Introduction

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

Function

Classification

The pharmacology of antibiotics involves destroying bacterial cells by either preventing cell reproduction or altering a necessary cellular function or process. Antimicrobial agents are classically grouped into two main categories based on their in vitro effect on bacteria: bactericidal and bacteriostatic. Common teaching often states that bactericidal antibiotics "kill" bacteria, whereas bacteriostatic antibiotics "prevent the 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 antibiotic concentration 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: bactericidal antimicrobials may also be bacteriostatic against certain bacterial strains and under certain conditions. Conflicting data exist as to whether the necessity for bactericidal antibiotics is needed for severely ill or immunosuppressed patients.[3]

Types of 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 by optimizing 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 target site of infection. 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 the 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 antibiotic concentration rises.[6] Penicillins and tetracyclines are time-dependent; therefore, the duration of their effective concentrations determines bactericidal activity.[6]

After an antibiotic is absorbed, the distribution influences the extent of antimicrobial activity. The ratio of the total amount of drug in the body to its serum concentration is the volume of distribution.[5] The level of protein binding will affect the availability of the active drug at the site of infection. If an antibiotic is highly protein-bound, less free drug will be available for 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 lipophilic properties.[7]

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

Issues of Concern

Complications

Adverse Reactions

All medications have the potential for an adverse reaction, and antibiotics are no exception. One in five hospitalized patients has been shown to develop an adverse reaction to an antibiotic, and nearly the same proportion of drug-related Emergency Department visits are due to adverse antibiotic reactions.[8][9] An immune-mediated reaction or hypersensitivity is classified as an allergy.[10] This includes IgE-mediated anaphylaxis and angioedema. Medications often reach harmful levels in the body 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, then it is considered a side effect.[11]

Anticipating 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 require monitoring of drug levels to guide therapy for efficacy and to prevent adverse effects, such as vancomycin and aminoglycosides.[12] Renal toxicities may develop if these antimicrobials maintain high trough levels; therefore, monitoring renal function and measuring drug levels is necessary.

Adverse Reactions Associated with Organ Systems

Renal

• Acute tubular necrosis
• Interstitial nephritis
• Renal failure
• Crystallization in renal tubules [11]

Cardiac

• QT prolongation [11]

Hematologic

• Thrombocytopenia
• Leukopenia
• Agranulocytosis
• Abnormal platelet aggregation
• INR increase (often due to drug interactions) [11]

Dermatologic

• Rash
• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis [11]

Neurologic

• Ototoxicity
• Vestibular dysfunction
• Seizure
• Peripheral neuropathy [11]

Other

• Hepatotoxicity
• Myopathy
• Electrolyte abnormalities (ie, hypokalemia, hypoglycemia)
• Drug-induced fever
• Drug-induced diarrhea [11]

Antibiotic Resistance

The increased use of antimicrobial agents in clinical practice and other industries, such as livestock farming, has led to bacterial resistance to antibiotic agents. Bacteria have developed mechanisms to promote this resistance 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 antibiotic susceptibility threshold will be reported as a resistant infection. 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 lacks the target for a particular antibiotic, it is considered to have intrinsic resistance.[14] Vancomycin, an antibiotic known to act against Gram-positive bacteria, cannot 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 acquire resistance genes from other bacteria or develop mutations that reduce or eliminate 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

Reducing Intracellular Antibiotic Concentrations

• Increased efflux
• Decreased influx[14][15]

Antibiotic Inactivation

• Enzymatic modification
• Chemical degradation[14][15]

Target Site Alteration

• Mutation of the target site
• Antibiotic modification
• Target site protection
• Elimination of the target site[14][15]

Clinical Significance

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 diagnosis of the infectious disease 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 test results and antibiotic susceptibilities are known, definitive antibiotic treatment can be tailored to the specific infection's etiology.[16]

Prophylactic therapy is used to prevent infections in patients without an active infection. Immunocompromised patients may receive prophylaxis against specific opportunistic pathogens. Prophylactic antibiotics are also used before surgical procedures and 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 promptly after sepsis is identified and continued until more information is available regarding the etiology and causative bacteria.[12] Empiric antibiotics are used to cover all potential bacteria until culture results are available. Once bacterial cultures are available and results are available, antibiotics can be de-escalated to only what is necessary. This approach is termed directed antibiotic therapy.[16] Often, empiric antibiotics are broad-spectrum, meaning they target many different bacterial classes (eg, Gram-positive, Gram-negative, and anaerobic bacteria). 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 the urgency of the situation, various patient factors merit 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 pharmacokinetics of antibiotics, influencing dosing to optimize efficacy.

Enhancing Healthcare Team Outcomes

A Word on Antimicrobial Stewardship

In the United States, it has been reported that nearly half of the antibiotics prescribed were incorrect in some way, and almost one-third of antibiotics were deemed unnecessary in hospitalized patients.[17] Appropriate antibiotic use has become a public health issue (CDC 19). The practice of antimicrobial stewardship centers on optimizing antimicrobial therapy and reducing adverse events through cost-effective methods.[18] These interprofessional programs work to identify ways to improve patient outcomes. Stewardship programs are becoming increasingly common to address issues related to antibiotic use, including antimicrobial resistance.

Antibiotic therapy and accompanying stewardship require the effort of an interprofessional healthcare team that includes physicians (MDs and DOs), mid-level practitioners (NPs and PAs), pharmacists, and nursing staff. This includes using these agents only when clinically indicated, using targeted therapy based on the susceptibility of the infectious organism, and monitoring side effects and, where indicated, drug levels. Employing interprofessional strategies with open information sharing can improve therapeutic results with antibiotic therapy and minimize adverse events. [Level 5]

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Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Harrison Wermuth declares no relevant financial relationships with ineligible companies.

Disclosure: Chara Calhoun declares no relevant financial relationships with ineligible companies.

Disclosure: Gregory Hall declares no relevant financial relationships with ineligible companies.