-This therapy takes advantage of differences between bacteria and human cells to kill them with a selective toxicity at therapeutic concentrations. This selective toxicity is relative though, and high concentrations can produce autotoxicity.

-To pick an antibiotic, you need to keep in mind: 1. The infecting organism, 2. the susceptibility to drugs, 3. the site of infection, 4. patient factors, 5. safety of the drug, and 6. cost.

1. Gram staining (rapid, morphological features of microorganisms), bacterial culture (conclusive and susceptibility determination), and other identifying protocol (antigens, DNA/RNA detection, immune response detection) to determine what we’re dealing with.

   1. Before identification, empiric therapy is administered. It’s usually a antibiotic that treats a wide variety of infections. It’s usually after sampling the patient, but will be administered immediately for the critically ill. Empiric therapy is very short.

2. Some organisms have predictable susceptibility (streptococcus pyogenes and Neisseria meningitides) and treatment can begin quickly. Some are not, and further testing is needed.

   1. Bacteriostatic drugs stop bacteria proliferation. They buy the immune system time to take care of the pathogens. They cannot be stopped prematurely

   2. Bactericidal drugs kill bacterial cells, and are used for the immunocompromised and the seriously ill.

   3. Minimum Inhibitory Concentration (MIC): The lowest concentration of a drug that prevents visible bacterial growth after 24 hours of incubation. This is a measure of susceptibility.

   4. Minimum Bactericidal Concentration (MBC): The lowest concentration that causes 99.99% decline in colony count after overnight dilution incubation. It takes time and labor, and therefore isn’t usually used clinically.

3. Antibiotics need to reach the infection site in effective concentrations. Natural barriers (prostate, testes, placenta and the CNS) stop drug from teaching the site.

   1. This is based on drug lipid solubility, drug molecular weight, and protein binding.

      1. Lipid soluble means it can pass the Blood Brain Barrier

      2. Prominent protein binding means they are hesitant to leave the blood, and don’t penetrate the BBB well.

4. Patient Factors

   1. Lifestyle and immune system status.

   2. Poor renal function can cause issues with eliminating drug

   3. Poor hepatic function can cause blood/tissue toxicity

   4. Poor perfusion causes issues with the antibiotic reaching regions of the body, and possibly to the site of infection

   5. Very young and very old patients cannot excrete antibiotics as optimally as healthy patients.

   6. Pregnancy makes most drugs unusable. They are detrimental or teratogenic.

   7. To prevent “super bugs,” consider immune system status and prior therapy or hospitalization.

5. Safety

   1. Penicillin is the least toxic. Other drugs are less selective, and can be toxic.

6. Cost

   1. Some drugs can be similarly effective, but vary in cost.

Route of Administration

-Oral route is preferred. It’s economical and easy. This is nuanced to each drug though

-Parental route is for drugs that aren’t absorbed well in the GI tract. It’s also used for patients with serious infections, and for those that need high serum concentrations of the drug.

Antibiotic Dosing

1. Concentration dependent killing (drugs)

   1. Bacterial death rate rises as concentration does.

2. Time dependent killing (drugs)

   1. These don’t exhibit the above relationship. Rather, the concentration needs to stay above a therapeutic level.

   2. Examples: glycopeptides, macrolides, clindamycin, and linezolid. Also Beta-lactams.

3. Post Antibiotic Effects (PAE)

   1. Persistent depression of microbial growth after therapeutic concentrations fall off.

   2. Antibiotics with a long PAE can be dosed once daily.

Chemotherapeutic Spectra

1. Narrow-spectrum antibiotics

   1. Some drugs only act on a single or small group of bacteria types. Isoniazid only works on Mycobacterium tuberculosis, for example.

2. Extended-Spectrum antibiotics

   1. Effective against gram positive bacteria and a lot of gram negative bacteria. Ampicillin is a good example.

3. Broad-Spectrum antibiotics

   1. Attack nearly everything

   2. Examples include tetracyclines, fluoroquinolones and carbapenems

   3. *These will mess with normal flora in the body cavities. This creates the perfect scenario for superinfections from bacteria like Clostridium difficile (C. difficile) which is normally kept in check by normal flora.

Combination Therapy

-Typically, we don’t. With just one agent at a time, we minimize toxicity, reduce resistance emergence, and reduces chance of a superinfection.

1. Advantages to drug combination

   1. Synergism. Some antibiotics show a incredible additive response against infections when used together.

   2. Infections with unknown origin can be dealt with.

   3. Microorganisms with variable sensitivity can be treated (2-3 antibiotics are sued to treat tuberculosis).

   4. Treatment of enterococcal endocarditis

2. Disadvantages to drug combination

   1. Selection pressure creates resistant infections

   2. Drug interactions can cause issues

   3. Toxicities can stack onto each other

   4. Wasted potential. Some antibiotics can only act when microbes are replicating (bacteriostatic drugs can make other drugs useless)

Mechanisms of Resistance

-When the maximum tolerated dose cannot control bacterial growth, that bacteria is resistant.

-Some microorganisms are inherently resistant to things. Most gram-negative microorganisms and inherently resistant to vancomycin

1. Bacteria develop resistance via

   1. Spontaneous mutations and acquired resistance (moving plasmids)

   2. Pressure Selection (natural selection)

   3. Altered expression of proteins in drug resistant organisms (ALL Antibiotics)

      1. Bacteria can modify their target sites for drugs, making them useless

      2. Bacteria can decrease accumulation of drugs within them by blocking entry via porins, or pumping drug out

      3. Bacteria can destroy or inactivate antibiotics. There are three of these:

         1. Beta-lactamases

         2. Acetyltransferases

         3. Esterase’s

Prophylactic Use

-Antibiotics are helpful to use during surgery and dental work. Used carefully to prevent super infections and resistance

Complications

-Hypersensitivity; imagine an allergic reaction

-Direct toxicity; aminoglycosides can cause ototoxicity, for example

-Superinfections; opportunistic bacteria take advantage of changes to microbial flora.

DRUGS

1. Cell Wall Inhibitors

   1. Interferes with the synthesis of the cell wall, which is made of peptidoglycan polymers linked together with cross links. This drug class requires active division of the bacterial cells to work. The members are Beta-Lactams, Vancomycin and Daptomycin

      1. Penicillin’s

         1. Widely effective with minimal toxicity, but resistance has built up in most microorganism, making it less useful.

         2. Break the cross links to create cell lysis. They also inhibit transpeptidase and autolysins, creating issues with remaking the cell wall and original wall integrity.

         3. It is a time dependent bactericidal agent, that only works on cells with a peptidoglycan cell wall

         4. Penicillin’s are classified by spectrum

            1. Natural Penicillin’s—Penicillin G and Penicillin V

            2. Antistaphylococcal penicillin’s

               1. Very important

            3. Extended-spectrum penicillin’s—Ampicillin and Amoxicillin

            4. Antipseudomonal penicillin’s—Piperacillin and Ticarcillin

               1. Drugs that target pseudomonas are incredibly important. also works against gram-negative bacteria

         5. Resistance

            1. Gram positive bacteria are incredibly susceptible, but gram negative bacteria are resistant

            2. Resistance happens via B-lactamases (primary resistance method), decreases permeability (Klebsiella pneumoniae is notorious for this), and altered PBP’s

         6. Complications

            1. Neurotoxicity, Diarrhea

      2. Cephalosporins

         1. Penicillin, but more resistant to B-lactamases

         2. First Gen

         3. Second Gen

            1. Cefotetan and Cefoxitin cover Bacteroides fragilis

         4. Third Gen

         5. Fourth Gen

         6. Advanced Gen

            1. Ceftaroline convers MRSA

         7. Resistance is same as penicillin

         8. Complications

            1. MUST be delivered parentally

            2. Poor CNS penetration

            3. Adverse reactions same as penicillin

      3. Carbapenems

         1. Imipenem! With cilastin, to prevent toxic metabolites

         2. Resistant to B-lactamases, excellent CSF penetration

         3. TREATS P. aeruginosa

         4. Complications

            1. Eliminated renally and toxically, so needs to taken with cilastatin

            2. NVD

      4. Monobactams

         1. Aztreonam is the only approved member and targets pseudomonas

         2. Used when patient is allergic to other B-lactam antibiotics

      5. B-lactamase inhibitors

         1. Used with B-lactam’s to prevent their degradation and allow effective antibacterial activity.

         2. Combined with amoxicillin increases the effect

      6. Vancomycin

         1. Binds to peptidoglycan precursors with a bactericidal activity

         2. Treats MRSA and used typically in life-threatening situations. Sterilizes the colon to maintain condition for surgery.

         3. Not absorbed orally, and so easily treats C. difficile

         4. We are restricting it’s use to prevent resistance

      7. Daptomycin

         1. Bactericidal, concentration dependent and works as an alternative to other agents. Kills resistant, gram-positive organisms. CANNOT be used for lung infections

      8. Lipoglycopeptides

         1. Telavancin. Performs like vancomycin. An alternative to other cell wall inhibitors.

         2. Last choice because of significan adverse effects

      9. Fosfomycin

         1. Used to treat UTI caused by E. coli and E. faecalis

         2. Minimal cross resistance

         3. Distributes well, and orally infected.

      10. Polymixins

          1. Detergent-like function, destroying cell membranes.

          2. Concentration dependent, bacteriacidal

          3. Polymyxin B ad Colistin (polymyxin E

          4. VERY nephrotoxic and neurotoxic