Antimicrobial Pharmacotherapy in Children



ANTIMICROBIAL PHARMACOTHERAPY IN CHILDREN

Antibiotics and Basic Principles of Antimicrobial Therapy

Paul C. Walker, Pharm.D.

Clinical Associate Professor, College of Pharmacy

Clinical Assistant Professor, School of Nursing

The University of Michigan

These notes provide an overview of antimicrobial agents and their pharmacodynamics, and should help to explain or reinforce concepts from the required reading. The lecture notes not intended to replace or obviate the need to read the required material for this lecture as indicated in the coursepack.

I. Definitions. Two basic definitions that should be understood prior to embarking on the lecture are:

A. Antimicrobial agent – a drug that kills or inhibits the growth of microbial organisms. Antimicrobial agents are generally specific in the type of microbes they affect. Thus, there are antibiotics, antiviral agents, antifungal agents, and antiprotozoal agents.

B. Antibiotic – a drug that specifically kills or inhibits the growth of bacterial. Many antibiotics are available, each having its own spectrum of antibacterial activity and mechanisms of action.

II. Classifying Antibiotic Agents. There are a number of ways to classify antibiotics. The most common classification scheme is based on chemical structure and mechanism of action (or overall effect on the microbial cell). To cause bacterial killing, antimicrobials must gain access to the microbial cell and, without being metabolized themselves, must act on specific drug cellular targets. Antibiotics disrupt cellular function by binding to these specific targets within the cell, which may be microbial enzymes or other proteins. Based on their mechanisms of action and end result on the microbial organism, antibiotics can be classified into at least 6 groups:

1 Inhibition of cell wall synthesis

2 Alteration cell membrane permeability

3 Reversible inhibition of protein synthesis

4 Irreversible disruption of protein synthesis

5 Disruption nucleic acid metabolism

6 Blocking essential metabolic events

III. Inhibitors of Cell Wall synthesis

A. To understand how antibiotics can affect the cell wall, structure, synthesis and function of the bacterial cell wall must be considered.

Bacteria, with the exception of Chlamydia, have a semirigid cell wall containing a semi-rigid, tight-knit molecular complex called peptidoglycan. Peptidoglycan is a vast polymer consisting of interlocking chains of identical peptidoglycan monomers. A peptidoglycan monomer, which is the building block for peptidoglycan, consists of two joined amino sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), with a tetrapeptide coming off of the NAM.

Peptidoglycan monomers are synthesized in the cytosol of the bacterium, and are then transported across the cytoplasmic membrane by a transporter called bactoprenol. Enzymes insert the monomers into the existing cell wall. This is what enables bacterial growth following binary fission. Once the new peptidoglycan monomers are inserted, glycosidic bonds then link these monomers together to form long chains of peptidoglycan subunits. These long sugar chains are then joined to one another by means of peptide cross-links between the tetrapeptides coming off of the NAMs. By linking the rows and layers of sugars together in this manner, the peptide cross-links provide tremendous strength to the cell wall, enabling it to function similar to a molecular chain link fence around the bacterium.

New peptidoglycan synthesis occurs at the cell division plane by way of a collection of cell division machinery known as the divisome. The following sequence of events occurs at the divisome:

1. Bacterial enzymes called autolysins:

a. Break the glycosidic bonds between the peptidoglycan monomers at the point of growth along the existing peptidoglycan; and

b. Break the peptide cross-bridges that link the rows of sugars together

2. Transglycosidase enzymes then insert and link new peptidoglycan monomers into the breaks in the peptidoglycan

3. Finally, transpeptidase enzymes reform the peptide cross-links between the rows and layers of peptidoglycan to make the wall strong. This is called transpeptidation.

Slide 3 contains an animation of this sequence of events.

The cell walls of bacteria are essential for their normal growth and development. The cell wall is also helps with important functions, such as conferring and maintaining the cell shape and protection from lysis when the bacteria enter low solute environments. Thus it is essential to survival of the bacterium.

Comparison of the structure and composition of gram positive and gram negative cell walls: There are 3 classifications used in describing cell walls: Gram positive (gram+), Gram negative (gram-), and Acid-fast. These 3 types of cell walls all use peptidoglycan as a common component in their structures, although they differ considerably in the actual construction.

In gram (+) organisms, this matrix is about 50 to 100 molecules thick; in gram (-) organisms, it is relatively thin, being only about 1 to 2 molecules thick.

Many antibiotics work by inhibiting normal synthesis of peptidoglycan in bacteria causing them to burst as a result of osmotic lysis. Interference with this process results in a weak cell wall and lysis of the bacterium from osmotic pressure. Antibiotics that inhibit cell wall synthesis to cause loss of microbial viability: penicillins, cephalosporins, carbapenems, monobactams, and vancomycin.

B. Antibiotics that Inhibit Cell Wall Synthesis

1. Beta (() Lactam Antibiotics: This is a “family “ of antibiotics that shares a common chemical structure called the beta lactam ring. It includes several groups of antibiotics: penicillins, cephalosporins, carbapenems, and monobactams.

One mechanism involved in the antibacterial effects of (-lactam antibiotics is their action on penicillin-binding proteins PBPs. This is a family of membrane proteins that function as the (–lactam receptor. All bacteria appear to have several of types of these proteins. The PBPs vary in their affinities for different of (-lactam antibiotics. PBPs are involved in the production of peptidoglycan. Slide 7 contains an animation of the effects of penicillin (as a prototype) on transpeptidation.

a. The Penicillins: classified by spectrum of antimicrobial activity

• Natural Penicillins: Penicillin G, Penicillin V – These agents are highly active against sensitive strains of gram (+) cocci, including streptococci (S. pneumoniae, Viridans streptococci), against Neisseria sp., and against many anerobic organisms, such as Clostridium spp, Peptocococcus and Peptostreptococcus, and spirochetes. Penicillin is not effective against staphylococci because many of these organisms produce (-lactamase, an enzyme that hydrolyses the antibiotic. Some strains of B. fragilis also produce (-lactamase and also may be resistant. Finally, increasing resistance is being seen among S. pneumoniae and N. gonorrhea strains.

• Aminopenicillins: Ampicillin, Amoxicillin, Bacampicillin - Ampicillin and the two related aminopenicillins comprise a group of agents whose spectrum of activity has been extended to include some gram (-) bacteria and Enterobacteriaceae, such as E. coli, Proteus miribilis, Salmonella, Shigella. Some of these species, however, are becoming resistant. For example, it is reported that 30 to 50% of E. coli are resistant to ampicillin, and a significant number of H. influenza and Proteus mirabilis are insensitive, as well.

• Penicillinase-Resistant Penicillins: Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Nafcillin – This group of penicillins was developed in response to increasing expression of (-lactamases by staphylococci. Many organisms which are resistant to the penicillins produce these enzymes which hydrolyze the antibiotic molecule, rendering them ineffective. Oxacillin, methicillin, and nafcillin have less potent antibacterial potency against microorganisms than penicillin G; however, they are active against many penicillinase-producing staphylococci.

Carboxypenicillins: Ticarcillin, Carbenicillin. The carboxypenicillins, ticarcillin and carbenicillin, have activity against gram positive organisms similar to that of penicillin G and have increased Pseudomonas species. However, their activity against Klebsiella and H. influenza is poor. Current use of carbenicillin is mainly limited to urinary tract infections and prostatitis.

Ureidopenicillins: Mezlocillin, Pipericillin. The uriedopenicillins, mezlocillin, and pipericillin, have a spectrum of activity similar to that of ticarcillin and carbenicillin except that the range of gram (-) bacteria is broader, including Klebsiella and H. influenza. These agents also provide coverage against Pseudomonas sp., Enterobacter, and Serratia, as well as the Enterobacteriaceae.

b. The Cephalosporins: Cephalosporins are structurally similar to the penicillins. They are classified into “generations” based on features of their antimicrobial activity.

3 The first generation agents have good activity against gram (+) organisms and relatively modest activity against gram (-) bacteria. Most gram (+) cocci are sensitive to first generation agents; however, some (-lactamase producing strains and those resistant to methicillin are resistant to first generation cephalosporins.

4 Second generation cephalosporins have somewhat increased activity against gram (-) bacteria, but are much less active than the third generation drugs. A subset of second generation agents is also active against Bacteroides fragilis; this group consists of cefoxitin and cefotetan.

5 Third generation agents are substantially less active than other cephalosporins against gram (+) bacteria, but have significantly greater activity against gram (-) organisms.

6 None of the cephalosporins demonstrate reliable activity against penicillin-resistant streptococci, methicillin-resistant Staphylococcus aureus or S. epidermidis, Enterococci, or Listeria.

7 The Carbapenems and Monobactams

1 Carbapenems: Imipenem/Cilastatin, Meropenem, Ertapenem: These agents are active against a wide variety of aerobic and anerobic organisms. Their use is reserved for moderate to severe infections caused by organisms resistant to other antibiotics or polymicrobial infections. The carbapenems are effective against staphylococci, streptococci, Enterobacteriaceae (Enterobacter, Escherichia, Klebsiella, Morganella, Proteus, Providencia, Salmonella, Serratia, Shigella, and Yersinia), Pesudomonas aeruginosa, and a variety of anerobes.

o The antimicrobial activities for imipenem/cilastatin and meropenem are comparable.

▪ Meropenem is labeled for use in

□ Intra-abdominal infections (caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroids fragilis and B thetaiotaomicron, Peptostreptococcus species)

□ Meningitis, bacterial (caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis)

▪ Imipenem is labeled for use in the following infections caused by organisms such as Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa

□ Serious infections due to susceptible gram-negative organisms, multiple organism infections, gram-positive organisms, anaerobic organisms

□ Bone and joint infections

□ Endocarditis

□ Gynecologic infections

□ Intra-abdominal infections

□ Lower respiratory tract infections

□ Polymicrobic infections

□ Septicemia

□ Skin/skin structure infections

□ Urinary tract infections, complicated and uncomplicated

o Ertapenem’s antimicrobial spectrum more closely resembles that of ampicillin-sulbactam (see section below on (-lactamase and antimicrobial resistance) than that of the other carbapenems.

▪ Major side effect of concern: seizures. Risk appears lowest with meropenem and it is thus labeled for use in patients with meningitis.

▪ Imipenem is marketed as a combination product with cilastatin, an enzyme inhibitor that prevents the inactivation of imipenem by renal enzymes

2 Monobactams: Aztreonam: excellent antibacterial activity that more closely resembles that of the aminoglycosides; activity against Enterobacteriaceae, Pseudomonas aeruginosa, H. influenza, and gonococci is excellent. Gram (+) bacteria and anaerobes are generally resistant.

9 Toxicity of the Penicillins and Cephalosporins

• hepatic dysfunction

• neurotoxicity with seizures

• transient blood dyscrasias: neutropenia, leukopenia, thrombocytopenia

• allergic reactions

• phlebitis

• hypersensitivity reactions interstitial nephritis

• neurotoxicity

• renal dysfunction

• coagulopathy

11 Other Inhibitors of Cell Wall Synthesis:

c. Vancomycin: exerts its effects by binding to the cell wall precursors that form the peptidoglycan lattice, specifically to the D-alanine-D-alanine terminus of the peptidoglycan precursor. This action prevents peptidoglycan biosynthesis.

1) Pathogens usually susceptible to vancomycin include staphylococci, Streptococcus pneumoniae, Group A beta-hemolytic streptococci, enterococci, Listeria, and Corynebacteria. Most staphylococcal strains, including those resistant to methicillin, are susceptible to concentrations of vancomycin of 1.6 mcg/ml or less.

2) Vancomycin Toxicity: Nephrotoxicity, ototoxicity, Red Man Syndrome

i) Vancomycin is generally presumed to be nephrotoxic and ototoxic, however, the potential for ototoxicity or nephrotoxicity is poorly defined. When used alone, nephrotoxicity is rare and while some increases in serum creatinine may occur during treatment, a direct relationship to vancomycin has been difficult to prove. This is especially true for neonates, whose renal function is undergoing significant maturational change and because of the number of other ototoxic and nephrotoxic stimuli to which these babies are exposed. If nephrotoxicity truly occurs, its incidence appears to be very low. When used in combination with other nephrotoxic agents, such as the aminoglycosides or amphotericin B, the risk for nephrotoxicity is increased as the data available suggest that synergistic nephrotoxic effects may occur. Careful attention should be given to changes in renal function (i.e., increasing serum creatinine and BUN, decreased output), therefore, when vancomycin is used with other nephrotoxic agents and in patients with preexisting renal insufficiency/renal failure.

ii) Red man syndrome is an infusion-related anaphylactoid reaction associated with vancomycin. It is not a true hypersensitivity, but is mediated by histamine released induced by vancomycin. The syndrome manifests commonly as flushing and development of a macular or maculopapular rash of the neck, face, upper torso, and extremities. Symptoms may also include tachycardia or bradycardia, pruritus, mild pyrexia, chest pain, agitation, facial swelling, and cyanosis. In newborns, it may manifest as lethargy, poor perfusion, cold extremities, and increasing oxygen requirements. It usually occurs within 10 to 60 minutes of a dose. It is managed by increasing the duration of infusion (generally infusing the drug over 1-2 hours) and/or by premedicating the patient with antihistamines, such as diphenhydramine.

IV. Disrupters of Protein Synthesis

A. Antibiotics have numerous ways of attacking protein synthesis in bacterial cells to impair the production of proteins essential to bacterial metabolism and survival. Usually antibiotics target activities occurring at the ribosome. Most clinically useful antibiotics that work by this mechanism are specific for prokaryotic ribosomes (i.e., ribosomes of bacterial cells); prokaryotic ribosomes differ from eukaryotic ribosomes. Therefore are effective agents for the treatment of bacterial infections without harming cells containing eukaryotic ribosomes (i.e., human cells). These drugs affect the ribosome and do not bind to any other components of the protein synthesis process.

Agents that affect the function of the 30S and 50S subunits of the prokaryotic ribosome cause misreading and/or premature termination of mRNA translation. Slide 14 contains an animation depicting the effect of antibiotics on protein synthesis. The aberrant or nonfunctional proteins produced may be inserted into cell membranes to cause altered permeability, or may cause progressive disruption of other vital cellular processes within the microbe.

2 Aminoglycosides: This is a bactericidal group of antibiotics that bind to the 30s ribosomal subunit. Other mechanisms which are not yet fully understood may also be operative.

3 Ativity of the aminoglycosides is primarily directed against aerobic gram (-) bacilli; activity against gram (+) organisms is very limited (although they are sometimes used for synergy against gram (+) organisms), and they have virtually no activity against anaerobes.

1. Susceptible organisms include the Enterobacteriaceae (such as E. coli, Klebsiella, Proteus, Citrobacter, Enterobacter, Providencia). Most aminoglycosides have low activity against Serratia and Pseudomonas. The exceptions are tobramycin and amikacin, which have been effective, with MICs usually reported as less than 4 mg/ml.

2. Aminoglycosides diffuse through aqueous channels formed by porins in the outer bacterial membranes; they subsequently attain access into the cell of gram negative bacteria by being transported across the inner membrane. Antibacterial effects are mediated through binding to the 30S ribosome; attachment to this ribosomal subunit disrupts the normal cycle of ribosomal function and the initiation of protein synthesis. This leads to accumulation of abnormal initiation complexes, early termination of mRNA translation, and incorporation of incorrect amino acids into the proteins, which results in abnormal, nonfunctional bacterial proteins.

3. The available aminoglycosides include:

Kanamycin

Gentamicin

Tobramycin

Amikacin

Netilmicin

Sisomycin

Kanamycin has a limited spectrum of activity compared to the other aminoglycosides. It was used extensively in treating neonatal sepsis, but a significant amount of resistance has developed and so it is rarely, if ever, used.

4. Toxicity of Aminoglycosides:

a. Nephrotoxicity. Amioglycosides are toxic to the proximal renal tubule. Nephrotoxicity presents early as an increase in tubular cell enzyme excretion (N-acetylglucosaminidase) or increased excretion of low molecular weight proteins (b2-microglobulin), which reflect reduced reabsorption by the proximal tubule. However, patients’ urine is not monitored for these changes. Early tubular damage may progress to reduced glomerular filtration rate (GFR) with increasing serum creatinine and decreasing urine output. The extent of GFR reduction usually parallels the severity and extent of proximal tubular damage/necrosis. In most patients who manifest increased serum creatinine during aminoglycoside treatment, the renal changes are mild and reversible when the drug is discontinued.

Factors associated with aminoglycoside nephrotoxicity include dose, duration of therapy, trough serum concentrations, state of hydration, coadministration of other potentially nephrotoxic agents like vancomycin or amphotericin B.

While aminoglycoside associated nephrotoxicity is reasonably well described in adults, there is still a considerable lack of information on this problem in neonates and infants. Some studies have failed to demonstrate any significant adverse effects of these agents on the neonatal kidney. Consistent significant effects on serum creatinine have not been demonstrated, particularly in light of the normal developmental changes in serum creatinine in the first days to weeks of post-natal life. Studies that have explored enzymuria and excretion of low molecular weight proteins in neonates have failed to demonstrate any consistent findings; increased excretion of these substances has been observed in some patients, but the changes are transient and are not predictive of glomerular function impairment. A normal developmental change in the level of these substances in the urine of neonates has also been suggested, thus no conclusive evidence of aminoglycoside nephrotoxicity in the neonate has been found. Further, it is suggested that accumulation of the drugs in the proximal tubule of neonatal kidneys does not occur to the same extent as it does in adults because of immature reuptake mechanisms. Having said that, however, aminoglycoside levels and serum creatinine are routinely monitored in all pediatric patients.

b. Ototoxicity. By damaging the hair cells in the cochlear apparatus and the type 1 vestibular sensory cells, aminoglycoside antibiotics can induce high frequency hearing impairment and vestibular toxicity that may manifest as vertigo, loss of equilibrium, nystagmus, and nausea. The ototoxicity is often reversible with discontinuation of the drug, but it may lead to total irreversible deafness.

Factors associated with ototoxicity include peak and trough serum concentrations, total dose, functional renal impairment and concomitant administration of other potentially ototoxic drugs, such as furosemide. Studies using brain stem evoked audiometry have been conducted to evaluate the ototoxic potential of these agents in neonates. Results of such tests in neonates are often difficult to interpret, and the role of other potential ototoxic factors must be ruled out, including meningitis, intracranial hemorrhages and other factors. Nevertheless, well conducted studies have identified only a few cases of permanent injury to neonates receiving treatment with high doses of aminoglycosides, which suggests that these patients are less susceptible to toxicity than older patients.

10 Agents that bind to the 50S ribosome:

Chloramphenicol: effective against Streptococcus pneumonia, H. influenza, Neisseria spp., Salmonella, Bordetella, a number of Enterobacteriaceae, and a variety of anerobes Enterobacteriaceae

• Macrolides: Erythromycin, Clarithromycin, Azithromycin: Erythromycin is most effective against gram (+) aerobic cocci and bacilli, including Streptococcus pneumonia and some staphylococci. However, a number of S. aureus are resistant to erythromycin. Although erythromycin has some activity against Listeria, it is not considered a drug of choice for infections due to this organism. It is not active against gram (-) bacilli. Most strains of Chlamydia trachomatis are inhibited effectively by erythromycin, and it is also very effective against Mycoplasma.

Erythromycin: S. pneumonia, S. pyogenes, Legionella, C. trachomatis, M. catarrhalis, H. influenza, Mycoplasma pneumonia

Clarithromycin: S. pneumonia, S. pyogenes, Legionella, C. trachomatis, M. catarrhalis, H. influenza, Mycoplasma pneumonia, MAC

Azithromycin: S. pneumonia, S. pyogenes, C. trachomatis, M. catarrhalis, H. influenza, Mycoplasma pneumonia, MAC

• Clindamycin: Clindamycin demonstrates activity against most aerobic gram-positive bacteria, but it is generally inactive against enterococcus and gram negative aerobes. It has activity similar to erythromycin for staphylococcus and streptococcus. It is active against anaerobes, especially B. fragilis. Other anaerobes inhibited by clindamycin include Fusobacterium, Peptococcus, Peptostreptococcus, and Clostridium. Clindamycin is used in combination with aminoglycosides (or other antibiotics with activity against Enterobacteriaceae) to treat intra-abdominal and gynecologic infections.

11 Toxicities of these antibiotics

c. Chloramphenicol

1) The gray syndrome is cardiovascular-respiratory collapse due to excessive doses of chloramphenicol. The underlying mechanism of toxicity is hloramphenicol-induced uncoupling of oxidative phosphorylation. The gray baby syndrome is most common in neonates, especially when the drug is given within the first 48 hours of life in high doses, due to the inability of this population to metabolize and excrete the drug. Symptoms first appear after 3 to 4 days of continuous treatment; symptoms generally appear in the following order - abdominal distention with or without emesis, progressive pallid cyanosis, and vasomotor collapse frequently accompanied by irregular respiration and death within a few hours.

2) Dose-dependent bone marrow suppression. Anemia is one of the most common, dose-related adverse effects of chloramphenicol therapy. Bone marrow suppression, including leukopenia, thrombocytopenia, and aplastic anemia, may be associated with chloramphenicol use. occurs regularly when plasma concentrations exceed 25 micrograms/milliliter. Complete recovery usually occurs within 1 to 2 weeks after discontinuation of the drug. Anemic patients will not respond to iron or vitamin B12 therapy while receiving chloramphenicol.

3) Aplastic anemia, pancytopenia. This is a rare (1/40,000 to 1/100,000) but generally fatal, non-dose-related adverse effect that can occur long after a short course of chloramphenicol therapy. Complete blood counts with reticulocytes and platelets should be performed periodically.

d. Macrolides

1) GI complaints. Gastrointestinal side effects are common and dose-related. Frequently occurring adverse effects include nausea, vomiting, abdominal pain, diarrhea, and anorexia

2) Rash

e. Clindamycin

1) Diarrhea

2) Pseudomembranous colitis. Clindamycin, like other antibiotics, is known to cause pseudomembranous colitis which is also known as Clostridium difficile colitis and antibiotic associated colitis. This condition is caused by the gram positive anaerobe Clostridium difficile. Administration of clindamycin (as well as other antibiotics) alters the normal GI flora, allowing overgrowth of C. difficile. C. difficile produces two toxins which cause damage to the intestinal wall and diarrhea.

3) Rash, urticaria

4) Hypotension

Miscellaneous Antimicrobial Agents: Finally, there is a group of miscellaneous antibiotics which include rifampin, metronidazole, the quinolones like ciprofloxacin and ofloxacin, and trimethoprim and the sulfonamides.

13 Disrupters of Nucleic Acid Metabolism: Some antibiotics attack the DNA or RNA of a cell. These agents can affect the synthesis/replication of the DNA (in some case RNA) or could affect how the specific genetic "messages" are read. This mechanism serves to block the natural growth of the cell and will lead to a death without replication. Slide 19 contains an animation depicting how this might occur.

15 Metronidazole: The mechanism of action of this drug has not been fully elucidated. Metronidazole selectively produces cytotoxic effects by a reduction reaction that deprives the organism of elements essential for nucleic acid metabolism. The drug acts as a preferential electron acceptor in important metabolic reactions. Reduction of the drug generates compounds that are toxic to the cell. The toxicity is due to short-lived intermediate compounds or free radicals that produce damage by interaction with DNA and possibly other macromolecules.

Metronidazole demonstrates activity against all anerobic cocci, both anerobic gram (-) bacilli such as B. fragilis and anerobic, spore-forming gram (+) bacilli. Aerobes, non-sporulating bacilli, and facultative anaerobes are resistant to the effects of metronidazole.

1 Quinolones: Ciprofloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Trovafloxacin

f. The quinolones are rapidly bactericidal against gram (-) bacilli, including Salmonella, Shigella, Enterobacter, E. coli, Campylobacter, and Neisseria. Pseudomonal species are generally resistant; the exception is ciprofloxacin, which has demonstrated anti-Pseudomonal activity.

2 Inhibition of two important enzymes, DNA-gyrase and topoisomerase II, is the primary mechanisms of action. This blocks relaxation of coiled DNA, preventing replication, and causes breaks in the double-stranded helix

g. Common adverse effects of metronidazole and the quinolones are shown in slide 22.

16 Antimetabolites: Trimethoprim and Sulfonamides interfere with bacterial folic acid metabolism. Specifically, they inhibit the enzyme dihydrofolate reductase (DHFR) which catalyzes the reduction of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is the active form of folic acid and is required in the biosynthesis of nucleic acids.

5. Sulfonamides include sulfamethoxazole, sulfisoxazole, and silver sulfadiazine. Bactrim and Septra are combination products containing sulfamethoxazole and trimethoprim.

B. Common adverse effects of these miscellaneous antibiotics are indicated in slides 23 and 24

a. Dizziness, headache, rash, crystalluria, blood dyscrasias (neutropenia, thrombocytopenia, aplastic anemia, hemolytic anemia), jaundice, acute nephropathy, and bilirubin displacement. Sulfonamides are not indicated for use in newborns (generally within the frist 2 months of life) because of the potential to displace bilirubin from albumin binding sites and precipitating kernicterus.

Proper Antimicrobial Selection: Factors to Consider

The choice of the proper antimicrobial agent for a given patient depends on a number of factors. Factors to consider when selecting an antibiotic include the identity of the infecting organism, the available information regarding susceptibility of the infecting organism to antimicrobial agents, and some host-specific factors (such as age, allergies, co-existing disease states and concomitant therapies).

C. Identity of infecting organism. Obviously, this may be impossible to determine prior to the start of antibiotic treatment. This is where knowledge of the epidemiology of pediatric infectious diseases and institutional-specific bacteriologic statistics becomes important. Application of our knowledge about the organisms most likely to cause infection in a given setting is critical for empiric treatment.

To determine the specific etiology of a patient’s infection, bacteria are cultured from the patient’s body fluids or tissues.

D. Susceptibility of infecting organism to antibiotics. Accurate information regarding susceptibility of the infecting organism to various antibiotics is also critical, and susceptibility patterns may differ from institution to institution. Again, knowledge of your hospital’s susceptibility patterns is important.

Once the causative microorganism has been identified, it is tested for antibiotic sensitivity. This helps to determine which antibiotic therapy is appropriate for the infection. Sensitivity testing is accomplished by exposing the bacteria to different antibiotics and assessing the response. Bacteria may be said to be sensitive to an antibiotic if its growth is inhibited in the presence of the antibiotic. The sensitivity of a bacterium to an antibiotic is generally described in terms of the minimum inhibitory concentration (MIC) of the antibiotic against the microbe. Minimum inhibitory concentration (MIC) is defined as the lowest concentration of the antibiotic that inhibits the growth of the bacteria. There are a number of ways to determine the MIC: broth dilution, Kirby Bauer disk diffusion, E-test. A second term that will be discussed later is the minimum bactericidal concentration (MBC). The MBC is the lowest concentration which will kill >99.9% of the original inoculum of the organism. It is of dubious value in deciding antibiotic treatment.

Susceptibility patterns vary between geographic locations, between the hospital and the community, and between hospitals. Resistance emerges as a result of inherent characteristics of the organism which are naturally present, or as a result of transfer of resistance genes from one organism to another. Resistance is significantly influenced by our antibiotic use patterns, which may help to select out organisms who, by virtue of their natural or acquired characteristics, are resistant to the antibiotics we use.

Although the specific MIC can be reported by the laboratory, results of sensitivity testing are usually reported for the isolate as:

1. Susceptible. This implies that an infection due to the bacteria tested may be appropriately treated with the usual dosage of the tested antimicrobial agent recommended for the type of infection present clinically.

2. Resistant. This predicts possible failure of the tested antimicrobial agent. The bacteria tested are not inhibited by the antibiotic concentrations achieved with the normal dosage.

3. Intermediate. This category provides a buffer zone between Susceptible and Resistant. Susceptibility/resistance is a continuum; some organisms fall into a "gray zone" where it is difficult to predict the response to a given antibiotic. Bacteria in this category may or may not respond to therapy with the tested agent.

Mechanisms of Resistance to Antimicrobial Agents

It goes without saying that bacteria develop antibiotic resistance. The required reading by McManus (Mechanisms of bacterial resistance to antimicrobial agents. Am J HealthSystem Pharm. 1997; 54:1420-33) provides an excellent overview of this problem. Antibiotic resistance represents genetic adaptation of bacteria to the effects of the drug(s) and is directly associated with our use of antibiotics. A brief description of the 5 common mechanisms of resistance follows.

E. Bacterial production of antibiotic-inactivating enzymes: This is the most common mechanism

1. (-lactamases (enzymes that degrade (-lactam antibiotics): penicillinases, carbenicillinases, oxacillinases, cephalosporinases, carbapenemases, and other extended-spectrum penicillinases.

2. Aminoglycoside resistance-modifying enzymes, coded by genes on chromosomes or on plasmids, provide the primary means by which bacteria acquire resistance to aminoglycosides.

3. Enzymes which provide resistance to chloramphenicol (chloramphenicol acetyltransferase) and to erythromycin (erythomycin esterase)

[Remember the convention used to identify proteins that are enzymes: they end in –ase.]

4. On therapeutic strategy to address resistance caused by production of (-lactamases is the use of (-lactamase inhibitors. Three agents, sulbactam, tazobactam and clavulanic acid, are sometimes combined with penicillins in an effort to restore sensitivity to these antibiotics. Examples include Augmentin (amoxicillin + clavulanic acid), Timentin (ticarcillin + tazobactam), Unasyn (Ampicillin + Sulbactam) and Zosyn (piperacillin + tazobactam). Sulbactam, tazobactam and clavulanic acid have no inherent antibacterial activity.

F. Alterations in bacterial membrane. Many gram (-) organisms are intrinsically resistant to broad classes of antibiotics because of their complicate membrane structures that do not permit drug entry into the cell. Alterations in both the number and size of membrane pores, and changes in the lipopolysaccharide membrane structure which occur after exposure to antibiotics may lead to decreased permeability of the cell membrane to antibiotics. This has been reported for penicillins, aminoglycosides, and quinolone antibiotics.

G. Promotion of antibiotic efflux out of the cell through use of membrane bound pumps. This mechanism has been identified to mediate some resistance to tetracyclines, chloramphenicol, and quinolones.

H. Altered antibiotic target sites/ production of antibiotic-resistant targets

1. altered target enzymes

2. penicillin-binding proteins

3. altered ribosomal target sites: erythromycin resistance

4. altered cell wall precursors: vancomycin resistance

I. Synthesis of antibiotic-resistant metabolic pathway that is unaffected by the antibiotic

Slide 28 depicts several of these mechanisms that are operative in N. gonorrhea that are resistant to penicillin.

IV. Resistance: What Problems Are We Seeing? Over the last 20 years, a heterogeneous group of aerobic gram negative pathogens that are resistant to one or more class of conventional antibiotics has emerged. These organisms primarily affect critically ill hospitalized patients, particularly those in tertiary care hospitals. These patients include critically ill neonates in neonatal ICUs. The species of bacteria most frequently implicated are the gram negative rods: Enterobacter, Hemophilus influenza, Moraxella catarrhalis, Klebsiella, Citrobacter, Pseudomonas, Acinetobacter, and recently Stenotrophomonas. Resistant E. coli have also been reported.

Resistant gram (+) organisms are also a concern. All of use are familiar with the emergence of resistant staphylococci, and over the last several years, resistant streptococci have been reported with increasing frequency.

One specific area of concern is the emergence of vancomycin-resistant enterococci. These organisms are intrinsically resistant to a number of antibiotics, including aminoglycosides, penicillins, cephalosporins, azetreonam, and clindamycin. Further, resistance may be acquired to other b-lactams, aminoglycosides, chloramphenicol, and erythromycin. Therapy generally consists of combination penicillin/aminoglycoside therapy. In spite of the emerging resistance to all these antibiotics, clinicians were always comfortable relying on the enterococcus being universally susceptible to vancomycin. So even if combination therapy failed, we always had an ace-in-the-hole.

While the incidence of enterococci as a cause of neonatal sepsis is very low, as many of you are aware, there has been an alarming increase in the number of nosocomial isolates of enterococci that are now resistant to vancomycin. From 1989 to 1993, the CDC reported a significant increase in the rate of resistance, from 0.3% to 7.9%. In ICU’s, the rate increased even more, going from 0.4% to 13.6%. many VRE are also resistant to penicillin/aminoglycoside therapy. This obviously complicates our choices of antibiotic therapy and may result in increasing morbidity and mortality from enterococcal sepsis. There is also concern that the enterococci may transfer resistance to staphylococci.

Antibiotic choices for VRE: Synercid (dalfopristin + streptogramin), linezolid

A. Gram Negative Organisms

1. Hemophilus influenza, Enterobacter, Klebsiella, Citrobacter, Serratia

B. Gram Positive Organisms

1. Staphylococcus aureus (methicillin-resistant S. aureus; MRSA), Staphylococcus epidermidis (methicillin-resistant S. epidermidis ; MRSE)

2. Streptococcus pneumonia

3. Vancomycin-Resistant Enterococci (VRE)

Antibiotic Pharmacodynamics: Rate and Extent of Bactericidal Effects

As you read through the required material, it should become clear that MICs do not tell the whole story; that is, they are not solely responsible for the therapeutic outcomes in patients with infections. Other factors, such as the pharmacodynamics of the antibiotics, are also important to consider.

The study of pharmacodynamics is concerned with the relationship between concentration of the drug in the body (or tissue), particularly its concentration at the site of action, and the response produced by the drug. With respect to antibiotics, pharmacodynamics relates the time course of antibiotic concentrations to the antibacterial effects at the site of infection and to any toxic effects of the drugs. Antibiotic pharmacodynamics include the rate and extent of antibacterial action, the post-antibiotic effect, the effects of sub-inhibitory concentrations of antibiotic (i.e., concentrations below the MIC), the post-antibiotic leukocyte effect, and the inoculum effect. Knowledge of these pharmacodynamic effects or characteristics provides a more rational basis for determining how to design a dosing regimen for antibiotics.

16 Classification of Agents Based on Pharmacodynamic Characteristics

Antibiotics can exert two general effects on bacteria: they can be bactericidal or they can be bacteriostatic. Bactericidal agents kill bacteria outright. Bacteriostatic agents do not kill bacteria; these drugs inhibit the ability of the organisms to grow, which enables the body’s own defense mechanisms (e.g., white blood cells) to eliminate the bacteria. It should be noted that bacterial killing is logarithmic.

19 Concentration-Dependent Agents: These are agents that demonstrate concentration dependent bactericidal activity over a wide range of concentrations. The aminoglycosides and quinolones typify this group.

For drugs with concentration dependent bactericidal activity, the rate and extent of bactericidal action increases with increasing drug concentration above the MIC up to a maximum point, which usually occurs at 5 to 10 times the MIC. For these drugs, the kill rate is greater near the peak concentration than the kill rate engendered by concentrations near the end of the serum concentration curve (or close to the MIC. Also, the kill rate changes continuously as drug concentrations change). Slide 33 depicts concentration-dependent bacterial killing. Note that the rate and extent of bacterial killing increases significantly as the antibiotic concentration is increased from ¼X to 64X the MIC.

22 Time-Dependent Agents: agents that demonstrate time-dependent bactericidal activity that has little relationship to the magnitude of the drug concentration, as long as the concentration exceeds a given level (the MIC). This group is typified by the (-lactam antibiotics and vancomycin. Slide 34 demonstrates time-dependent killing. Note that the extent of bacterial killing is not significantly different between 4X, 16X and 64X the MIC.

23 Bacteriostatic Agents: agents that exhibit predominantly bacteriostatic effects

a. Concentration dependent antibiotics kill at a greater rate and to a greater extent with increasing antibiotic concentrations, whereas time-dependent antibiotics kill bacteria at the same rate and to the same extent once an appropriate antibiotic threshold concentration has been achieved.

b. It should be recognized that what is important for bactericidal activity is the concentration of the drug at the site of infection. The antibiotic concentration at the site of infection is highly dependent on the distribution properties of the drug; the concentration of antibiotic at the site is typically lower than that of the plasma, and the peak concentration at the site lags behind the peak in the plasma.

Slide 35 categorized the common antibiotics by their pharmacodynamic characteristics.

C. Quantifiable Pharmacodynamic Parameters.

Slide 36 presents a plot of antibiotic concentration in the plasma (y-axis) over time (x-axis). The activity of the antibiotic changes as the plasma concentration changes, with 4 distinct phases of activity being noted: cidal (bactericidal) activity, static (bacteriostatic) activity, the post-antibiotic effect (defined and discussed later), and bacterial regrowth (which occurs at some point after the antibiotic concentration falls below the inhibitory concentration (MIC). These activities are also shown at the site of infection (changes in the antibiotic concentration at the site lags behind changes in the plasma concentration due to the distribution characteristics of the drug).

Note that these 4 phases of antibacterial activity are associated with the MIC and the MBC, the plasma concentrations needed to inhibit and kill the organisms, respectively. As long as the plasma concentration of the drug is above the MBC, the antibiotic exerts bactericidal activity. When the concentration falls below the MBC but remains above the MIC, bactericidal activity is not observed, but the drug inhibits growth of the organism so that the body’s defenses can eradicate bacteria. For a short time after the drug concentration falls below the MIC, the organisms still do not grow (post-antibiotic effect; see below) even though the concentration is too low to inhibit growth. Finally, however, the post-antibiotic effect dissipates and bacterial regrowth is observed.

With this in mind, let’s look at slide 37 and discuss the pharmacodynamic parameters that have been studied and found to correlate with therapeutic outcomes. Several important points are noted in this figure:

• Cmax - the maximum antibiotic concentration in the plasma produced by the dose/dosing regimen

• T> MIC - the time during which the antibiotic concentration in the plasma is above the MIC

• AUC – the area under the concentration-time curve, is used as a measure of overall antibiotic exposure

• PAE – the post-antibiotic effect; not that it occurs after the antibiotic concentration has fallen below the MIC

Three of these quantifiable pharmacodynamic parameters have been thoroughly investigated and have been found predictive of antibiotic therapeutic outcomes:

1. For time-dependent agents, the pharmacodynamic parameter that is predictive of outcomes is T>MIC (the duration of time in which the antibiotic concentration exceeds the minimum inhibitory concentration), although in special clinical circumstances, other parameters may become more important. The optimal T>MIC has not been established and the limited data available for some pathogens suggest that > 40% (maybe even 55-100% for some drugs, pathogens, and specific infections) of the dosing interval is effective. Values for selected pathogens may differ: e.g., 24% for staphylocci, 41% for streptococci, and 36% for gram negative bacilli.

One retrospective study correlated T>MIC of greater than 40% and bacteriological cure rates of 85-100% for S. pneumoniae and H. influenza in children with acute otitis media.

2. Ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC). The most appropriate for concentration-dependent agents appears to be 5-10 times the MIC; values in this range are associated with high rates of clinical and bacteriological cure. Data from aminoglycoside and fluoroquinolone research suggest that this parameter is associated with development of resistance; if high enough levels are not attained (i.e., > 8 X MIC), the greater the likelihood that resistance will develop.

3. AUC0-24:MIC (ratio of the area under the concentration-time curve during a 24 hour dosing period to MIC). The area under the plasma concentration time curve (AUC) is very useful for calculating the relative efficiency of different drug products. It is calculated by integrating the curve over a defined time period, and proveides an measure of drug exposure. The most appropriate target for concentration dependent agents (although this varies based on the drug under consideration):

a. gram positive organisms: AUC:MIC of 30-50

b. gram negative organisms: AUC:MIC of 100-125, maybe as high as 250?

Slide 40 presents some data that shows the correlation between AUC and therapeutic outcomes. Note that the bacteriologic and clinical outcomes are better with AUC > 125.

1 .

2 Clinical Breakpoints. The clinical breakpoint is a recently developed concept that takes into consideration both organism sensitivity and antibiotic pharmacokinetics and pharmacodynamics. Clinical breakpoints are supposed to indicate at which MIC the chance of bacterial eradication (or even clinical success) of antimicrobial treatment prevails significantly over therapeutic failure, given the dosing schedule of the drug. The breakpoint thus is not only dependent on the antimicrobial activity of the drugs itself, but also on its pharmacokinetics and pharmacodynamics and can be used to determine if a given agent should be used. For example, for a given infection, 500 mg of ciprofloxacin produces a Cmax of 2.8 mg/l and an AUC of 22 mg/l/hr. The clinical breakpoint is shown as 0.25 mg/l. Infections caused by organisms with an MIC of 0.25 or lower would be expected to have a favorable outcome on this regimen, whereas ciprofloxacin would not be preferred for those infections caused by bacteria with MICs > 0.25 as they would be considered to be resistant.

3 Post-antibiotic Effect is defined as delayed regrowth of surviving bacteria following limited exposure to an antimicrobial agent. This effect is seen with the concentration dependent antibiotics. Unlike the concentration dependent agents, the time dependent agents do not usually have a clinically significant PAE; while most antibiotics can demonstrate PAE, this effect with the time-dependent agents is very short-lived and clinically insignificant.

Now let’s look at what happens after a dose of antibiotic and tie this together. When a dose of antibiotic is administered, the number of infecting organisms decreases. For bactericidal drugs, when the level of free drug exceeds the MBC of the organism, the bacterial count decreases as a result of the combined effects of the drug and host defenses. With bacteriostatic agents, when the concentration equals or exceeds the MIC of the organism, bacterial growth is halted and the decline in bacterial counts is due to the effects of host defenses alone.

Recognize that all of the organisms are not killed after a given dose; as we saw in the previous graphs, the bacterial count decreases in a logarithmic fashion, so there is always a residual amount of bacteria that remains. The size of the residual population may influence outcomes, and is dependent on the rate and extent of bactericidal action. The more rapid the kill, the smaller the residual population will be.

For time-dependent drugs [Antibiotic 1] bacterial counts are expected to fall while the concentration equals or is above the MBC. For these drugs, susceptibility to the effects of the antibiotic would be expected to increase as bacterial counts fall, so that at low bacterial counts, even very low levels of drug may still exert a considerable antibacterial effect.

For the concentration-dependent drugs [Antibiotic 2], the higher the concentration above the MBC, the faster the kill and the smaller the residual population. When levels fall below the MBC, but remain above the MIC, the number of organisms remains stable, or may continue to decrease due to the effects of host defenses. Eventually, the concentration falls below the MIC; any persistent antibacterial effects may be due to the PAE, MAC, or the PALE.

Eventually, drug effects wane and the remaining bacteria regrow. Regrowth with the time-dependent agents starts very soon after the trough concentrations fall below the MIC. Ideally, the next dose of antibiotic is given before clinically significant regrowth can occur. Repeated dosing hopefully leads to accumulation of the drug. Combined with host defenses, such dosing should effectively eradicate the pathogen.

So what dose all this mean with respect to antibiotic dosing? Theoretically, large infrequent doses of concentration dependent agents that achieve maximal peak concentrations at the site of infection should produce superior bactericidal killing with lower residual bacterial populations between doses than smaller, more frequently administered doses. Trough concentrations of these agents may fall below the MIC for a period of time during the dosing interval without loss of efficacy because regrowth is inhibited by the PAE.

One additional issue with the concentration dependent agents is the potential to reduce emergence of resistance. In this regard, peak concentrations may be important. Large initial bacterial populations increase the probability that a subpopulation of organisms will have acquired a mutation that leads to insensitivity to the antibiotic. This may be another reason that regimens that achieve more rapid bactericidal activity with high peaks are preferred.

For the time-dependent drugs, small frequent doses or continuous infusions lead to similar or superior bactericidal effects compared to infrequent large doses. This has prompted some researchers to evaluate continuous infusions of these antibiotics. Further, an agent, such as ceftriaxone, that has a prolonged half-life and that provides persistent effective levels with infrequent dosing may be advantageous. Trough levels of time dependent drugs should be maintained above the MIC for the entire dosing interval because regrowth starts very soon after the trough falls below the MIC.

Antibiotic Combinations: Rationale, Indications, and Disadvantages

Combination antibiotic therapy is not uncommon. For example, penicillins + aminoglycosides are used frequently together. The rationale is that when used together, antibiotics may demonstrate additive effects or synergistic effects.

The figure in slide 45 shows the results of additive and synergistic effects of combination therapy against bacteria. Additive effects are seen when the two drugs work by same mechanism and the net result is the sum of each drugs individual effects (sort of a 1+1=2 type of response). Synergism results when the two drugs work by different mechanisms and the net effect is greater than the sum of each drug’s individual effects.

Combination therapy is indicated for

D. Prevention of emergence of resistance

E. Polymicrobial infections - certain infections due to multiple organisms may require more than one antibiotic to adequately eradicate the infection

F. Empiric therapy - when the nature of the presumed infection is unclear; switch to a single agent as appropriate based on culture and sensitivity results

G. Reduced drug toxicity - combination therapy may allow the amount of each potentially toxic agent to be reduced and thus decrease the potential for dose related toxicity

H. Synergism - use of synergistic combinations to treat infections due to resistant or relatively resistant organisms may provide a therapeutic advantage.

Disadvantages of combination therapy may include:

1 Antagonism – where one drug significantly reduces the effectiveness of the other.

2 Increased drug costs

3 Adverse drug reactions

26 Side Effects and Adverse Drug Reactions

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