and feces. Erythromycin inhibits cytochrome p450.

Therapeutic place: Used when the patient is sensitive to penicillin. Used to treat Legionnaire’s disease, M. pneumoniae, pertussis, and as an alternate drug for Lyme’s disease and chlamydia.

Clarithromycin – Used to treat M. avium-intracellulare infections in AIDS patients as well as peptic ulcers caused by H. pylori.

Azithromycin – Used to treat M. avium-intracellulare and toxoplasmosis encephalitis in AIDS patients.

Broad-spectrum antibiotics – Lincosamides

Clindamycin & Clindamycin phosphate

MOA: Lincosamides bind exclusively to the 50S subunit and either inhibit the peptidyl transferase reaction and/or prevent translocation of tRNA from the A site to the donor site.

Spectrum: Mostly G(+), some G(-); clindamycin phosphate targets G(+,-) AND anaerobes (drug of choice).

Resistance: Erythromycin-resistant organisms are likely to be resistant to clindamycin.

Pharmacokinetics: Well absorbed in the GI tract. Metabolized by liver. Excreted by kidney and in bile.

Toxicity: Most common problem is severe and persistent diarrhea (pseudomembraneous colitis may occur).

Therapeutic place: Clindamycin and clindamycin phosphate are effective against anaerobes (specifically B. fragilis) and are alternate drugs for pneumococci, streptococci, and staphylococci.

Broad-spectrum antibiotics – Tetracyclines

MOA: Tetracyclines binds to the 30S subunit and prevent attachment of aminoacyl tRNA to the A site. They also inhibit the attachment of N-formyl methionine tRNA to the 30S subunit. Bacteriostatic.

Spectrum: First-line treatment of infection from Brucellae, Mima, and Bacteroides. G(+,-) coverage.

Resistance: Develops gradually. Mediated by R factor in G(-) bacteria.

Pharmacokinetics: Tetracyclines chelate calcium, magnesium, and aluminum. The various tetracyclines are cleared by glomerular filtration (except doxycycline).

Toxicity: Hypersensitivity; irritation of GI tract; superinfection; photosensitivity; liver damage; renal damage (due to outdated tetracyclinesFanconi syndrome); vestibular reactions; damage to teeth, bones, and nails (don’t give to pregnant women or small children).

Therapeutic place: Broad spectrum, oddball-organisms.

Tetracycline – UTIs.

Minocycline – Lower renal clearance.

Broad-spectrum antibiotics – Chloramphenicol

MOA: Chloramphenicol prevents mRNA from binding to the 50S ribosome. Chloramphenicol also depresses the activity of peptidyltransferase. Net result is small incomplete fragments of protein. Bacteriostatic.

Selective toxicity: Inhibits protein synthesis in prokaryotes and eukaryotes.

Spectrum: Drug of choice only for S. typhii carrier state.

Resistance: R factor-mediated. May be due to acetylation of hydroxyl group.

Pharmacokinetics: Well absorbed from GI tract; hepatic metabolism is rapid; inactive conjugates are excreted in the urine (decreased renal function is no problem, decreased live function needs reduction in dose); excellent CSF diffusion as well as excellent diffusion intraocularly.

Toxicity: Dose-related bone marrow depression; dose-independent aplastic anemia; GI irritation; neurological problems; superinfection; gray baby syndrome

Drug interactions

Erythromycin-Clindamycin – Antagonism

Erythromycin-Penicillin – Synergism, antagonism, or antagonism.

Doxycycline-Carbamazepine/Phenobarbital/Phenytoin – Reduction in half-life of doxycycline due to induction of liver enzymes.

Chlortetracycline-Penicillin – Tetracycline derivatives may antagonize the bactericidal action of penicillin G under such conditions such as meningitis.

Tetracycline-Aluminum hydroxide/ferrous sulfate – Combination decreases absorption of tetracycline.

Tetracycline-oral contraceptives – Contraceptive failure.

Aminoglycosides

Resistance: R-factor mediated resistance resulting in 1. adenylation; 2. phosphorylation; 3. acetylation.

Pharmacokinetics: All are very poorly absorbed from GI tract (given before surgery for bowel sterilization); excreted almost entirely from the kidney via filtration; can reach very high levels in urine (alkaline environment improves effectiveness); do not pass thru BBB (although can be administered intrathecally).

Toxicity: Hypersensitivity (neomycin can produce contact dermatitis); curare-like effect on peritoneum; ototoxicity; nephrotoxicity.

Streptomycin

MOA: Streptomycin binds to the 30S subunit and blocks initiation of protein synthesis and causes misreading of the genetic code, resulting in synthesis of fraudulent proteins because of incorporation of false amino acids. Bactericidal/static depending on concentration.

Spectrum: Mainly used as an adjuvant in tuberculosis therapy. Also used for plague and in combination with penicillin against enterococci.

Resistance: Develops explosively.

Toxicity: 8th nerve toxicity (vestibular), high frequency sounds are lost first; renal damage; curare-like effect; skin rashes.

Therapeutic place: Miliary tuberculosis, S. faecalis (with penicillin), uncommon infections (with tetracycline).

Neomycin – Bowel sterilization; nephrotoxicity and ototoxicity prohibit parenteral use; curare-like effect.

Gentamicin – spectrum similar to kanamycin and neomycin but more active against many strains of E. coli, Klebsiella, Proteus, and Pseudomonas; more active at alkaline pH; nephrotoxic and ototoxic (vestibular).

Tobramycin – Similar to gentamicin.

Amikacin – Reserved for infections resistant to gentamicin and tobramycin.

Viomycin – Second line drug in treatment of tuberculosis.

Netilmicin – New.

Spectinomycin – Not officially an aminoglycoside; indicated only in the treatment on N. gonorrhoea; takes just one dose; no renal or ototoxicity.

Drug interactions

Gentamicin-Carbenicillin – BAD combination.

Gentamicin-Cephalothin – Additive nephrotoxicity.

Gentamicin-Polymixin B – Increased nephrotoxicity.

Gentamicin/Kanamycin-Ethacrynic acid – Increased oxotoxicity.

Usual regimen: INH/rifampin/pyrazinamde and either ethambutol or streptomycin (4 drug combo)

Prophylaxis: INH for 12 mos.

Primary drugs: INH, pyrazinamide, rifampin, ethambutol, streptomycin

INH

MOA: Uncertain, but INH does inhibit synthesis of mycolic acid, a component of the cell wall.

Selectivity: INH is only effective against mycobacteria. Bactericidal.

Resistance: Develops rapidly. Mutants decrease catalase and peroxidase, increase mycolic acid synthesis, cleave off the hydrazine group from the drug with hydrazide enzyme (most common), or survive with less mycolic acid in their cell wall.

Pharmacokinetics: Acetylation occurs in the liver and is different between fast and slow acetylators. The slow inactivator is homozygous recessive. One of the toxicities of INH is pyroxidine (B6) deficiency and slow acetylators are more likely to suffer. Also, INH inhibits the metabolism of phenytoin, which can lead to toxicity in slow acetylators. Acetyl-INH is excreted in the urine.

Toxicity: Peripheral neuropathy reversed by vitamin B6 (due to drug competing with B6 for enzyme apotrytophanase); hepatitis seen during prophylactic use in those over 35 yrs old.

Therapeutic place: Treatment is aimed at the active state of Tb. Also used for prophylaxis.

Ethambutol

MOA: Unknown, but interferes with mycolic acid and RNA synthesis.

Toxicity: Optic neuritis (color blindness), loss of visual acuity, and retrobulbar neuritis.

Therapeutic place: M. tuberculosis, M. bovis.

Contraindicated: In children under 5 yrs old.

Rifampin

MOA: Rifampin inhibits DNA-dependent RNA polymerase ( subunit).

Spectrum: M. tuberculosis and G(+) organisms.

Toxicity: Turns body fluids orange (not harmful).

Pharmacokinetics: Rifampin induces p450 enzymes, thereby decreasing the half-lives of a number of drugs.

Pyrazinamde – Can cause liver damage and uric acid retention.

Second-line drugs: Cycloserine, viomycin, kanamycin, capreomycin, PAS, ethionamide

Cycloserine – Cell wall inhibitor, CNS toxicity.

Capreomycin – Renal and oxtotoxicity.

PAS – Bad shits.

Drug interactions

INH-Rifampin – Hepatotoxicity.

Rifampin-oral contraceptives – Decreased effectiveness of contraceptive.

Dapsone – Sulfa drug; adjunct therapy with corticosteroids, aminoglycosides, or antimalarials may be helpful; can cause anemia and methemoglobinemia.

Amithiazone – Greater effect on tuberculoid form than on lepromatous form; substitute for patients intolerant of sulfones.

Clofazamine – Substitute; discoloration of the skin.

Rifampin – Hepatitis and inhibits metabolism of 35 drugs.

Thalidomide – Highly effective.

Ethionamide

Tx of M. avium complex – Rifabutin, macrolides, quinolones, clofazimine, amikacin.

Malaria: P. vivax (fever spike every 24-48 hrs), falciparum (irregular fever spike pattern, blood stage only), malariae (fever spike every 4th day), ovale.

• Stages – primary stage in liver for all four species; secondary stage is either erythrocytic (P. falciparum) or extraerythrocytic (stay in liver, other 3 species).

• MOA of drugs – affect DNA synthesis or folic acid metabolism

Erythrocytic drugs effective against P. falciparum: Chloroquine, mefloquine, quinine

1. Chloroquine – Inhibits DNA synthesis; effective against P. falciparum blood form; ocular and cardiac toxicities; hemolytic anemia in G6PDH deficient individuals; cures P. falciparum but has no effect on relapsing malarias (Pp. malariae, ovale, vivax); take once a week for two weeks before trip and six weeks after leaving.

2. Mefloquine – Like chloroquine; can also be used prophylatically; contraindicated in epilepsy, psychiatric disorders, cardiac problems, and pregnancy.

3. Quinine – Effective against P. falciparum; inhibits DNA synthesis; cinchoism (ototoxicity, GI toxicity, visual toxicity); blackwater fever; hemolytic anemia in G6PDH deficient; used in combination with pyrimethamine or sulfadiazine.

Extraerythrocytic drugs effective against PP. vivax, ovale, malariae: Primaquine

1. Primaquine – Affects DNA synthesis in liver tissue; also inhibits electron transport; hemolytic anemia in G6PDH deficient; methemoglobinemia; radical cure of vivax, ovale, malariae.

Drugs useful in both stages: Pyrethamine, trimethoprimm sulfones, sulfonamides – All are folic acid inhibitors that act slowly (as opposed to above listed drugs, which act quickly).

Metronidazole – Tissue and lumenal amebicide; prodrug that when activated interferes with DNA synthesis; metallic taste; disulfiram-like reaction with alcohol.

Tetracycline, erythromycin, paramomycin – Indirect-acting lumenal amebicides; work by killing bacteria that provide amoeba with nutrition.

Diiodohydroxyquin & diloxanide furoate – Direct-acting lumenal amebicides.

Emetine – Tissue amebicide; “big gun.”

Other antiprotozoals

Suramin – Trypansomes.

Pentamidine – Trypanosomes, leishmaniasis, P. carinii (in AIDS patients intolerant to cotrimoxazole); administered as aerosol or IV.

Melarsoprol – Organic arsenic.

Stibogluconate – Antimony compound.

Nifurtimox

Quinacrine – Giariasis.

Metronidazole – Trichomoniasis.

Toxoplasmosis: Organism resides in cat feces and is dangerous to the fetus during pregnancy (death, blindness, retardation); treat with pyrimethamine, trimethoprim, or a sulfa drug.

Antihelminthics – Nematodes (roundworms)

Piperazine citrate – Broad-spectrum effective against nematodes (ascariasis and pinworms); contraindicated in epileptics.

Thiabendazole – Treatment of trichinosis (undercooked pork)

Mebendazole – Anti-nematode.

Albendazole – Anti-nematode.

Pyrantel pamoate – Anti-nematode.

Antihelminthics – Trematodes (flukes)

Praziquantel – DOC; schistosomiasis; wonder drug; DO NOT use when ocular cysticerosis exists.

Antihelminthics – Cestodes (flatworms and tapeworms)

Niclosamide – Causes worms to relax their scolexes, thereby falling off the intestinal wall; does not kill tapeworm.

Paramomycin – Useful against tapeworms.

Penicillins

Chemistry: Penicillin contains a thiazolidine ring, a Beta-lactam ring, and a side chain. Amidase splits penicillin at the side chain linkage; the side chain is required for antibacterial activity. Penicillinase opens the beta-lactam ring to produce penicilloic acid.

Shortcomings of penicillin G:

1. Short half life (acid labile; weak acid that is both secreted and filtered; probenecid given to decrease secretion; procaine, a PABA derivative, added to delay absorption)

2. Acid instability (penicillin V contains an oxygen atom in the side chain that decreases acid lability);

3. Penicillin-resistant staphylococci (methicillin, oxacillin, cloxacillin, and naficillin are penicillinase-resistant)

4. Narrow spectrum (ampicillin and carbenicillin are broad spectrum).

Degradation products of penicillin: Penicillamine, a cysteine derivative, is a chelating agent used in the treatment of Wilson’s disease, as well as for removing mercury and lead from the body. Penicilloic acid serves as a hapten for antigens.

General toxicities: High therapeutic index; GI distress; neurological problems; hematuria; hemolytic anemia; carbenicillin is administered as a sodium salt, while penicillin G is administered as a potassium salt (caution in patients with electrolyte problems, cardiovascular, or renal disease).

Hypersensitivity reactions: 10-15%; can be immediate, accelerated, or delayed; often results from previous hidden exposure. Skin testing using the antigenic determinant, a penicilloyl derivative of lysine, is useful, but not 100% accurate.

Narrow spectrum penicillins: Penicillin G

Indications: G(+) organisms.

Pharmacokinetics: Approximately 3-5 times more penicillin G must be administered orally than parenterally. To assure maximum and prompt absorption, oral penicillin should be prescribed one hour before or two hours after a meal. Penicillin G poorly penetrates the BBB unless the meninges are inflamed. Excretion is via the kidneys and is blocked by probenecid.

Penicillinase-resistant penicillins: Methicillin, oxacillin, nafcillin, cloxacillin

Indications: G(+) penicillinase-producing organisms (S. aureus).

Pharmacokinetics: Excreted by kidneys; does not penetrate BBB well; methicillin deteriorates rapidly in solution; methicillin has high incidence of nephrotoxicity.

Resistance: Plasmid-mediated.

Broad spectrum penicillins: Ampicillin

Indications: DOC for L. monocytogenes; additional G(+) and G(-) coverage; NOT ACTIVE AGAINST PSEUDOMONAS OR KLEBSIELLA.

Pharmacokinetics: Renal and biliary excretion; high incidence of rash; GI disturbances are common.

Broad spectrum penicillins: Amoxicillin – better absorbed from the gut than ampicillin.

Broad spectrum penicillins: Carbenicillin

Indications: P. aeruginosa, Proteus, E. coli, Enterobacter. NOT ACTIVE AGAINST KLEBSIELLA. Less active than penicillin G against G(+).

Pharmacokinetics: Extra carboxylic acid  caution about salt content when used in large quantities.

Broad spectrum penicillins: Ticarcillin – 2-4 times more active against P. aeruginosa.

Broad spectrum penicillins: Azlocillin – 10 times more effective against P. aeruginosa.

Broad spectrum penicillins: Mezlocillin & Piperacillin – ACTIVE AGAINST KLEBSIELLA AND PSEUDOMONAS.

Murein cell wall synthesis in G(+):

1. Formation of UDP-N-acetyl muramic acid;

2. Formation of UDP-N-acetyl-muramyl pentapeptide;

3. Formation of linear peptide-polysaccharide;

4. Cross linking.

Stages 1&2 occur in the cytoplasm, while stages 3&4 occur in the periplasmic space. Racemase (inhibited by cycloserine) converts L-alanine to D-alanine.

Penicillin MOA: beta-lactam drug attaches to the specific penicillin binding proteins on the bacteria; cell wall synthesis is inhibited by blocking transpeptidation; autolytic enzymes are activated in the cell wall resulting in lesions and bacterial cell death.

Cephalosporins

Advantages: The greatest advantage of the cephalosporins are their relative resistance to staphylococcal penicillinase and somewhat broad antibacterial spectrum which includes P. mirabilis, E. coli, and Klebsiella (drugs of choice for Klebsiella).

MOA: Same as penicillins.

Characteristics: 1st generation do not penetrate CSF; 2nd-4th generation penetrate CSF; as you advance thru the generation you gain G(-) coverage and lose G(+) coverage.

First-generation cephalosporins: Higher nephrotoxicity than subsequent generations.

1. Cephalothin – Parenteral; agent of choice to treat staph infection (endocarditis)

2. Cefazolin – Parenteral; effective against E. coli and Klebsiella; surgical prophylaxis.

3. Cephalexin – Oral; acid-stable and well-absorbed.

4. Cefadroxil – Oral; UTIs.

Second-generation cephalosporins

1. Cefaclor – Oral; used for sinusitis and otitis media if allergic to amoxicillin.

2. Cefamandole – Parenteral; good G(+), G(-), and anaerobic coverage; adverse effect on vitamin-K dependent clotting.

3. Cefoxitin – Parenteral; good for anaerobes and mixed infections.

4. Cefuroxime – Parenteral; passes thru BBB and useful in treatment of meningitis.

Third-generation cephalosporins

1. Cefixime – Oral.

2. Cefoperazone & Moxolactam – Adverse effect on vitamin-K dependent clotting; “don’t use this one.”

3. Cefotaxime – Parenteral; good for multiple drug-resistant G(-) bacilli nosocomial infections.

Fourth-generation cephalosporins: Cefepime – Parenteral; excellent CSF penetration; active against G(+,-).

Adverse effects: Nephrotoxicity (1st generation); bleeding problems (2nd and 3rd generation) due to methylthiotetrazole; disulfiram-like reaction. Superinfection may also be a problem with broad-spectrum (3rd generation) cephs.

Hypersensitivity: Cephalosporins may demonstrate cross-allergenicity with the penicillins.

Summary: Cephalothin & cephaloridine (1st generation) are good against endocarditis but nephrotoxic. Cefamandole (2nd) and moxolactam and cefoperazone (3rd) have bleeding problems due to methylthiotetrazole side group.

Carbapenems

Imipenem – Broad spectrum of activity that includes Pseudomonas, Actineobacter, and anaerobes (B. fragilis); given with cilastin to prevent inactivation by renal dipeptidase.

Beta-Lactamase Inhibitors

Clavulanic acid, Sulbactam & Tazobactam – Suicide inhibitors of Beta-lactamases.

Clavulanic acid is used amoxicillin and is the treatment of choice for bite wound infections.

Piperacillin/tazobactam sodium, Ticaricillin/clavulanate potassium.

Monobactams

Aztreonam – Resistant to Beta-lactamase; useful only for G(-); can lead to superinfection.

Miscellaneous

Cycloserine – MOA is inhibition of racemase; used in combination treatment of tuberculosis.

Vancomycin –

• MOA inhibits cell wall synthesis by binding the D-alanyl-D-alanine dipeptide in cell walls and thus inhibits peptidoglycan synthesis by interfering with transfer of the peptide.
• Bactericidal.
  
• Limited to treatment of S. aureus infections that are resistant to less toxic agents as well as C. difficile infections.
  
• Toxicities are like the aminoglycosides and include ototoxicity, peripheral neuropathies, and injection irritation.

Polypeptides

General: All are nephrotoxic and parenteral administration is reserved for special, difficult clinical situations.

Bacitracin – MOA is inhibition of cell wall synthesis by inhibiting pyrophosphatase reaction. Use is limited to topical application for treatment of staph infections. Intrathecal or intrapleural instillation reserved for treatment of resistant-penicillin Staphylococcal meningitis or empyema. Toxicities include nephrotoxicity and eosinophilia.

Polymixin B sulfate – MOA is disruption of cell plasma membrane. Main used is topical against G(-) bacilli. Effective against a host of organisms but toxicity is severe (curare-like effect, nephrotoxicity, phlebitis).

Colistin sulfate – Same as polymixin.

Drug interactions

Carbenicillin-Gentamicin – Antagonistic effect.

Penicillin-Chlortetracycline – Theory says no, practice says okay.

Ampicillin-Oral contraceptive – Breakthrough bleeding and loss of contraceptive power.

Cefoperazone/Moxolactam/Cefamandole-Alcohol – Disulfiram-like reaction.

Quinolones – Nalidixic acid, Cinoxacin

Fluoroquinolones – Norfloxacin, Ciprofloxacin, Ofloaxacin, Levofloxacin

Mechanism of action: Inhibit DNA gyrase mediated supercoiling.

Contraindications: Pregnancy and young children due to cartilage problems; NOT USEFUL IN TREATING C. DIFFICILE.

Indications: UTIs (nalidixic acid and cinoxacin), general bacterial infections (norfloxacin), bone and soft tissue infections caused by staphylococci and gram(-) organisms (ciprofloxacin, ofloxacin, levofloxacin).

Urinary Antiseptics

Nitrofurantoin – Used for treatment of UTIs; contraindicated in severe renal insufficiency; vomiting is most common side effect.

Importance of folate: Biosynthesis of thymine and formylation of methionine-tRNA.

Structure-activity relationship of large molecule antifolates: Can make an isoteric replacement of an amino group for a hydroxyl group at C4. Leaving a hydrogen yields aminopterin while adding a methyl group yields methotrexate.

Structure-activity relationship of small molecule antifolates: Two amino groups for multiple substitutions (R1 and R2), which affect inhibitory properties. Relatively non-toxic compounds.

Mechanism of action: Inhibition of dihydrofolate reductase (pseudoirreversible).

Resistance: Genetic phenomenon leading to increased in dihydrofolate reductase.

Trimethoprim-sulfamethoxazole – TMP has a Vd of 100 L and its concentration in tissues exceeds that of plasma; the opposite is true of sulfamethoxazole; both agents are excreted in the urine in both free and metabolized form; SMX clearance is increased by high urine flow rate and urinary alkalization; TMP clearance is increased in acid urine; combined action is synergistic.

Indications: UTIs, prostatitis, otitis media, bronchitis, p. carinii, shigella, malaria & toxoplasmosis (given with pyrimethamine).

Structure-activity relationship: Acetylation or conjugation with glucuronic acid takes place in the N4 amine group with the resulting acetylation derivatives being inactive.

Mechanism of action: Sulfonamides are bacteriostatic, enhancing phagocytosis of susceptible organisms. Sulfonamides compete with PABA for incorporation into folic acid. Only organisms that endogenously synthesize folate are susceptible.

Resistance:

1. Decreased permeability of cell wall;

2. Decreased enzyme affinity for sulfonamide;

3. Increase in PABA production.

Importance of folate: Folate coenzymes specifically catalyze the transfer and utilization of single carbon moieties that are necessary in the biosynthesis of purines, thymine, and AA (serine, glycine, methionine, histidine).

Pharmacokinetics:

Peak level reached in 3-4 hrs; effect lasts for 3-4 days; absorbed from duodenum; orally administered; renal excretion rate varies; good penetration (CSF 50-80% of plasma level); acetylated derivatives are more highly bound and thus more difficult to excrete  can lead to crystalluria in kidneys; alkalinization of the urine promotes excretion.

Toxicity and side effects: Hypersensitivity with Steven-Johnson syndrome (long acting sulfamethoxypyridazine and sulfadimethoxine); hemolytic anemia in individuals deficient in G6PDH; agranulocytosis; hepatitis; nausea, vomiting, diarrhea; crystalluria; reduction in gut bacteria can lead to vitamin K deficiency.

Drug interactions:

1. Sulfonamides given to mothers during delivery can precipitate kernicterus in neonates due to displacement of bilirubin;

2. Hypoglycemia when given with tolbutamide;

3. Cotrimoxazole increases warfarin levels;

4. Sulfa drugs displace thiopental so anesthesia lasts longer;

5. Vitamin K deficiency-associated bleeding;

6. Increased half-lives of some anticonvulsants (phenytoin).

Spectrum: Gram(+), gram (-), some filterable agents, trachoma, Nocardia.

Indications: UTIs, nocardiosis (agent of choice), chlamydial infections, shigellosis (nonabsorbable sulfas), trachoma/inclusion conjunctivitis (with tetracyclines).

• Sulfadiazine – short-acting, liquid suspension available.
• Sulfisoxazole – short-acting
• Sulfamethylthiadazole – short-acting
• Sulfamethoxazole – intermediate-acting, more likely to cause crystalluria, liquid suspension available.
• Mafenide – topical, used for chronic burn lesions, alpha-amino-p-toluensulfonamide.
• Succinylsulfathiazole & Salicylazosulfapyridine – poorly-absorbed, used to decrease gut flora, prodrugs.

There are many drugs used to treat COPD. Cromolyn sodium is a mast cell membrane stabilizer, it prevents mast cells from dumping out histamines and mediators that cause many of the symptoms we see in COPD. It is NOT an antihistamine or bronchodilator.


The inhaled steroids are becoming the drug of choice in managing asthma because it is recognized that chronic asthma is an inflammatory condition of the bronchial tree. During an acute attack there are huge amounts of inflammatory cells in the lungs.


Theophyline is basically on its way out, it is a methyl xanthine derivative and has long been the mainstay first-line drug and is a bronchodilator. Because of toxicity and difficulty of titration and the necessity of measuring blood levels, theophyline is no longer the first-line drug of choice.


Ipatropium bromide is an atropine derivative. In many pts there is excessive cholinergic muscarinic activity in the bronchial tree, which cause bronchospasm and mucous secretion. If you can block the muscarinic receptor selectively, you have an effective drug. It is inhaled, and is more selective in the bronchial tree than oral ingestion of atropine.

There are many drugs used to treat COPD. Cromolyn sodium is a mast cell membrane stabilizer, it prevents mast cells from dumping out histamines and mediators that cause many of the symptoms we see in COPD. It is NOT an antihistamine or bronchodilator.


The inhaled steroids are becoming the drug of choice in managing asthma because it is recognized that chronic asthma is an inflammatory condition of the bronchial tree. During an acute attack there are huge amounts of inflammatory cells in the lungs.


Theophyline is basically on its way out, it is a methyl xanthine derivative and has long been the mainstay first-line drug and is a bronchodilator. Because of toxicity and difficulty of titration and the necessity of measuring blood levels, theophyline is no longer the first-line drug of choice.


Ipatropium bromide is an atropine derivative. In many pts there is excessive cholinergic muscarinic activity in the bronchial tree, which cause bronchospasm and mucous secretion. If you can block the muscarinic receptor selectively, you have an effective drug. It is inhaled, and is more selective in the bronchial tree than oral ingestion of atropine.