Interactions Between Drug and Host

Organ Toxicity

The accumulation of antimicrobial drugs and their metabolic byproducts in organs can be toxic, leading to organ damage.

Learning Objectives

Outline the two major types of organ toxicity and their effects, recognizing additional types of toxicity

Key Takeaways

Key Points

  • Antimicrobial drugs can have unintended side effects, including being toxic to organs.
  • The liver and kidney are particularly susceptible to organ toxicity as they are the sites of toxin filtration and toxin metabolic breakdown.
  • Almost any organ or tissue in the human body can be affected by antimicrobial toxicity.
  • The toxic effects of antimicrobial drugs, while potentially harmful are very rare.

Key Terms

  • antimicrobrial drugs: A drug administered to a patient, with the purpose of killing or slowing the growth of a microorganism, including protozoans, fungi and bacteria.
  • antibiotics: A chemical that slows the growth of, or kills a bacteria.

The use of antimicrobial drugs can have many unintended side-effects. The use, particularly when repeated, of many drugs can lead to an accumulation of a drug, or harmful byproducts from the metabolism of a drug, in tissues or organs. This accumulation of toxic chemicals can lead to organ damage, and in extreme cases, even organ failure and death. Two severe types of organ toxicity associated with antimicrobial drugs are nephrotoxicity and hepatotoxicity, toxicity of the kidneys and liver respectively.

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Methane: This space-filling model of methane shows the approximately spherical nature of this molecule.

The liver and kidneys are common organs affected by chemical toxicity. The kidneys are responsible for the filtration of the blood, so it is not surprising that deleterious agents in the blood may accumulate there. The liver is an important site for the breakdown of most metabolites in the body, and is referred to as the “metabolic clearing house” of the body. As drugs are quite often broken down in the liver, they can accumulate there and cause damage, or the byproducts of a drug’s metabolism can be toxic. In addition to direct damage to the liver by an antimicrobial drug, antimicrobial drugs can lead to the formation of dangerous toxins through the breakdown of microbes or due to interaction with other tissues in the body. These secondary toxins from drug metabolism then accumulate in the liver, potentially causing damage. Drug damage to the liver or kidneys can be particularly catastrophic as these organs are needed for the proper “cleaning” of the body. If they are compromised, this leads to further accumulation of potentially toxic metabolites further damaging organs in the body.

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Sun Poisoning: This rash seen on a forearm is a typical reaction observed when an antibiotic causes phototoxicity.

Some of the toxic effects can be more benign, as is the case with ototoxicity, or damage to the ear. Use of some antibiotics, such as gentamicin, can cause a lose of hearing, or tinnitus (“ringing in the ears”). Ototoxicity is usually temporary with antibiotics, but permanent hearing damage, while rare, has been reported. Some antibiotics such as Tetracycline can cause phototoxicity, also known as sun poisoning; the result of which is that very short exposures to direct sunlight can cause severe skin irritation, with the appearance being quite similar to a rash or sunburn. The Tetracycline in a patient’s skin becomes toxic when exposed to sunlight, which causes an allergic reaction and leads to rash on the affected area. Broad-spectrum antibiotics in the family of fluoroquinolones can cause neurotoxicity by directly damaging neuronal receptors. This can lead to any number of psychological effects from mild cognitive dysfunction (brain fog) to more severe effects, such as hallucinations and suicidal thoughts.

While a few specific examples have been outlined here, toxic effects are not limited to the organs mentioned. In fact, almost any tissue or organ can be affected by antimicrobial drugs. However, it should be noted that the side-effects due to broad-spectrum antibiotics are actually quite rare, with organ damage being even more rare.The potential side-effects of antibiotics or other antimicrobial drugs are offset by the benefits of combating the microbial infection.

Allergic Responses to Drugs

Antimicrobrial drugs can cause immune responses which can be fatal.

Learning Objectives

Explain the physiology of an immune response responsible for an allergic reaction to drugs

Key Takeaways

Key Points

  • Antimicrobial drugs, can like almost any other substance, act as an allergen.
  • Using a drug may not induce an allergic response the first time it is taken, however, subsequent use of the antimicrobial drugs may lead to allergic reactions.
  • The most common antimicrobial drug allergy is penicillin. 1-5% of people who have taken it have suspected penicillin allergies.

Key Terms

  • allergen: A substance, known as an antigen, which stimulates an immune response from a sensitive individual.
  • anaphylaxis: A rapid and severe allergic reaction which can lead to death
  • Beta-lactam antibiotics: A broad class of antibiotics of which penicillin is a member.
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sp3 hybridization: In the process of sp3 hybridization in methane, the single 2s and three 2p orbitals of carbon mix into four sp3 hybrid orbitals, which are chemically and geometrically identical. Bond angles are 109.5°.

Virtually any substance, when exposed internally or externally to the body, can act as an allergen and illicit an immune system response, such is the case with antimicrobial drugs. While the drug acts as an allergen, the drug itself is not causing direct damage to the individual, but rather it is the response of an individual’s immune system which is deleterious. An allergic reaction is the body’s response to clear a foreign substance. Once the body recognizes a substance as foreign (in this case an antimicrobial drug), it starts producing antibodies, specifically immunoglobulin E (IgE) against the drug. The IgE binds directly to the drug and sets off a cascade of events, including the activation of receptors on immune system cells. This results in the production of histamines. The worst allergic reactions can be very severe and result in anaphylaxis. Anaphylaxis is an extremely severe allergic reaction caused when histamines are overproduced leading to severe contraction of bronchial muscles. In the most extreme cases, the airways close, which can lead to death. Other less severe symptoms of an allergic reaction can include, hives, angioedema (tissue swelling under the skin, often on the face), tight throat, coughing, wheezing, or watery eyes.

The exposure to a drug may not elicit an allergic reaction during the first exposure, but after the first exposure, the body creates antibodies and memory lymphocyte cells against the drug, therefore later exposures to the drug will illicit an immune response. There are many factors that can determine if an individual is sensitive to an antimicrobial drug, as with other allergens. Some factors include genetics and past exposures to other allergens, typically a person who has allergies to other things, such as various foods, is more prone to have or develop drug allergies. The most reported drug allergy is to Beta-lactam antibiotics, of which penicillin is the most well-known type, affecting 1-5% of people who take penicillin. While the most severe cases can result in anaphylaxis, most reactions are not severe. Additionally the allergic reaction may not even be due to the penicillin, as dyes and other chemicals added to antimicrobial drugs may in fact cause the allergic response instead. Taken together, recent studies show that perhaps only 1/5 people who suspect they have an allergy to penicillin do indeed have such an allergy.

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Anaphylaxis: A representation of the signs and symptoms of anaphylaxis that result from an allergic reaction. Signs include CNS symptoms such as confusion or lightheadedness, respiratory symptoms such as shortness of breath, gastrointestinal issues such as pain or vomiting, skin issues such as hives or itchiness, vascular symptoms such as change in heart rate or low blood pressure, and swelling of the mouth or eyes.

Suppression and Alteration of Microbiota by Antimicrobials

Our bodies depend upon, and host, a vast number of complex microbial flora that can be affected negatively by antimicrobial treatments.

Learning Objectives

Describe the role and function of the microbiota

Key Takeaways

Key Points

  • The intestinal system has many different species of microbes and huge numbers of individual microbes; we rely on these microbes for proper metabolism of food.
  • The use of antimicrobial agents to slow down or kill pathogenic microbes can often kill beneficial bacteria, causing deleterious health effects.
  • Our body hosts some microbes that inhibit the growth of pathogenic microbes; using antimicrobial agents can alter the flora allowing pathogenic microbes to overgrow and cause diseases.

Key Terms

  • Candidal vulvovaginitis: Candidal vulvovaginitis or vaginal thrush, or yeast infection, is an infection of the vagina’s mucous membranes by Candida albicans.
  • microbiota: The microbial flora harbored by normal, healthy individuals.
  • pathogenic bacteria: Bacteria which infect and cause deleterious health effects.

The human body hosts thousands of different species of microbial organisms, known as the microbial flora or microbiota. Microbiota serve many functions in our body; most notable is the gut flora, crucial for the proper digestion of food, carbohydrate fermentation, and nutrient absorption. The gut flora in the human intestinal system has hundreds of species of microbes and over 100 trillion individual microbes; in comparison, the human body has around 10 trillion cells. Most of these microbes are bacterial and fungal. This is especially a problem when broad-spectrum antimicrobial agents are used, as antimicrobial treatments while helping to clear up pathogenic microbes from the body will often kill symbiotic bacteria. In addition, some microbial infections are due to translocation, the movement of advantageous bacteria to parts of the body where they might be harmful. An example is gut flora getting into the body’s blood stream. The treatment of translocated or pathogenic bacteria may necessitate the use of antibiotics that will kill symbiotic bacteria. Antimicrobial agents which can kill beneficial gut flora can reduce the numbers of individual microbes or reduce the species of beneficial bacteria. In the case of the gut flora, this may impair the ability of a patient to properly metabolize food. If advantageous bacteria do not repopulate the intestine, this can lead to serious malnutrition problems.

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Gut bacteria: This is an electron micrograph, at 10,000X magnification. The oblong structures are Escherichia coli (E. coli), a symbiotic bacteria found in the human intestinal system.

In addition to serving a necessary function as gut flora due in metabolism of food, some microbiota in our bodies serve the function of keeping pathogenic microbes from inhabiting or dominating other flora at locations in our body. This is exemplified by Candida albicans, a yeast which is often found on humans. C. albicans is normally harmless, but when women take some antibiotics this can kill beneficial bacteria, specifically lactobacilli, in the vulvo-vaginal area. Without lactobacilli, C. albicans growth is not suppressed and can thus overgrow. This causes candidal vulvovaginitis, or yeast infections, a potentially painful infection of the vaginal mucous membranes by overgrown C. albicans. Yeast infections can be caused by antibiotics, as well as using aggressive topical cleaning agents such as detergents which again kill off beneficial lactobacilli allowing C. albicans to overgrow.

Fortunately there are antimicrobial agents that specifically target pathogenic bacterial species, which opposed to broad-spectrum treatments can reduce harmful effects on beneficial microbes. Sometimes the use of broad-spectrum antimicrobial agents is unavoidable; in these situations, consuming foods such as yogurt which contains beneficial bacteria can replenish the body’s symbiotic microbes. In extreme cases microbes can be transplanted from a healthy individual to someone with whose symbiotic microbes have been compromised.

Effects of Drug Combinations

Antimicrobial drugs can interact with other drugs in deleterious ways or can be used in combination to combat microbial infections.

Learning Objectives

Give examples of interactions that can render an antimicrobial ineffective

Key Takeaways

Key Points

  • The interaction between one antimicrobial agent and another is very complex, along with the way they target microbes and the organism.
  • While it is not certain that a drug may interact with antibiotics, it is considered wise to err on the side that there are potentially unknown and harmful interactions from mixing drugs.
  • The use of more than one antimicrobial agent is an effective and widely used practice to reduce the chance that microbes will resist a treatment.

Key Terms

  • contraindication: In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.
  • tuberculosis: An infectious disease of humans and animals caused by a species of mycobacterium mainly infecting the lungs where it causes tubercles characterized by the expectoration of mucus and sputum, fever, weight loss, and chest pain, and transmitted through inhalation or ingestion of bacteria.
  • combination therapy: Combination therapy is the use of more than one medication or other therapy. Most often, these terms refer to the simultaneous administration of two or more medications to treat a single disease.

Pharmacodynamics is the field that attempts to understand the unintended effects of the use of two or more drugs. Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body. It also looks at the mechanisms of drug action and the relationship between drug concentration and effect. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that, in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones.

Two well described interactions between antimicrobial drugs and other drugs are between antibiotics and alcohol and antibiotics and the birth control pill. Interactions between alcohol and certain antibacterials may occur, cause side-effects, and decrease effectiveness of antibacterial therapy. Potential risks of side-effects and effectiveness depend on the type of antibacterial administered. Despite the lack of a categorical contraindication, the belief that alcohol and antibacterials should never be mixed is widespread. Some antibacterials may inhibit the breakdown of alcohol, which may result in alcohol-induced vomiting, nausea, and shortness of breath. Other effects of alcohol on antibacterial activity include altered activity of the liver enzymes that break down the antibacterial compound. In addition, serum levels bacteriostatic antibacterials may be reduced by alcohol consumption, resulting in reduced efficacy and diminished pharmacotherapeutic effect.

Another well studied interaction is between antibiotics and the contraceptive pill. The majority of studies indicate that antibiotics do not interfere with contraceptive pills. In cases where antibacterials have been suggested to affect the efficiency of birth control pills may be due to an increase in the activities of hepatic liver enzymes causing increased breakdown of the pill’s active ingredients. Effects on the intestinal flora, which might result in reduced absorption of estrogens in the colon, have also been suggested, but such suggestions have been inconclusive and controversial. Clinicians have recommended that extra contraceptive measures be applied during therapies using antibacterials that are suspected to interact with oral contraceptives.

Additionally, when dealing with a microbial infection, sometimes the use of two or more antibiotics can effectively combat the infection while each drug individually has little or no effect. This method is called combination therapy and is used when the nature of a microbial infection is unknown, as typified by the combination of the antibiotics ampicillin and sulbactam. The use of two antibiotics with different modes of microbial inhibition increases the chance that the treatment will combat the microbial infection. Further, tuberculosis has been treated with combination therapy for over fifty years. This is due to the phenomenon of resistance, whereby a micro-organism gains the ability to resist an antimicrobial drug, while initially the drug effectively slowed the growth of or even killed the target micro-organism. Treating tuberculosis, or other pathogenic microbes with more than one antibiotic reduces the chance that the microbe will adapt and survive the treatment, especially if the two drugs have different methods of reducing the microbe’s normal functions.

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Tuberculosis: This x-ray of a tuberculosis patient shows the lung on the left side completely infected and the right lung partially infected (the dark areas), with tuberculosis.