DRUGS USED IN INFECTIOUS DISEASE_Antibiotics

Prepared and presented by Marc Imhotep Cray, M.D. Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human neutrophil. “Granulocytic Phagocytes,” From cover of DeLeo, FR and Nauseef, WM. Principles and Practice of Infectious Diseases, 8th Ed.

Drugs Used In Infectious Disease: Introduction

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Marc Imhotep Cray, M.D.

Learning Objectives_ Antibiotics I: An Introduction 1. The identification of bacteria according to characteristics observed on gramstain including cell wall staining results (gram-positive vs. gram-negative), morphology (cocci vs. bacilli), and growth characteristics (aerobic vs. anaerobic) 2. Description of the normal flora, including the identification of the anatomic sites where normal flora are commonly present and body sites that are usually “sterile� and the identification of the bacteria that are considered to be normal flora in each of the sites that are normally colonized.

3. The differences between contamination, colonization, and infection.

4. The typical clinical, laboratory and radiologic signs and symptoms of infection (fever, white blood cell count, infiltrate on chest x-ray, etc), and how the results of these tests may impact the process of antibiotic selection.

NOTE: These topics are presented and discussed in the Infectious Disease Pathology Sequence Marc Imhotep Cray, M.D.

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Learning Objectives_ Antibiotics I: An Introduction 6. The most likely pathogens associated with infection at a particular anatomic site of infection.

7. The definition of the terms MIC, MBC, and MIC susceptibility breakpoints and the differences between the antimicrobial susceptibility testing methods.

8. The definition of the common pharmacodynamic terminology used to describe the effects of antimicrobial therapy such as bacteriostatic, bactericidal, concentration- dependent, and time-dependent bactericidal activity. Know examples of antibiotics that display each of these properties.

9. The factors that should be considered in the antibiotic selection process for each patient in the treatment of infection.

Marc Imhotep Cray, M.D.

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Drugs Used In Infectious Disease: Introduction The goal of the drugs discussed in this unit is total destruction of a disease-causing organism (bacteria, fungus, or virus) Because antimicrobials are by design cytotoxic, distinguishing feature of each agent is relative selectivity for particular pathogens rather than host Greater selectivity for pathogen  fewer adverse effects drug Companion: Illustrations of Concepts in Antimicrobial Chemotherapy.pdf Marc Imhotep Cray, M.D.

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Introduction to Antimicrobials (2)  Antibiotics exploit differences between prokaryotic and eukaryotic cells to promote specificity and limit toxicity  

For example, bacterial enzymes involved in DNA replication and RNA synthesis are different from those found in eukaryotic cells bacterial ribosome is also significantly different, allowing selective targeting o Prokaryotic ribosomes consist of 30S and 50S subunit , whereas o Eukaryotic ribosomes subunits are 40S and 60S

 One of major differences betw. bacteria and eukaryotic cells is peptidoglycan-containing bacterial cell wall  synthesis is inhibited by several classes of antibiotics

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Introduction to Antimicrobials (3) A major concern for this therapeutic class is emergence of resistance of pathogens to drugs Antimicrobials selectively kill or inhibit replication of a pathogen by interfering with a phase of cell physiology that is required by pathogen Antibiotics classified and subclassified according to MOA, chemical structure, and spectrum of activity against particular organisms

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Introduction to Antimicrobials (4) Narrow-spectrum antibiotics act on a single group or a limited number of groups of organisms, whereas broad-spectrum antibiotics act on wide variety of microbes  Tetracyclines have broadest antibacterial spectrum of any class of antibiotics o MOA: They inhibit initiation of translation by binding to 30S ribosomal subunit inhibit binding of aminoacyl-tRNA to mRNA translation complex

Aminoglycosides and Macrolides inhibit bacterial protein synthesis by binding directly and irreversibly to 30S and 50S subunits, respectively, of bacterial ribosome Marc Imhotep Cray, M.D.

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Introduction to Antimicrobials (5) β-Lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams, and vancomycin) act by interfering with bacterial wall synthesis causes rapid cell lysis  However, β-lactam antibiotics are subject to inactivation by β lactamase– producing organisms so are used in combination with β-lactamase inhibitors (sulbactam, tazobactam, and clavulanate)

Carbapenems are broadest spectrum β-lactam antibiotics

Quinolones are broad-spectrum bacteriocidal antibiotics 

MOA: inhibit intracellular DNA topoisomerase II (DNA gyrase) or topoisomerase IV, which are essential for duplication, transcription, and repair of bacterial DNA

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Introduction to Antimicrobials (6)  Fungi have more rigid cell walls than bacteria and are resistant to antibiotics  Drugs used to treat systemic fungal infections include amphotericin B, azole antifungals caspofungin, and voriconazole o All interfere with critical components of normal physiology of fungi (See Respiratory Pharmacology Q&A_UWorld #s 3, 6, 15, 19)

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Introduction to Antimicrobials (7)  Human immunodeficiency virus infection is a particularly difficult viral infection to treat b/c of ability of virus to rapidly mutate to drug-resistant forms 

HIV attacks and binds to CD4 receptors on specific cells of immune system  Over time, HIV causes host cell lysis and prevents production of new CD4+ cells See HIV Infection and Antiretroviral Agents Video Education: Mechanism of Medicine HIV Science-Antiviral Drugs Animations Marc Imhotep Cray, M.D.

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Introduction to Antimicrobials (8) In pharmacologic management of HIV Infection  Nucleoside reverse transcriptase inhibitors (NRTIs) suppress viral replication by inhibiting the enzyme responsible for conversion of viral RNA into DNA  Protease inhibitors (PIs) inhibit enzyme required for proteolysis of viral polyprotein precursors into individual functional proteins a conversion essential for HIV to be infectious  Nonnucleoside reverse transcriptase inhibitors (NNRTIs) prevent viral replication through noncompetitive inhibition of reverse transcriptase enzyme  These and other drugs are often used in multidrug cocktails to enhance their effectiveness and minimize resistance Marc Imhotep Cray, M.D.

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Selection of Antimicrobial Agents  Selection of most appropriate antimicrobial agent requires knowing 1. organism’s identity, 2. organism’s susceptibility to a particular agent, 3. site of infection, 4. patient factors, 5. safety of agent, and 6. cost of therapy  However, some patients require empiric therapy (immediate administration of drug(s) prior to bacterial identification and susceptibility testing) Marc Imhotep Cray, M.D.

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Selection of Antimicrobial Agents (2) Identification of infecting organism:  Central to selection of proper drug  A rapid assessment of nature of pathogen can sometimes be made on basis of Gram stain useful in identifying presence and morphologic features of microorganisms in body fluids that are normally sterile, ie. o blood, o cerebrospinal fluid, o pleural fluid, o synovial fluid, o peritoneal fluid, o Urine  However, it is necessary to culture infective organism to arrive at a conclusive diagnosis and determine the susceptibility to antimicrobial agents Marc Imhotep Cray, M.D.

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Selection of Antimicrobial Agents (3)

Some lab. techniques useful in Dx of microbial diseases

It is essential to obtain a sample culture of organism prior to initiating treatment  Otherwise, impossible to differentiate whether a negative culture is due to absence of organisms or result of antimicrobial effects of admin. antibiotic

 Definitive ID of infecting organism may require other laboratory techniques such as detection of microbial antigens, DNA, or RNA, or an inflammatory or host immune response to microorganism Marc Imhotep Cray, M.D.

Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia,: Wolters Kluwer, 2015; 472.

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Selection of Antimicrobial Agents (4) Empiric therapy prior to ID of organism:  Ideally, antimicrobial agent used to treat an infection is selected after organism has been identified and its drug susceptibility established  However, in critically ill patient, such a delay could prove fatal immediate empiric therapy is indicated

o Timing 1. Acutely ill pts. w infections of unknown origin—for example, a neutropenic patient or a patient with meningitis require immediate treatment 2. Therapy should be initiated after specimens for lab. analysis have been obtained but before results of C&S are available

Marc Imhotep Cray, M.D.

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Selection of Antimicrobial Agents (5) Empiric therapy prior to ID of organism cont 'ed. o Selecting a drug: • Drug choice in absence of susceptibility data is influenced by site of infection and patient’s history  For example, previous infections, age, recent travel history, recent antimicrobial therapy, immune status, and whether infection was hospital- or community-acquired

• Broad-spectrum therapy may be indicated initially when organism is unknown or polymicrobial infections are likely

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Selection of Antimicrobial Agents (6) o Selecting a drug cont 'ed • Choice of agent(s) may also be guided by known association of particular organisms in a given clinical setting • For example, gram-positive cocci in CSF of a newborn infant is unlikely to be Streptococcus pneumoniae and most likely to be Streptococcus agalactiae (a group B streptococci) sensitive to penicillin G By contrast • Gram-positive cocci in CSF of a 40-year-old pt. are most likely to be Streptococcus pneumoniae frequently resistant to penicillin G and often requires Tx w a high-dose third generation cephalosporin (such as ceftriaxone) or vancomycin To learn more see: Infectious Disease: Antibiotic Ladder –OnlineMedEd Mini-Lecture Marc Imhotep Cray, M.D.

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Selection of Antimicrobial Agents (7) Minimum inhibitory concentration: MIC is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation  This serves as a quantitative measure of in vitro susceptibility and is commonly used in practice to streamline therapy  Computer automation has improved the accuracy and decreased turnaround time for determining MIC results  most common approach used by clinical laboratories

Minimum bactericidal concentration:  MBC is lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations  MBC is rarely determined in clinical practice due to time and labor requirements Marc Imhotep Cray, M.D.

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Time course of systemic drug concentration following drug administration.

MIC: Minimal Inhibitory Concentration. Inset: Illustrates how the MIC is determined. The minimum concentration of antibiotic that results in a visually clear solution (indicating lack of bacterial growth) is the MIC.

Marc Imhotep Cray, M.D.

http://tmedweb.tulane.edu/pharmwiki/doku.php/time-_concentrationdependent_killing

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Selection of Antimicrobials: Patient factors  In selecting an antibiotic, attention must be paid to condition of patient  For example o Status of patient’s immune system, o Renal Function, o Liver Function, o Circulatory Status, and o Age  In women, pregnancy or breast-feeding also affects selection of the antimicrobial agent Read: Summary Tables on Antimicrobials_High Yield Facts.pdf Marc Imhotep Cray, M.D.

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Patient factors (2) Immune system:  Elimination of infecting organisms from body depends on an intact immune system host defense system must ultimately eliminate invading organisms       

Alcoholism, Diabetes, HIV infection, Malnutrition, Autoimmune diseases, Pregnancy, Advanced age

These factors can all affect a patient’s immunocompetence, as can immunosuppressive drugs

High doses of bactericidal agents or longer courses of Tx may be required to eliminate infective organisms in these individuals.

Marc Imhotep Cray, M.D.

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Patient factors (3) Renal dysfunction: Poor kidney function may cause accumulation of certain antibiotics  Dosage adjustment prevents drug accumulation and therefore AEs  Serum creatinine levels are frequently used as an index of renal function for adjustment of drug regimens • However, direct monitoring of serum levels of some antibiotics (for example, vancomycin, aminoglycosides) is preferred to identify maximum and/or minimum values to prevent potential toxicities Remember: Number of functional nephrons decreases with age. Thus, elderly patients are particularly vulnerable to accumulation of drugs eliminated by kidneys Marc Imhotep Cray, M.D.

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Patient factors (4) Hepatic dysfunction:  Antibiotics that are concentrated or eliminated by liver (for example, erythromycin and doxycycline) must be used with caution when treating patients with liver dysfunction

Poor perfusion:  Decreased circulation to an anatomic area, such as lower limbs of a diabetic patient reduces amount of antibiotic that reaches that area making these infections difficult to treat

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Patient factors (5) Age: Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to toxic effects of chloramphenicol and sulfonamides Young children should not be treated with tetracyclines or quinolones affect bone growth and joints/tendons, respectively Elderly patients may have decreased renal or liver function may alter pharmacokinetics of certain antibiotic Marc Imhotep Cray, M.D.

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Patient factors (6)

FDA categories of antimicrobials and fetal risk.

Pregnancy and lactation:  Many antibiotics cross placental barrier or enter nursing infant via breast milk  The graphic summarizes U.S. FDA risk categories of antibiotic use during pregnancy (list not all inclusive)  Although conc. of an antibiotic in breast milk is usually low total dose to infant may be sufficient to produce detrimental effects NEW Replacement for CATEGORIES: “Pregnancy and Lactation Labeling Rule” (PLLR).pdf Marc Imhotep Cray, M.D.

Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia,: Wolters Kluwer, 2015; 472.

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FDA Pregnancy Risk classification scheme was recently modified (replaced), but the old scheme shown in previous is still useful.

Acronym: MCAT & F 1. Metronidazole (mutagenic and carcinogenic potential - Category B) 2. Chloramphenicol is contraindicated in infants (Gray baby syndrome b/c infants donâ&#x20AC;&#x2122;t produce enough glucoronyl transferase - Category C during pregnancy for teratogenicity) 3. Aminoglycosides (potential 8th nerve damage - Category C) 4. Tetracycline (retardation of bone growth; stains teeth - Category D) 5. Fluoroquinolones (cartilage toxicity; avoid in <18 yo - Category C risk in pregnancy) 6. Thalidomide (severe birth defects - Category X) Marc Imhotep Cray, M.D.

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Patient factors (7) Risk factors for multidrug-resistant organisms: ď ąInfections with multidrug-resistant pathogens need broader antibiotic coverage when initiating empiric therapy

ď&#x201A;§ Common risk factors for infection with these pathogens include: o prior antimicrobial therapy in preceding 90 days, o hospitalization for greater than 2 days within preceding 90 days, o current hospitalization exceeding 5 days, o high frequency of resistance in community or local hospital unit (assessed using hospital antibiograms), and o Immunosuppressive diseases and/or therapies Marc Imhotep Cray, M.D.

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Determinants of Rational Dosing ď ąRational dosing of antimicrobial agents is based on their pharmacodynamics (relationship of drug concentrations to antimicrobial effects) and pharmacokinetic properties (absorption, distribution, metabolism, and elimination of the drug) ď ąThree important properties that have a significant influence on frequency of dosing 1. Concentration dependent killing, 2. Time-dependent killing, and 3. Postantibiotic effect (PAE)

ď ą Utilizing these properties to optimize antibiotic dosing regimens can improve clinical outcomes and possibly decrease development of resistance Marc Imhotep Cray, M.D.

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Concentration-Dependent vs. Time-Dependent Killing Bactericidal drugs can be divided into two subgroups: 1. Concentration-Dependent Killing •The rate & extent of killing increases as the peak drug concentration increases •A property associate with drugs inhibiting protein or DNA synthesis, largest for AMINOGLYCOSIDES & FLUOROQUINOLONES •These drugs also exhibit a “POST-ANTIBIOTIC EFFECT” or persistent suppression of bacterial growth after limited exposure to an antibiotic Spivey JM (1992): The postantibiotic effect. Clin Pharm. 1992 Oct;11(10):865-75.

• Proposed mechanisms include: • slow recovery of bacteria after non-lethal damage to cell structures • persistence of the antibiotic at its binding site • a need for bacteria to synthesize new proteins before growth can continue •CLINICAL SIGNIFICANCE: • Antibiotics w a long post-antibiotic effect can be administered at longer dosing intervals than would be predicted by their PK half-life • Longer dosing intervals (fewer tablets/day) can reduce blood levels & side effects, yet maintain clinical efficacy • Fewer doses per day tends to increase adherence to therapy • Example: this characteristic is responsible for the efficacy of “once-daily” dosing of aminoglycosides Marc Imhotep Cray, M.D.

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Concentration-Dependent vs. Time-Dependent Killing Bactericidal drugs can be divided into two subgroups: 2. Time-Dependent Killing A property associated with cell wall synthesis inhibtors e.g. β-LACTAMS & VANCOMYCIN Bactericidal activity continues as long as the plasma concentration is greater than the minimum bactericidal concentration (or MIC).

CLINICAL SIGNIFICANCE: The free concentration of these drugs should be maintained above the MIC for a drug-specific fraction of time (e.g. >30% or >50%) in-between repetitive doses in order to achieve a favorable clinical outcome (Moehring R, Sarubbi C (2018): Prolonged infusions of beta-lactam antibiotics. In: UpToDate, Basow, DS (Ed), Waltham, MA.

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A. Significant dose-dependent killing effect shown by tobramycin B. Nonsignificant dose-dependent killing effect shown by ticarcillin

Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 473, Fig. 37.6.

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Determinants of Rational Dosing: 3. Postantibiotic effect  PAE is a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below MIC  Antimicrobial drugs exhibiting a long PAE (for example, aminoglycosides and fluoroquinolones) often require only one dose per day particularly against gram negative bacteria •Spivey JM (1992): The postantibiotic effect. Clin Pharm. 1992 Oct;11(10):865-75.

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Bacterial Infections: Antibiotics

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“An Admonition” Mild, kind , yet earnest reproof. Cautionary advice or warning.

“Learning the characteristics of antibiotics simplifies learning infectious disease pharmacotherapy. Students and clinicians who attempt to learn the antibiotics of choice for different types of infections before knowing the characteristics of those drugs never truly understand the context of what they are attempting to learn. Once the characteristics of the antibiotics are known, making a logical choice to treat an infection is much easier.”

Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed. Jones & Bartlett Learning, 2012.

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Classification of Antibiotics

 Antibiotics are classified according to MOA, chemical structure, and spectrum of activity against particular organisms  Drug classes include:  Cell wall synthesis inhibitors (β-lactam drugs such as penicillins, cephalosporins, carbapenems, monobactams);  Protein synthesis inhibitors (eg, tetracyclines, aminoglycosides, macrolides);  DNA gyrase inhibitors (fluoroquinolones);  RNA polymerase inhibitor (rifampin); and  Folate synthesis inhibitors (eg, sulfonamides) Read: Antibiotic Targets.pdf

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Marc Imhotep Cray, M.D.

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Key Concepts  Antibiotics exploit differences between prokaryotic and eukaryotic cells to promote specificity and limit toxicity  For example, bacterial enzymes involved in DNA replication and RNA synthesis are different from those found in eukaryotic cells  bacterial ribosome is also significantly different, allowing selective targeting

 One of major differences between bacteria and eukaryotic cells is peptidoglycan-containing bacterial cell wall whose synthesis is inhibited by several antibiotics Marc Imhotep Cray, M.D.

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Antibiotics target bacteria by five major mechanisms 1.

2.

3.

4.

5.

Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acids Alterations of cellular membranes Antimetabolites

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Mechanisms of antibiotic action A: Schematic showing cell wallâ&#x20AC;&#x201C;active, membrane-active, & cytoplasm-active antimicrobial agents B: Antibiotics that inhibit protein synthesis by interacting with different ribosome subunits C: Antibiotics that inhibit nucleic acid synthesis

Marc Imhotep Cray, M.D.

Somers KD and Morse SA. Lange Flash Cards: Microbiology & Infectious Diseases. New York: McGraw-Hill, 2010

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1. Inhibition of cell wall synthesis β-lactam antibiotics such as penicillin and cephalosporins target peptidoglycan cross-linking by binding to and inhibiting action of transpeptidase enzymes  Vancomycin inhibits cross-linking by binding terminal Dalanine- D-alanine precursor and preventing transpeptidation Cycloserine inhibits formation of D-alanine-D-alanine linkage Bacitracin inhibits transport of new peptidoglycan precursors through cell membrane  Isoniazid and ethionamide inhibit mycolic acid synthesis in mycobacteria

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2. Inhibition of protein synthesis Aminoglycosides such as gentamicin, tobramycin , neomycin, and kanamycin irreversibly bind and inhibit function of 30S ribosomal subunits  contrast to most inhibitors of microbial protein synthesis, which are bacteriostatic, aminoglycosides are bactericidal

Tetracyclines reversibly inhibits binding of aminoacyl-tRNA to 30S subunit Macrolides such as erythromycin, azithromycin, and clarithromycin attach to a 23S RNA on 50S subunit resulting in its inhibition Chloramphenicol blocks attachment of amino acids to nascent peptide chain on 50S subunit resulting in its inhibition Marc Imhotep Cray, M.D.

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3.Inhibition of nucleic acids  Quinolones and fluoroquinolones such as ciprofloxacin inhibit DNA synthesis by blocking DNA gyrase  Rifampin binds strongly to DNA-dependent RNA polymerase and thus inhibits RNA synthesis  Metronidazole interacts with DNA, altering its helical structure and causing DNA fragmentation

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4. Alterations of cellular membranes ď ą Polymyxin targets cell membranes rich in phosphatidylethanolamine, causing an increase in cellular permeability

5. Antimetabolites ď ą Sulfonamides and trimethoprim inhibit folic acid metabolism

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Sites of Action of Major Antibacterials Summary Table Folate pathway

DNA

Antimetabolites Sulfamethoxazole Trimethoprim

Quinolones Ciprofloxacin

Marc Imhotep Cray, M.D.

RNA Inhibits RNA synthesis Rifampin

Ribosomal subunit 30S

50S

Aminoglycosides Gentamicin and Tetracyclines Doxycycline

Macrolides Erythromycin Lincosamides Clindamycin Chloramphenicol Oxazolidinones Linezolid Streptogramins Quinupristin/ dalfopristin

Cell wall β-lactam antibiotics Penicillins Cephalosporins Aztreonam Imipenem Vancomycin Polymyxin B

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Definitions: Bacteriostatic Versus Bactericidal Bacteriostatic antibiotics arrest microbial growth and replication limits spread of infection while host’s immune system naturally eliminates pathogens  If therapy ends before immune system completely eliminates organisms a second cycle of infection may begin

 Bactericidal agents kill bacteria leads directly to a reduced total number of viable pathogens in host  Preferred for patients with neutropenia b/c these individuals have compromised immune systems may not be able to eliminate remaining pathogens  Life-threatening infections such as endocarditis and meningitis should also be treated with bactericidal agents Marc Imhotep Cray, M.D.

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Bacteriostatic Versus Bactericidal

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Marc Imhotep Cray, M.D.

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Bacteriostatic Versus Bactericidal cont’ed. Although practical, classification may be too simplistic b/c it is possible for an antibiotic to be bacteriostatic for one organism and bactericidal for another  For example, linezolid is bacteriostatic against Staphylococcus aureus and enterococci but is bactericidal against most strains of S. pneumoniae

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Bactericidal drugs

KILL BACTERIA, by inhibiting cell wall synthesis or DNA gyrases; One exception to this rule is aminoglycosides which are bactericidal inhibitors of translation

Include: β-Lactams (cell wall synthesis inhibitors)  Penicillins  Cephalosporins  Aztreonam  Imipenem Vancomycin (cell wall synthesis inhibitor) Quinolones (DNA gyrase inhibitors)  Aminoglycosides (translation inhibitors) Remember: Bactericidal drugs are necessary for  Patients with severe infections  Patients with severe or debilitating diseases  Patients who are immunocompromised Marc Imhotep Cray, M.D.

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Bacteriostatic drugs ONLY INHIBIT replication of bacteria, by reducing protein synthesis or interfering w folic acid metabolism The immune system eradicates infection

Include: Tetracyclines (translation inhibitors) Erythromycin (translation inhibitors) Chloramphenicol (translation inhibitors) Clindamycin (translation inhibitors) Sulfonamides (folic acid synthesis inhibitors) Trimethoprim (folic acid synthesis inhibitor)

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Spectrum of Activity  An antibiotic’s spectrum of activity refers to range of pathogenic organisms affected by that drug  Antibiotics with a narrow spectrum of activity act on a single organism or a few groups of organisms;  Broad-spectrum agents such as fluoroquinolones are effective against a wide variety of microbes  Extended-spectrum antibiotics such as ampicillin-sulbactam have an intermediate range of activity and target gram-positive organisms and some gram-negative species

 Because broad-spectrum and extended-spectrum antibiotics eliminate a wide variety of microbial species can alter nonpathogenic bacterial flora that normally colonizes host result in superinfection by organisms (eg, Candida, Clostridium difficile) whose growth would otherwise be suppressed Marc Imhotep Cray, M.D.

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Click for expanded view.

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Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014

Mechanisms of Resistance  Bacteria such as Staphylococcus strains are resistant if growth is not halted by maximal level of an antibiotic that is tolerated by host  Organisms develop into more virulent strains through mechanisms such as spontaneous DNA mutations  Main mechanisms of resistance are  Lower permeability of antibiotic through the cell wall (eg, ampicillin),  Presence of antibiotic-inactivating enzymes (eg, β lactamases), and  Lack of drug-binding sites (eg, penicillin)

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Mechanisms of Resistance (2)  Various factors contribute to emergence of resistant strains one of which is overprescribing of antibiotics in community setting 

Diagnostic uncertainty may be responsible: o rapid diagnostic testing is available for only a few infections, so community physicians often distinguish betw. viral and bacterial infections on basis of symptoms alone • For an uncertain Dx, physicians tend to use antibiotics

 Other factors include o inappropriate or indiscriminate drug use and o patients’ not completing courses of Tx Marc Imhotep Cray, M.D.

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Antibiotic Resistance Mechanisms (3) ď ąBacteria have evolved a number of mechanisms to protect themselves from action of antibiotics ď ąOften genes encoding antibiotic resistance are carried on transposons and plasmids, and are therefore easily transferred from one organism to another, creating bacteria resistant to multiple antibiotics

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Four major mechanisms are involved 1. Inactivation of antibiotic through hydrolysis  An example is β-lactamases that cleave β-lactam ring of penicillins and cephalosporins 2. Chemical modification of antibiotic through acetylation, phosphorylation, or adenylylation  An example is chloramphenicol acetyl transferase that transfers an acetyl group from acetyl CoA to chloramphenicol, resulting in its inactivation

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Four major Ab resistance mechanisms cont’ed.

3. Alteration of antibiotic targets through mutation  An example is alteration of a single amino acid in ribosomal protein S12 prevents streptomycin binding to 30S ribosome subunit without affecting protein synthesis 4. Alterations that affect permeability (ie, decrease intracellular concentration of antibiotic) are used by a variety of antibiotics  This can involve a decreased influx or an increased efflux from bacterial cell Marc Imhotep Cray, M.D.

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

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Whalen K. Ed. Lippincott Illustrated Reviews-Pharmacology, 6 Ed. 2015.

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USMLE World 2015.

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Learning Objectives_ Antibiotics II: PENICILLINS 1. The differences in the chemical structure between the penicillins, cephalosporins, carbapenems, and monobactams.

2. β-lactam antibiotics including their mechanism of action, bactericidal vs. bacteriostatic activity, elimination half-life, route of elimination, and potential for cross-allergenicity.

3. The differences in the spectrum of activity between the natural penicillins, the penicillinase-resistant penicillins, the aminopenicillins, the carboxypenicillins, the ureidopenicillins-β-lactamase inhibitor combinations with special attention to the specific agents that have activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Bacteroides fragilis.

4. The distribution characteristics of the penicillins into the cerebrospinal fluid, urinary tract, lungs, skin/soft tissue, and bone.

5. The indications, mechanism of action, adverse effects and contraindications of each group of penicillins 6. The mechanisms by which bacteria develop resistance to the penicillins.

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Relevant Drugs A. Natural Penicillins: Penicillin G Benzathine Penicillin Procaine Penicillin G Penicillin VK B. Penicillinase-Resistant Penicillins: Nafcillin Oxacillin Dicloxacillin C. Aminopenicillins: Ampicillin, Amoxicillin Marc Imhotep Cray, M.D.

D. Carboxypenicillins: Ticarcillin E. Ureidopenicillins: Piperacillin F. Beta-Lactamase Inhibitor Combinations: Ampicillin-Sulbactam (Unasyn ®) Amoxicillin-Clavulanate (Augmentin®) Piperacillin-Tazobactam (Zosyn®)

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Penicillins Capsule EXAMPLES (in order of narrowest to broadest spectrum)  Natural penicillins – benzylpenicillin, phenoxymethylpenicillin  Antistaphylococcal penicillins – nafcillin, oxacillin  Aminopenicillins– ampicillin, amoxicillin MECHANISM OF ACTION (MOA)  β lactam moiety binds to and inhibits transpeptidase required for formation of peptidoglycan cross-links within bacterial cell wall results in defective bacterial cell wall synthesis and subsequent cytolysis  Nafcillin & oxacillin are relatively resistant to staphylococcal β lactamases  Aminopenicillins have enhanced activity against aerobic Gram-negative bacilli  Piperacillin when combined with tazobactam (a β-lactamase inhibitor) has good activity against Pseudomonas spp.  Augmentin (or) Co-amoxiclav is a combination of amoxicillin and clavulanic acid (a β lactamase inhibitor) Marc Imhotep Cray, M.D.

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ACTIVE NUCLEUS of penicillin molecule is a 4membered ring, called βâ&#x20AC;&#x201C;lactam ring General structure of the penicillins

Weiss, X T. High-Yield Pharmacology, 3rd ed. Philadelphia: LWW/Wolters Kluwer2009, Pg. 121, Fig. 9.1.

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Penicillins MOA Penicillin Binds to Penicillin Binding Proteins and induces many effects that inhibit cell wall synthesis (e.g., inhibition of transpeptidases)  Cross-linking of the bacterial cell wall is reduced.  Cell wall is weakened and bacteria rupture due to high internal osmotic pressure thus pens are bactericidal  Autolytic enzymes are activated

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Natural Penicillins: Peniciliin G and Peniciliin V  Originally obtained from fermentation of mold Penicillium chrysogenum oldest and still most widely used of all antibiotics  Exert bactericidal activity by interfering w last step of bacterial cell wall synthesis, which causes rapid cell lysis, therefore pens are ineffective against organisms that lack a cell wall such as mycoplasma, mycobacteria, protozoa, fungi, and viruses  Natural penicillins target gram-positive and gram negative cocci, gram-positive bacilli, oral anaerobes, and spirochetes  Historical cornerstone of therapy for a diverse group of infections including pneumococcal pneumonia, syphilis, meningitis, tetanus, and gonorrhea  Drug of choice for Group A Strep - universally PCN sensitive  Penicillin G and penicillin V have similar spectra of activity, penicillin V acid stable and thus better absorbed by oral route, whereas penicillin G is administered via injection Marc Imhotep Cray, M.D.

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Typical therapeutic applications of penicillin G

Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 485, Fig. 38.4.

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β Lactamase-Resistant Penicillins: Cloxacillin, Dicloxacillin, Oxacillin, and Nafcillin β Lactamase–resistant penicillins are semisynthetic penicillins same coverage as natural penicillins but remain stable in presence of β lactamase– producing staphylococcal organisms  Dicloxacillin is used for Tx of skin and soft tissue infections;  Oxacillin is used for Tx of sepsis, toxic shock syndrome, and infections of wounds and vascular catheters;  Nafcillin is used for Tx of endocarditis, osteomyelitis, skin and soft tissue infections, and encephalitis Unfortunately, many strains of S aureus have developed ability to inactivate methicillin leading to increase of methicillin resistant S aureus (MRSA)  MRSA is considered a serious source of HAIs and produces diseases that are usually treated with vancomycin Marc Imhotep Cray, M.D.

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Aminopenicillins: Amoxicillin and Ampicillin Aminopenicillins (aka extended spectrum pens.) are similar to natural penicillins in spectrum of activity but are also active against many gram-negative organisms (eg, Helicobacter pylori) and against Listeria Used for septicemia; gynecologic, skin, and soft tissue infections; and urinary, respiratory, and GI tract infections Inactivated by β lactamase–producing bacteria (eg, Escherichia coli and Haemophilus influenzae),  CDC still indicates amoxicillin as drug of choice (DOC) for uncomplicated acute otitis media, despite presence of drug-resistant S pneumoniae (DRSP) and H influenzae  CDC urged use of a high-dose regimen to give amoxicillin a better chance to eliminate DRSP for very young patients with recent exposure to antimicrobials

 If amoxicillin fails, antibiotics with activity against DRSP (eg, cefuroxime) or β lactamase– producing strains (ie, amoxicillin-clavulanate) should be tried Marc Imhotep Cray, M.D.

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In vitro growth of Escherichia coli in presence of amoxicillin, with and without clavulanic acid

Marc Imhotep Cray, M.D.

Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 493, Fig. 38.15.

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Antipseudomonal Penicillins: Carbenicillin, Piperacillin, and Ticarcillin  Carbenicillin, piperacillin, and ticarcillin display improved activity against gramnegative  usually used in combination with aminoglycosides in pts. with febrile neutropenia and in those with hard to treat nosocomial infections caused by strains of Enterobacter, Klebsiella, Citrobacter, Serratia, Bacteroides fragilis, and Pseudomonas aeruginosa o Antibacterial effects of all β-lactam antibiotics are synergistic with aminoglycosides b/c β-lactams inhibit cell wall synthesis, which enhances diffusion of aminoglycosides into bacterium o NB: These drugs should never be placed into same IV bag b/c positively charged aminoglycosides can form a precipitate with negatively charged penicillins

 Like other penicillins, antipseudomonal agents can be inactivated by β lactamase  commonly used together w β-lactamase inhibitors Marc Imhotep Cray, M.D.

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β-lactamase lnhibitors Penicillins and other β-lactam antibiotics have in common a β-lactam ring  essential to stability and antibacterial activity After years of exposure to β-lactam antibiotics, a large number of bacterial organisms have developed resistance to drugs by producing β lactamase an enzyme that hydrolyzes β-lactam ring and inactivates the antibiotic

β Lactamase inhibitors--clavulanate, sulbactam, and tazobactam-were developed to address this problem  With no antibacterial activity of their own, these inhibitors are used only in combination with β-lactam antibiotics creates a product that has extended activity against β lactamase–producing strains Marc Imhotep Cray, M.D.

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014.

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Antimicrobial activity of ampicillin (A) and antipseudomonal penicillins (B)

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Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 485, Fig. 38.5.

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Stability of penicillins to acid or action of penicillinase

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Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 487, Fig. 38.6.

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Adverse Effects of Penicillins  Although considered safest of all antibiotics, penicillins can still cause significant adverse effects hypersensitivity reactions being most notable  Approximately 5% of patients experience some kind of reaction is actually an immune response to penicillin metabolite penicilloic acid and can range from a maculopapular rash to angioedema and more significant anaphylaxis  Cross-allergic reactions occur among all β-lactam antibiotics Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014.

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Adverse Effects of Penicillins contâ&#x20AC;&#x2122;ed.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014.

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Penicillin Antibacterials Summary Table

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Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

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Learning Objectives_ Antibiotics III: CEPHALOSPORINS, CARBAPENEMS, AND MONOBACTAMS 1. The differences in the spectrum of activity between the four generations of cephalosporins, as well as the carbapenems and aztreonam 2. The indications, mechanism of action, adverse effects and contraindications of the cephalosporins, carbapenems and aztreonam.

3. The mechanisms by which bacteria develop resistance to cephalosporins, carbapenems and aztreonam.

4. The pharmacokinetics of the cephalosporins, carbapenems and aztreonam, particularly those drugs able to penetrate the CNS and those drugs that require dosage adjustment in the presence of renal impairment.

5. The risk of cross-reactivity between penicillins and cephalosporins, carbapenems and aztreonam 6. The major clinical uses of representative agents within each generation of cephalosporins, carbapenems, and aztreonam.

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Relevant Drugs A. 1st Generation Cephalosporins Cefazolin Cephalexin (Prototype) B. 2nd Generation Cephalosporins Cefuroxime (Prototype) Cefoxitin Cefotetan Cefprozil C. 3rd Generation Cephalosporins Ceftriaxone Ceftazidime Cefixime

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D. 4th Generation Cephalosporins Cefepime E. Carbapenems: Imipenem Meropenem Ertapenem Doripenem F. Monobactams: Aztreonam

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Cephalosporins Chemically and pharmacologically similar to penicillins cephalosporins inhibit cell wall synthesis and cause rapid cell lysis Classified into first, second, third, and fourth generations on basis of spectrum of activity and susceptibility to β lactamases  Agents in first generation tend to have excellent gram-positive coverage but minimal gram-negative coverage, whereas agents in higher generations tend to possess reverse spectrum of activity= good gram-negative coverage but minimal gram-positive coverage

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Cephalosporins cont’ed Also like penicillins, all cephalosporins can produce hypersensitivity reactions ranging from a mild rash and fever to fatal anaphylaxis  Patients who are allergic to penicillins should avoid these agents b/c of cross-sensitivity of 5% to 15% between 2 classes Other adverse effects include GI disturbances and hematologic reactions including positive Coombs test results, thrombocytopenia, transient neutropenia, and reversible leukopenia Marc Imhotep Cray, M.D.

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Generation of cephalosporin and antimicrobial profile  First generation (cefazolin, cephalexin)=Gram-positive cocci, Proteus, E. coli, Klebsiella

 Second generation (cefoxitin, cefaclor, cefuroxime)=Grampositive cocci, H. influenzae, Enterobacter, Neisseria, Proteus, Klebsiella, Serratia  Third generation (ceftriaxone, cefotaxime, ceftazidime)=Gramnegative infections

 Fourth generation (cefepime)=Pseudomonas, gram-positive organisms Marc Imhotep Cray, M.D.

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Summary of therapeutic applications of cephalosporins

Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia: Wolters Kluwer, 2015; 490, Fig. 38.10.

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Therapeutic advantages of some clinically useful cephalosporins. [Note: Drugs that can be administered orally are shown in reverse type. More useful drugs shown in bold.]

Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia,: Wolters Kluwer, 2015; 491, Fig. 38.12.

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Carbapenems: Imipenem/Cilastatin, Ertapenem, and Meropenem  Carbapenems broadest spectrum β-lactam antibiotics  Derive potent activity from  resistance to bacterial β lactamases,  affinity for penicillin-binding protein 2, and  lack of permeability barrier

 Act against aerobic (gram-positive and negative) and anaerobic bacteria, including P aeruginosa, B fragilis, and Serratia, Enterobacter, Acinetobacter, and Enterococcus species  Alone or w an aminoglycoside used for severe mixed infections (pulmonary, intraabdominal, soft tissue) caused by multidrug-resistant bacteria  Meropenem is beneficial in febrile neutropenia, urinary tract infections (UTIs), and meningitis

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Carbapenems cont’ed. Adverse Effects  All these agents can have injection site reactions and should be avoided in penicillin-allergic patients  Imipenem-cilastatin (and ertapenem) can cause abnormal liver function test results, thrombophlebitis, and seizures

 Imipenem is used with cilastatin to avoid nephrotoxicity*  Severe CNS toxicity, including seizures, will occur if dose of imipenem is not reduced in patients with renal impairment

 Meropenem can cause agranulocytosis, neutropenia, Stevens-Johnson syndrome, and angioedema *Note: Cilastatin inhibits human enzyme dehydropeptidase. Dehydropeptidase is an enzyme found in kidney and is responsible for degrading imipenem protect imipenem from degradation, prolonging its antibacterial effect Marc Imhotep Cray, M.D.

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Monobactams: Aztreonam Aztreonam is a monobactam antibiotic that inhibits bacterial cell wall synthesis and is resistant to most β lactamases Activity only against gram-negative organisms, including P aeruginosa, E coli, Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis, H influenzae, and Enterobacter and Citrobacter species  Aztreonam is used for Tx of septicemia, lower respiratory tract infections (including pneumonia and bronchitis), and urinary tract, skin and skin structure, intraabdominal, and gynecologic infections For Tx of mixed infections combined w other antibiotics to ensure coverage of gram-positive and anaerobic bacteria Marc Imhotep Cray, M.D.

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Aztreonam cont’ed. Adverse effects include frequent increases in liver function test results, nausea, vomiting, rashes, and phlebitis Aztreonam may be safe for use in pts. who are allergic to cephalosporins and penicillins

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Learning Objectives_ Antibiotics IV: VANCOMYCIN AND OTHER AGENTS WITH ACTIVITY AGAINST GRAM-POSITIVE AEROBES 1. The general spectrum of activity of vancomycin, quinupristin-dalfopristin, linezolid, and daptomycin.

2. The indications, mechanism of action, adverse effects and contraindications for vancomycin, quinupristin-dalfopristin, linezolid, and daptomycin.

3. The mechanisms by which bacteria become resistant to vancomycin, quinupristin- dalfopristin, linezolid, and daptomycin.

4. The major pharmacokinetic characteristics of vancomycin, quinupristindalfopristin, linezolid and daptomycin including bioavailability, half-life, CSF penetration, route of elimination, necessity for dosage adjustment in renal insufficiency, and removal by hemodialysis.

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Relevant Drugs A. Glycopeptides Vancomycin B. Streptogramins Quinupristin-dalfopristin (Synercid®) C. Oxazolidinones Linezolid (Zyvox®) D. Lipopeptides Daptomycin (Cubicin®)

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Vancomycin Vancomycin, a glycopeptide, inhibits bacterial cell wall synthesis by binding to cell wall phospholipids and inhibiting polymerase and transpeptidation leads to cell wall lysis Because its site of action is different from that of other β-lactam antibiotics, no cross-resistance occurs Vancomycin is of last resort targets methicillin-resistant staphylococci, Staphylococcus epidermidis, Streptococcus viridans or Streptococcus bovis (alone or with an aminoglycoside), and Enterococcus faecalis (with an aminoglycoside) Marc Imhotep Cray, M.D.

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Vancomycin cont’ed. Vancomycin should be used only for serious infections caused by  β lactam–resistant gram-positive bacteria infections caused by gram-positive bacteria in patients with serious allergy to β-lactam antibiotics  Antibiotic-associated pseudomembranous colitis that is unresponsive to metronidazole,  enterococcal endocarditis, and  As prophylaxis for endocarditis after implantation of prosthetic materials or  devices at institutions with a high rate of MRSA-related infection Marc Imhotep Cray, M.D.

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Vancomycin Treatment Difficulties: Resistance After long-standing efficacy against deadly gram-positive pathogens resistance of Enterococcus and Staphylococcus species to vancomycin has begun  such as case of a S aureus isolate from a patient w renal disease that showed intermediate levels of resistance patient had undergone longterm peritoneal dialysis and multiple courses of vancomycin for recurring MRSA associated peritonitis  Patients with renal failure who receive peritoneal dialysis are sometimes given once-weekly vancomycin, which is removed to some extent during each dialysis session thus, drug concentrations decrease, and patient has low drug levels for latter part of the week  During this time organism can mutate and develop resistance Marc Imhotep Cray, M.D.

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Vancomycin Treatment Difficulties: Adverse Effects  AEs of IV vancomycin include infusion-related events “red man syndrome”:  decreased blood pressure,  wheezing, NB: Syndrome can be prevented  urticaria, by slow infusion of antihistamine  pruritus,  upper body flushing,  pain,  muscle spasms, Also thrombophlebitis, hypersensitivity, fever, neutropenia, ototoxicity, and nephrotoxicity Marc Imhotep Cray, M.D.

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014.

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Quinupristin/ Dalfopristin (Synercid) quinupristin/dalfopristin is an injectable streptogramin destined to replace vancomycin as drug of last resort for certain pathogens  2 compounds act synergistically to inactivate bacteria via effects on protein synthesis in bacterial ribosome: o dalfopristin inhibits early phase of synthesis, and quinupristin inhibits late phase

Used for life threatening bloodstream infections (BSIs) caused by vancomycin resistant Enterococcus faecium and skin and skin structure infections caused by methicillin-susceptible S aureus or Streptococcus pyogenes

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Quinupristin/ Dalfopristin cont’ed.  Identifying Enterococcus species (faecium and faecalis) by blood culture is critical to avoid misuse of this drug (it is active against only former)  Most common adverse effects are pain at infusion site, arthralgia, and myalgia  Drug interactions  with agents metabolized by cytochrome P450 3A4 system (eg, cyclosporine, nifedipine) and with drugs prolonging QTc interval  Synercid inhibits the cytochrome P450–3A4 enzyme system Marc Imhotep Cray, M.D.

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Linezolid For otherwise untreatable infections, linezolid is an oxazolidinone derivative MOA- binds to ribosomal subunits and interferes w bacterial protein synthesis by inhibiting initiation process of protein synthesis Intended for Tx of multidrug-resistant gram-positive cocci particularly as an alternative in infections caused by vancomycinresistant Enterococcus, multidrug-resistant S pneumonia (including vancomycin-ceftriaxone resistant), and MRSA or methicillin-resistant S epidermidis

Bacteriostatic against Enterococcus and staphylococci and bactericidal against most streptococcal strains Marc Imhotep Cray, M.D.

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Linezolid Adverse Effects  Most common AEs are nausea, diarrhea, and headache  Linezolid may cause myelosuppression could predispose pts. to anemia, leukopenia, pancytopenia, and thrombocytopenia  DDIs Linezolid inhibits MAO consumption of foods w high tyramine content or concomitant use of adrenergic or serotonergic drugs should be avoided can cause hypertensive crisis or serotonin syndrome, respectively

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Daptomycin (Cubicin) MOA- A cyclic lipopeptide antibiotics that binds to bacterial membrane, depolarizes it, and thus causes inhibition of DNA, RNA, and protein synthesis Indicated for Tx of complicated skin and skin structure infections and bacteremia caused by S. aureus, including those with rightsided infective endocarditis  Efficacy of Tx with daptomycin in left-sided endocarditis has not been demonstrated

Daptomycin is inactivated by pulmonary surfactants it should never be used in Tx of pneumonia Marc Imhotep Cray, M.D.

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Learning Objectives_ Antibiotics V: TETRACYCLINES AND SULFONAMIDES 1. The spectrum of activity of the tetracyclines and sulfonamides.

2. The indications, mechanism of action, adverse effects, contraindications and major drug interactions of the tetracyclines and sulfonamides.

3. The pharmacokinetic characteristics of the tetracyclines and sulfonamides with respect to oral bioavailability, distribution into the central nervous system, route of elimination, removal by hemodialysis, and dosage adjustment in endorgan dysfunction.

4. The potential therapeutic advantages of the glycylcycline antibiotics.

5. The mechanisms by which bacteria develop resistance to the tetracyclines.

6. The mechanisms by which bacteria develop resistance to the sulfonamides

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Relevant Drugs A. Tetracyclines Tetracycline Doxycycline Minocycline B. Glycylcyclines Tigecycline (TygacilÂŽ) C. Sulfonamides Sulfadiazine Sulfisoxazole Trimethoprim-Sulfamethoxazole Marc Imhotep Cray, M.D.

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Tetracyclines  MOA: Tetracyclines bind reversibly to 30S subunits of bacterial ribosome and inhibit protein synthesis with broadest spectrum of any antibiotic class: they are bacteriostatic for most gram-positive organisms, many gram-negative organisms, and certain anaerobic bacteria  They are DOC for many animal-borne infections (eg, Lyme disease), sexually transmitted diseases (eg, gonorrhea), and other infections (eg, with Mycoplasma pneumoniae).  Tetracycline is used for prostatitis, travelers’ diarrhea, acne, Chlamydia infections, and H pylori infections;  Doxycycline is used for prophylaxis and Tx of multidrug-resistant malaria Marc Imhotep Cray, M.D.

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Tetracyclines cont’ed. Mechanism Bacteriostatic; bind to 30S and prevent attachment of aminoacyl-tRNA; Limited CNS penetration Doxycycline is fecally eliminated can be used in pts w renal failure  Caution: Do not take tetracyclines with milk (Ca2+), antacids (eg, Ca2+ or Mg2+), or iron-containing preparations b/c divalent cations inhibit drugs’ absorption in gut

Clinical Use Borrelia burgdorferi, M pneumoniae; Drugs’ ability to accumulate intracellularly makes them very effective against Rickettsia and Chlamydia  Also used to treat acne  Doxycycline effective against community-acquired MRSA Marc Imhotep Cray, M.D.

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Tigecycline MOA Tetracycline derivative. Binds to 30S, inhibiting protein synthesis. Generally bacteriostatic Clinical Use Broad-spectrum anaerobic, gram ⊝, and gram ⊕ coverage; Multidrug-resistant organisms (MRSA, VRE) or infections requiring deep tissue penetration Adverse Effects GI symptoms: nausea, vomiting

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Tetracyclines Adverse Effects  Most common adverse effects target GI tract; photosensitivity  more serious effects include pseudotumor cerebri, superinfections, and hepatotoxicity  Tetracyclines should be avoided in children, b/c discoloration of teeth and inhibition of bone growth in children, and in renal disease (except doxycycline)  Contraindicated in pregnancy  they can render oral contraceptives less effective Mechanism of Resistance: decrease uptake or increase efflux out of bacterial cells by plasmid-encoded transport pumps Marc Imhotep Cray, M.D.

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Sulfonamides MOA Sulfonamides inhibit synthesis of folic acid and thus synthesis of purines and pyrimidines bacteria fail to grow and divide USE These bacteriostatic agents are used for trachoma (caused by Chlamydia), UTIs caused by E coli, and Nocardiosis  Trimethoprim, a dihydrofolate reductase inhibitor, is often used with sulfamethoxazole (as co-trimoxazole) for synergy and a broader spectrum of activity  Co-trimoxazole is used for Pneumocystis jiroveci pneumonia (a common opportunistic infection in pts. with AIDS), chronic UTIs, GI infections (shigellosis and nontyphoid salmonella), and acute gonococcal urethritis, Listeria monocytogenes (DOC ampicillin w or w/o aminoglycoside )  Used against toxoplasma gondii, both Px and Tx of toxoplasmosis in AIDS o leading cause of focal CNS disease in AIDS Marc Imhotep Cray, M.D.

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Sites of sulfonamide and trimethoprim actions are indicated ď&#x201A;§

ď&#x201A;§

Co-trimoxazole MOA sulfamethoxazole component inhibits formation of dihydrofolic acid from para-aminobenzoic (PABA), whereas trimethoprim inhibits dihydrofolate reductase Both drugs block folic acid synthesis, preventing bacterial cell synthesis of essential nucleic acids

Weiss, X T. High-Yield Pharmacology, 3rd ed. Philadelphia: LWW/ Wolters Kluwer2009, Pg. 131, Fig. 9.3.

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Sulfonamides cont’ed.  Adverse effects of sulfonamide include  crystalluria (minimized by hydration and alkalinization of urine),  hypersensitivity reactions: skin reaction=most common, angioedema, and Stevens-Johnson syndrome=most severe;  kernicterus in newborns displacement of bilirubin from plasma albumin–binding sites  Adverse effects of trimethoprim (megaloblastic anemia, leukopenia, granulocytopenia) are related to folate deficiency NB: Seven drugs to avoided in patients with allergies to sulfa drugs: Sulfasalazine, sulfonylureas, thiazides, acetazolamide, furosemide, probenecid, and celecoxib Marc Imhotep Cray, M.D.

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Co-trimoxazole DDIs  Cyclosporine: Increases risk of nephrotoxicity. Avoid use together  Digoxin: Increases digoxin levels Monitor serum levels closely  Indomethacin: May increase sulfamethoxazole levels Dosage adjustment may be needed  Methotrexate: Increases methotrexate levels. Use together cautiously  Oral anticoagulants: Co-trimoxazole may inhibit hepatic metabolism, enhancing anticoagulant effects Observe patient for signs of bleeding  Oral sulfonylureas: Enhances hypoglycemic effects Monitor blood glucose levels  Para-aminobenzoic acid: Antagonizes sulfonamide effects. Monitor patient closely  Phenytoin: Inhibits phenytoin metabolism Dosage adjustment may be needed  Pyrimethamine: May cause megaloblastic anemia with pyrimethamine doses greater than 25 mg weekly Avoid use together Marc Imhotep Cray, M.D.

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Learning Objectives_ Antibiotics VI: AMINOGLYCOSIDES 1. The spectrum of activity of the aminoglycoside antibiotics, with special attention to those agents that display activity against Staphylococcus aureus, Pseudomonas aeruginosa, and tuberculosis.

2. The indications, mechanism of action, adverse effects and contraindications for the aminoglycosides 3. The mechanisms by which bacteria become resistant to the aminoglycosides.

4. The major pharmacokinetic characteristics of the aminoglycosides (absorption, distribution, metabolism, elimination) including an understanding of the patient characteristics that may alter the pharmacokinetic parameters of volume of distribution and clearance, as well as how these alterations may influence dosing of aminoglycosides.

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Relevant Drugs Gentamicin Tobramycin Amikacin Netilmicin Streptomycin Neomycin

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Aminoglycosides MOA: Aminoglycosides are bactericidal agents that bind directly and irreversibly to 30S ribosomal subunits and inhibit bacterial protein synthesis They target many aerobic gram-negative and some gram-positive organisms but not anaerobes Monotherapy is limited to infections caused by gram-negative bacilli (eg, septicemia, intraabdominal infections, serious UTIs)

Usually used with other antibiotics for enhanced diffusion Once-daily higher dosing allows less frequent drug level monitoring

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Aminoglycosides cont’ed. Adverse Effects Aminoglycosides tend to cause ototoxicity, which is reversible only if noted early and if drug is stopped (otherwise irreversible effects on vestibular function, hearing loss can also occur)  Increased risk for hearing loss can occur when other ototoxic drugs are given  Ototoxicity is enhanced by loop diuretics

Nephrotoxicity leads to often reversible tubular necrosis Neuromuscular blockade causing skeletal weakness and respiratory distress often occurs after high doses given by an intraperitoneal or an intrapleural route Neostigmine and calcium gluconate are antidotes Note: Safer drugs (eg, third-generation cephalosporins, imipenem-cilastatin) have somewhat replaced aminoglycosides Marc Imhotep Cray, M.D.

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Learning Objectives_ Antibiotics VII: FLUOROQUINOLONES 1. The spectrum of activity of the older and respiratory fluoroquinolones, particularly, the fluoroquinolones that have the best activity against Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, atypical bacteria, and anaerobes.

2. The indications, mechanism of action, adverse effects, contraindications and major drug interactions of the fluoroquinolones 3. The mechanisms by which bacteria develop resistance to the fluoroquinolone antibiotics.

4. The major pharmacokinetic differences between the fluoroquinolones in terms of oral bioavailability, half-life, dosing interval, penetration into the CSF, route of excretion, necessity for dosage adjustment in renal insufficiency, and removal by hemodialysis.

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Quinolones

MOA Quinolones (eg, ciprofloxacin, levofloxacin), broad-spectrum bactericidal antibiotics that inhibit DNA gyrase or topoisomerase IV (essential for duplication, transcription, and repair of bacterial DNA) USE target various aerobic gram-positive (eg, methicillin-resistant and β lactamase–producing Staphylococcus species, S pneumoniae) and gramnegative (eg, H influenzae, M catarrhalis, P aeruginosa, Legionella, Chlamydia) organisms  They are used for resistant respiratory infections; chlamydial infections; UTIs; and infections of the GI tract, joints, bones, skin, and skin structures NB: ciprofloxacin is preferred regimen for prophylaxis of adults against Neisseria meningitidis. Rifampin can also be used.

Children can be protected using a single dose of ceftriaxone as fluoroquinolones are usually contraindicated in children.

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Quinolones Adverse Effects  Most common adverse effects are nausea, headache, phototoxicity, and dizziness  More serious are CNS effects (psychosis, agitation, tremors), hepatotoxicity, interstitial nephritis, tendonitis or joint rupture, and prolonged QTc interval and thus arrhythmias Contradictions  Patients with neurologic disorders (eg, seizure), those taking certain antiarrhythmics, and those with a prolonged QTc interval should avoid quinolones  Fluroquinolones are contraindicated in children due to tendon damage and effects on cartilage development Marc Imhotep Cray, M.D.

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New-Generation Quinolones Compared with older quinolones, newer drugs (eg, levofloxacin, sparfloxacin, grepafloxacin, gaitfloxacin, moxifloxacin) possess enhanced activity against gram-positive organisms, including S pneumoniae strains that are resistant to other antibiotics  Thus often used to treat multidrug-resistant community-acquired pneumonia o As with all antibiotics, new drugs are used excessively and inappropriately in community setting leads to bacterial resistance to the antibiotics

 Ciprofloxacin is a good example of future for these newer drugs:  this older quinolone was once 95% effective against P aeruginosa today it affects only 70% of those isolates  Older quinolones were also once active against MRSA but today, activity of ciprofloxacin against S aureus is variable  Although new quinolones are quite effective against pneumococci, increased minimal inhibitory concentrations for ofloxacin against S pneumoniae strains have been reported Marc Imhotep Cray, M.D.

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Learning Objectives_ Antibiotics VIII: CLINDAMYCIN AND METRONIDAZOLE 1. The spectrum of activity of clindamycin and metronidazole, with special emphasis on their activity against anaerobes and Clostridium difficile.

2. The indications, mechanism of action, adverse effects, contraindications and major drug interactions of clindamycin and metronidazole 3. The mechanisms of resistance to clindamycin and metronidazole.

4. The pharmacokinetic characteristics of clindamycin and metronidazole with respect to oral bioavailability, distribution into the central nervous system, route of elimination, removal by hemodialysis, and dosage adjustment in endorgan dysfunction.

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Relevant Drugs Clindamycin Metronidazole

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Clindamycin Although chemically distinct, clindamycin is similar to erythromycin in MOA and spectrum of activity bind to 50s ribosomal subunit of bacteria disrupts protein synthesis by interfering w the transpeptidation reaction, which thereby inhibits early chain elongation Used mainly for infections caused by anaerobic bacteria such as B fragilis, which is responsible for abdominal infections related to trauma Also used for aspiration pneumonia and infections caused by streptococci and methicillin-sensitive S aureus in patients who are allergic to penicillin Marc Imhotep Cray, M.D.

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Clindamycin Adverse Effects  Most serious adverse effect is pseudomembranous colitis a possibly fatal superinfection (C difficile overgrowth in t bowel)  This complication, which is more likely to occur with clindamycin than with other antibiotics may present with watery diarrhea, abdominal pain, fever, and leukocytosis  Symptoms begin 3 to 10 days after starting drug or soon after stopping it  Tx PO metronidazole and vancomycin effectively eradicate superinfection latter is usually used only if the former fails  Other adverse effects include nausea, rash, and impaired liver function

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Metronidazole  Metronidazole (Flagyl) is an antibiotic and antiprotozoal medication  MOA Forms toxic free radical metabolites in bacterial cell that damage DNA Bactericidal, antiprotozoal  USE Treats Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes (Bacteroides, C difficile/pseudomembranous colitis ); can be used in place of amoxicillin in H pylori “triple therapy” in case of penicillin allergy  Treats anaerobic infection below the diaphragm vs clindamycin (anaerobic infections above diaphragm)  available by mouth, as a cream, and by injection into a vein  Adverse Effects: Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol; headache, metallic taste Marc Imhotep Cray, M.D.

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Antibiotics IX_Macrolides: Erythromycin, Azithromycin, and Clarithromycin MOA: The bacteriostatic macrolides bind to 50S subunit of bacterial ribosome and inhibit protein synthesis USE: effective for sexually transmitted diseases and community-acquired pneumonia  Erythromycin is active against Chlamydia, Treponema pallidum, M pneumoniae, Ureaplasma, Corynebacterium diphtheriae, and Legionella  Erythromycin’s spectrum of activity parallels penicillin used if penicillin allergy exists  Clarithromycin has greater activity against Chlamydia, Legionella, and Ureaplasma plus coverage for Haemophilus influenzae  Azithromycin is less effective than erythromycin for Streptococcus and Staphylococcus but better for respiratory infections caused by H influenza, Moraxella catarrhalis, and M pneumoniae o Azithromycin is preferred for Mycobacterium avium intracellulare complex 125

Macrolides Adverse Effects  most common adverse effect is epigastric pain  Erythromycin can cause cholestatic jaundice and thrombophlebitis should be avoided in hepatic dysfunction

 Primary mechanism of resistance = Methylase production and methylation of receptor site are established mechanisms of resistance of gram-positive organisms to macrolide antibiotics   

enzymes may be inducible by macrolides or constitutive; in latter case, cross-resistance occurs between macrolides and clindamycin Increased expression of efflux pumps is also a mechanism of macrolide resistance Esterase formation is a mechanism of macrolide resistance seen in coliforms

 Inhibition of liver cytochrome P450 by erythromycin has led to serious drug interactions  Erythromycin also inhibit CYP1A2 which metabolizes methylxanthines Marc Imhotep Cray, M.D.

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Chloramphenicol MOA Chloramphenicol Inhibits peptidyl transferase (enzyme responsible for incorporating new amino acid into growing peptide strand) on 50S ribosomal subunit USES It has broad-spectrum coverage for both gram-positive and gram-negative bacteria, and is most commonly used to treat meningitis and Rocky Mountain spotted fever ď&#x201A;§ Rarely used now due to significant side effects, which include myelosuppression (both a dose dependent anemia and dose-independent aplastic anemia) â&#x20AC;˘ Used more widely in developing countries where benefit often outweighs risk Marc Imhotep Cray, M.D.

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Fosfomycin ď&#x201A;§ Fosfomycin is a novel class of antibacterial drugs w a chemical structure unrelated to other known antibiotics ď&#x201A;§ MOA bactericidal drug that disrupts cell wall synthesis by inhibiting phosphoenolpyruvate synthetase and N-acetylmuramic acid thus interferes with production of peptidoglycan

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Fosfomycin (2) Use b/c both Gram-negative and Gram-positive bacteria require N-acetylmuramic acid for cell wall synthesis, fosfomycin is as a broad-spectrum antibiotic w activity against a wide range of bacteria, including Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter spp., Citrobacter spp. ď&#x201A;§ Oral fosfomycin is FDA approved at a single 3-g dose to treat uncomplicated urinary tract infection (UTI) (ie, acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis PK Excreted renally, thus caution in renal in kidney disease Side Effects may include: nausea, upset stomach, mild diarrhea; headache, dizziness; weakness; sore throat, runny nose; back pain; vaginal itching or discharge Marc Imhotep Cray, M.D.

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THE END

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Further study: eLearning (Cloud)  Unit 10_Antibiotics & Other Antimicrobials Learning Tools  Summary Tables on Antimicrobials  Principles-Antimicrobial Therapy, Mayo-Clinic, 2011.pdf  Antibiotics Video Lectures_Strong Medicine

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