Antibiotics are common agents used in modern healthcare. This was not always the case. From ancient times, people sought ways to treat those who were afflicted with infections. Dyes, molds, and even heavy metals were thought to hold promise for healing.[1] Various microorganisms hold medical significance, including bacteria, viruses, fungi, and parasites. Antibiotics are compounds that target bacteria and thus, are intended to treat and prevent bacterial infections.

Classification

The pharmacology behind antibiotics includes destroying the bacterial cell by either preventing cell reproduction or changing a necessary cellular function or process within the cell. Antimicrobial agents are classically grouped into 2 main categories based on their in vitro effect on bacteria: bactericidal and bacteriostatic. Common teaching often explains that bactericidal antibiotics "kill" bacteria and bacteriostatic antibiotics "prevent growth" of bacteria. The true definition is not so simple. To accurately define each category, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) must be understood. The lowest concentration that inhibits visible bacterial growth at 24 hours is the MIC.[2] The MBC is the concentration of an antibiotic that reduces bacterial density by 1000-fold at 24 hours.[2] Bacteriostatic activity is further defined by an MBC to MIC ratio greater than 4; whereas, an MBC to MIC ratio less than or equal to 4 is bactericidal.[2] The clinical implications of antibiotic efficacy depend heavily on many factors not limited to: pharmacokinetic and pharmacodynamic principles, the particular bacteria, bacterial load, and site of infection. This is further complicated by the ability of some bacteriostatic antibiotics to exhibit bactericidal activity against particular bacteria.[3] Therefore, bacteriostatic antibiotics also kill bacteria, but the laboratory definition makes it seem as if they do not. For example, a bacteriostatic antibiotic such as linezolid can be bactericidal against Streptococcus pneumoniae.[3] This concept works in reverse, and bactericidal antimicrobials may also be bacteriostatic against certain bacterial strains and conditions. Conflicting data exist as to whether the necessity for bactericidal antibiotics is needed for severely ill or immunosuppressed patients.[3]

Types Antimicrobial Agents[3]  

Drug Class and Specific Antibiotics

Bacteriostatic

• Glycylcyclines: Tigecycline
• Tetracyclines: Doxycycline, minocycline
• Lincosamides: Clindamycin
• Macrolides: Azithromycin, clarithromycin, erythromycin
• Oxazolidinones: Linezolid
• Sulfonamides: Sulfamethoxazole

Bactericidal

• Aminoglycosides: Tobramycin, gentamicin, amikacin
• Beta-lactams (penicillins, cephalosporins, carbapenems): Amoxicillin, cefazolin, meropenem
• Fluoroquinolones: Ciprofloxacin, levofloxacin, moxifloxacin
• Glycopeptides: Vancomycin
• Cyclic Lipopeptides: Daptomycin
• Nitroimidazoles: Metronidazole

Pharmacokinetics and Pharmacodynamics

Pharmacokinetic (PK) and pharmacodynamic (PD) parameters are used together to maximize the efficacy of antimicrobial therapy through optimization of dosing in patients. Absorption, distribution, metabolism, and excretion are the PK components that affect the antibiotic concentration over time.[4] These processes describe how an antibiotic moves through the body from the time it enters the body until the parent drug or metabolites are removed. PD of an antibiotic describes the drug effect within the body when it reaches the infection target. The main principles that guide PD are the percent of the time the free drug is over the MIC, the amount of free drug area under the concentration to MIC, and maximum concentration to MIC.[5] Bactericidal activity is either concentration-dependent or time-dependent. If an antibiotic displays concentration-dependent killing, for example, fluoroquinolones or daptomycin, the efficacy of bacterial killing increases as the concentration of the antibiotic increases.[6] Penicillins and tetracyclines are time-dependent; therefore, the duration of the effective concentration of these antibiotics determines bactericidal activity.[6]

After an antibiotic is absorbed, the distribution influences the extent of antimicrobial activity. The total amount of drug in the body to serum concentration is the volume of distribution.[5] The level of protein binding will affect the availability of active drug at the site of infection. If an antibiotic is highly protein bound, there will be less free drug available for an antimicrobial effect as seen in patients with hypoalbuminemia.[5] Increased adipose tissue in a patient will increase the volume of distribution if a drug has high lipophilicity properties.[7]

The location of infection is very important to note because some antibiotics are inappropriate to treat certain infections. In the treatment of meningitis, for example, the penetration of the blood-brain-barrier is critical if one wants to achieve therapeutic antibiotic levels at the infection site to prevent treatment failure.[5]

Complications

Adverse Reactions

All medications have the potential for an adverse reaction and antibiotics are no exception. One of 5 hospitalized patients has been shown to develop an adverse reaction to an antibiotic,[8] and nearly the same proportion of drug-related Emergency Department visits are due to adverse antibiotic reactions.[9] An immune-mediated reaction or hypersensitivity is classified as an allergy.[10] This includes IgE-mediated anaphylaxis and angioedema. Medications reach harmful levels in the body often due to reduced metabolism and elimination, or high dosing regimens can cause toxicity due to supratherapeutic drug levels.[11] If a reaction occurs that is not mediated by the immune system and is unrelated to the drug level, it is known as a side effect.[11]

The anticipation of adverse events is warranted when initiating antimicrobial therapy. Certain patients are at higher risk, for example, the elderly, patients with multiple co-morbidities, and hospitalized patients.[8] It is important to monitor patients for reactions as many develop over time. Some antibiotics necessitate monitoring of drug levels to guide therapy for efficacy and prevention of adverse effects such as vancomycin and aminoglycosides.[12] Renal toxicities may develop if these antimicrobials maintain high trough levels; therefore, monitoring renal function is necessary for addition to drug levels.

Adverse Reactions Associated with Organ Systems[11]

Renal

• Acute tubular necrosis
• Interstitial nephritis
• Renal failure
• Crystallization in renal tubules

Cardiac: QT prolongation

Hematologic

• Thrombocytopenia
• Leukopenia
• Agranulocytosis
• Abnormal platelet aggregation
• INR increase (often due to drug interactions)

Dermatologic

• Rash
• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Neurologic

• Ototoxicity
• Vestibular dysfunction
• Seizure
• Peripheral neuropathy

Other

• Hepatotoxicity
• Myopathy
• Electrolyte abnormalities (i.e. hypokalemia, hypoglycemia)
• Drug-induced fever
• Drug-induced diarrhea

INR: International normalized ratio

Antibiotic Resistance

The increased use of antimicrobial agents in clinical practice and other industries such as livestock farming has lead to bacteria resistant to antibiotic agents.  Bacteria have developed mechanisms to promote this resistance in order to survive.  

The MIC of a bacterial isolate can serve as a metric for bacterial susceptibility to certain antibiotics.[13] A high MIC above the susceptibility threshold to an antibiotic will report as resistant. Bacteria may possess resistance to an antimicrobial agent due to intrinsic or acquired properties. Not all antibiotics are effective against all types of bacteria. If a bacterium does not contain the target for a particular antibiotic, it is known to have intrinsic resistance.[14] Vancomycin, an antibiotic known to target work against gram-positive bacteria, is not able to cross the cell wall of gram-negative bacteria.[15] Also, beta-lactam antibiotics require a cell wall to function and therefore, will not be effective against bacteria such as Mycoplasma species that lack this cellular component.

Bacteria also have the capability to gain resistance through attaining resistance genes from other bacteria or developing a mutation resulting in reduced or elimination of antibiotic efficacy. This type of resistance is known as acquired resistance.[14]

More than one type of bacterial resistance may be present in a bacterial organism. Common resistance strategies are listed here.

Mechanisms of Resistance and Examples[14][15]

Reducing Intracellular Antibiotic Concentrations

• Increased efflux
• Decreased influx

Antibiotic Inactivation

• Enzymatic modification
• Chemical degradation

Target Site Alteration

• Mutation of the target site
• Antibiotic modification
• Target site protection
• Elimination of the target site

Approach to Antimicrobial Therapy

The causative organisms and infection source are not always known when a patient first presents. Antibiotic therapy is often initiated before an exact infectious disease diagnosis is made and microbiological results are available. Antibiotics used in this manner are referred to as empiric therapy. This approach attempts to cover all potential pathogens. When microbiology tests result and antibiotic susceptibilities are known, definitive antibiotic therapy can then be tailored to the specific infection etiology.[16]

Prophylactic therapy is used to prevent infections in patients who do not have an active infection. Immunocompromised patients may receive prophylaxis against certain opportunistic pathogens. Prophylactic antibiotics are also used before surgical procedures and in traumatic injuries such as open fractures and animal bites.[16]

The severity of potential bacterial infection will determine the level of aggressiveness in antibiotic therapy. For example, in a life-threatening infectious disease such as sepsis, empiric broad-spectrum parenteral antibiotics should be administered quickly after sepsis identification and continued until more information is gathered regarding the etiology and causative bacteria.[12] Empiric antibiotics are used to cover all potential bacteria before culture results. After bacterial cultures are available and have resulted, antibiotics can then be deescalated to only what is necessary. This approach is termed as directed antibiotic therapy.[16] Often, empiric antibiotics are broad-spectrum which refers to medications that target many different types of bacterial classes (i.e., gram-positive, gram-negative, and anaerobic bacteria). Whereas, in a simple skin and soft tissue infection that does not require hospitalization, narrower spectrum antibiotics may be given orally.[12]

In addition to the possible source(s) of infection, likely pathogens, and situation urgency, different patient factors should be taken into consideration.[12] Patient age, medication allergies, renal and hepatic function, past medical history, the presence of an immunocompromised state, and recent antibiotic usage need to be evaluated before an antibiotic selection. Many of these patient factors contribute to the pharmacodynamics and pharmacokinetic actions of antibiotics that will influence dosing to optimize efficacy.