Intro to Antimicrobial Therapy

This is one of those rare instances in pharmacology where we are actually curing the issue.

We can cure most bacterial infections.  We can cure most fungal infections. But in regards to viral infections, here’s the blanket statement: If our body cannot clear a viral infection, we cannot cure it.  Our body can’t clear HIV and many of the hepatitis viral infections, so they can’t be cured using drugs.  Maybe we can control it, but we can’t cure it.  On the other hand, if our body is capable of clearing a virus, such as influenza, we have drugs that hasten the recovery of it.

An antimicrobial is a chemical substance which is capable, in low and safe concentrations, of inhibiting the growth or killing of microorganisms.

If it isn’t in a safe concentration, then it isn’t safe for our body. Mold, a fungus, is capable of producing penicillins that kill other micro-organisms. This is how we discovered penicillin. We found a zone of inhibition around the mold and made a medication out of it.  There’s many different types of penicillin’s and they all end in -cillin.  They all have the same penicillin backbone structure. What makes them different is what’s on the side-chains. The manufacturers have taken the backbone and modified the side chains.

Therapeutically the importance of changing these side chains is that it changes the spectrum. We could go from narrow spectrum all the way to extended spectrum eventually so it can kill other organisms. The other thing it changes are the pharmacokinetics (half-life). Instead of a 6 hour half life, another penicillin may be 12 hour so it may be dosed less frequently.

Broad Spectrum

Broad spectrum: A broad spectrum antimicrobial kills or inhibits the growth of many different organisms including infecting and non-infecting organisms, which means it also kills some of our natural flora.

We have natural flora anywhere from our mouth to our rectum (our alimentary tract). Even our skin has hundreds of microorganisms. In females, the vaginal tract has microorganisms as well.  Disturbing our natural flora can lead to a super-infection where yeast/fungus can take over in the intestinal tract or vaginal tract. These harmful organisms are naturally always in our body, but the other bacteria keep them at bay. When a broad spectrum antibiotic kills the bacteria that normally keep the fungus at bay, then we need another antibiotic that kills the fungus.

Pseudomembraneous Colitis is caused by Clostridium difficile (“C. diff”) and can go out of control when the normal flora is altered.  Toxins are produced by the bacteria that invade the intestinal lining and the intestines inflame and it could potentially be fatal. It is often a consequence of using broad spectrum antibiotics.

Why do we use broad-spectrum antibiotics if they may cause a superinfection?

The answer is several-fold. The organism we are working with may be unidentified. It may take 2-3 days until we find out for sure what organism we are dealing with and what the sensitivity of that organism is. If we don’t know what we’re dealing with, we’re going to treat for a whole range of organisms in the mean time. When we get the results, hopefully we can switch to a narrower spectrum drug.

The infection may also be a mixed infection, meaning there may be multiple organisms involved in the infection and it would make sense to use a broad spectrum antibiotic in this case.

We may also have no other alternatives.  If the Culture & Sensitivity results come back saying that no narrow spectrum antibiotics work on this particular organism, then our only choice is the broad spectrum.

Recap for broad spectrum:

• Kills or inhibits the growth of many different organisms including infecting and non-infecting organisms
• Alters natural flora – can lead to super-infection and pseudomembranous colitis
• Uses: Unidentified organism, mixed infections, no other alternatives

Narrow Spectrum

Narrow spectrum antibiotics inhibit the growth or kill a limited number of different organisms.  There’s less potential of killing natural flora with these and less risk of a super infection with the narrow spectrum antibiotics.

Example of narrow spectrum antibiotics:

• Penicillinase Resistant Antibiotics
  • Dicloxacillin (Dynapen) – p.o.
  • Methicillin (Staphcillin) – inj
  • Nafcillin (Unipen) – p.o., inj
  • Oxacillin (Bactocil, Prostaphlin) – p.o., inj

The above are quite specific for S. aureus infections.  You won’t see a super infection from these. You’d see it utilized specifically for staph infections. Staph exists on the skin and intestinal tract. The big problem with this penicillin class is that the bacteria are resistant to them already.  This is what we call MRSA, which stands for Methicillin Resistant Staphylococcus Aureus.  This bacteria is not only resistant to Methicillin but the entire class of Penicillinase resistant drugs.

Recap:

• Inhibits the growth or kills a limited number of different organisms
• Less potential for super-infections

Bacteriocidal

At safe serum levels, bacteriocidals kill the sensitive organisms.  These are especially effective in immuno-compromised individuals who don’t have an immune system to fight them.

Bacteriostatic

At safe serum levels, bacteriostatics inhibit the growth of sensitive micro-organisms. They don’t kill them. They prevent them from flourishing so the infection doesn’t get worse. Our body’s immune system kills off the micro-organisms. This won’t work in individuals who are immuno-compromised.  Certain diseases (HIV, Cancer) could make a person immuno-compromised. Certain drugs, such as the corticosteroids decrease the bodies immune response and pose a problem as well.

• Allows the body’s immune system to kill the micro-organisms
• Ineffective in immuno-compromised individuals

Mechanism of Action

In order to kill the organism, the organism must be growing, replicating or doing something like making proteins. If the organism is dormant, we can’t kill it. If the organism replicates extremely slowly, we can’t do much either.  Antibiotics work in numerous ways: Interrupt cell wall synthesis, protein synthesis or vitamin utilization.

• Only effective in replicating organisms
• Interrupts cell wall synthesis, protein synthesis, vitamin utilization

Resistance

This is one of our biggest problems in health care today. We’re going to break this down into inherent resistance and acquired resistance.

Inherent resistance is where the organism has never been sensitive to a particular antimicrobial agent.  This is not our problem. The problem is acquired resistant. Acquired resistance is when an organism had previously been sensitive but has acquired an insensitivity.  This is associated with over use of antimicrobials.

For example, MRSA. We were able to use penicillins to treat S. aureus but now we can’t. Penicillin used to be an easy therapy for Gonorrhea and now it’s ineffective. Even our backups don’t work. This has happened due to the over use of antimicrobial agents.

How Resistance Became Prevalent

S. aureas is part of the normal flora of our skin.  Let’s say for every 100 S. aureus cells, there was one that was mutated and resistant to antibiotics on our skin.  This mutated organism never got out of hand though because it was kept in control by all its brothers and sisters. Now let’s say the person was admitted into the hospital and was put on antimicrobial therapy. It killed all the brothers and sisters and didn’t kill the mutated organism. Then the mutated organism said, “It’s party time!” and started to replicate.  Because not everyone washes or purell’s their hands, it spreads to all the other units until the whole hospital has it lurking around.  Since the world is a global village, it didn’t take long for this to become a world wide problem. The more antibiotics we use, the more we’re going to go through this scenario.

Unfortunately the worst place to be when you’re sick, is in a hospital because if you get an infection while in the hospital, it’s most likely going to be an acquired-resistant organism.  This is called a nosocomial infection. If you gain an infection in a hospital, it’s very likely going to be a very bad organism.

Most surgeries are clean surgeries, meaning you’re not going in the intestinal tract. You’re going into cavities of the body that don’t have microbes in the first place. Regardless, most physicians will say during the surgery we need antibiotics, after surgery we need antibiotics, and when the patient goes home we need antibiotics. Warning letters keep coming out from the FDA to stop this practice.

Is there hope? There was a study in the 70’s. The only antibiotic we had back then were the cephalosporins. It became known as the non-thinking antibiotic. The patient has an infection? Just prescribe this without thinking.  At the VA hospital (in Los Angeles), there was resistance like crazy. The FDA took a bold move and said anytime you think you’re going to order a cephalosporin, you’re going to have to be consulted by a infectious disease doctor, much to the doctors dismay. As a result, the use of the antibiotic decreased. Six months later, after the restriction was put in place, there was a drop in resistance. So there may be hope.

We also do other crazy things. Soap is supposed to clean us but even our soap is antimicrobial. The feed in our animals even has antibiotics. and it goes up the food chain.

Recap

• Inherent – organism never has been sensitive to a particular antimicrobial agent
• Acquired – organism had previously been sensitive but has acquired an insensitivity
• Associated with over use of antimicrobial agents

Antimicrobial Selection

First, we have to isolate where the organism is coming from. If the person has meningitis, a bacterial infection of the membranes covering the brain and spinal cord (meninges), the antibiotic has to cross the blood brain barrier. If a person has a UTI, how does the body need to eliminate that antimicrobial agent? Through the kidneys and urine. If the body eliminates the antibiotic through the liver, that antibiotic is useless for the patient with a UTI.

Next, we have to select the most narrow spectrum agent possible so we don’t have a super infection such as pseudomembraneous colitis (“C. diff”).

If the person is allergic to any of the -cillin’s, then they are allergic to all of the -cillins.

Cost is also an issue.  Doctors tend to get bombarded and encouraged to use brand names by manufacturers. Fortunately today, usually the older, less expensive generics do the job just fine unless we are dealing with resistance.

In immuno-compromised patients (chemotherapy patients, etc), we must use synergistic combinations.

Recap

• Identify organism and its sensitivity
• Identify source of infection
• Select the most narrow spectrum agent possible
• Avoid hypersensitivity
• Cost
• Use synergistic combination in immuno-compromised patients

Causes of Antimicrobial Failure

Antimicrobial therapy fails cause sometimes we are treating a symptom and not an infection.  For example, a person may have a fever but a fever doesn’t always mean there’s an infection.  A fever may exist in other chronic disease states so an antimicrobial won’t do anything in this case.

• Fever not due to infection
• Improper dose
• Improper selection of antimicrobial (maybe due to resistance or wrong site of action)
• Improper duration of therapy
  • This is usually the patients fault (they stop taking the antibiotic prematurely once they feel better and the infection comes back with resistance)
• Failure to utilize ancillary measures
  • Sometimes we have to do incision and drainage because antibiotics can’t get to areas filled with puss.  If a person has a skin infection and the puss fills under the skin and we have these boils, an antibiotic can’t get there.  We have to cut open and drain the area so the antibiotic could work.

Patient Variables

• Genetics: metabolism of antimicrobial agents. Different people, based on genetic makeup, metabolize antibiotics differently. Some metabolize it faster than others so we have to adjust the dose.
• Allergies / cross allergies. If they’re allergic to one, they’re allergic to all. If you’re allergic to penicillin, there’s a 10% chance you’re allergic to cephalosporins.
• Age: You can’t prescribe quinolones or tetracyclines in children.
  • Quinolones affect tendons in children (also in some adults too).
  • Tetracyclines are not used in children due to adverse reactions of teeth mottling and effect on bone growth. Otherwise their teeth will grow deformed and stained and that’s a permanent problem.