Principles of Antimicrobial Therapy

Drugs Principles of Antimicrobial Therapy

• Antimicrobial drugs treat infections due to selective toxicity
• Selective toxicity is relative, requiring controlled drug concentrations to target microorganisms while being tolerated by the host

Selection of Antimicrobial Agents (AMAs)

• Selection requires knowing the organism's identity and susceptibility, the infection site, patient factors, agent safety, and therapy cost
• Empiric therapy involves immediate drug administration before bacterial identification and susceptibility testing

Identification of the Infecting Organism

• Identification is an essential step for proper drug selection
• Direct microscopic visualization, cultivation, and identification are common techniques

Empiric Therapy

• Antimicrobial agents should be selected after organism identification and drug susceptibility establishment
• Immediate empiric therapy is indicated in critically ill patients to avoid fatal delays
• Acutely ill patients with infections of unknown origin, such as meningitis, require immediate treatment

Selecting a Drug

• Drug choice, without susceptibility data, is influenced by the infection site and patient history such as prior infections, age, travel history, antimicrobial therapy, immune status, and whether the source was a hospital or the community Newborn infants with gram-positive cocci in spinal fluid are likely to have Streptococcus agalactiae, sensitive to penicillin G
• 40-year-old patients with gram-positive cocci in spinal fluid are likely to have S. pneumoniae, often resistant to penicillin G, requiring a third-generation cephalosporin like ceftriaxone or vancomycin

Determining Antimicrobial Susceptibility

• After culturing a pathogen, its susceptibility to specific antibiotics guides antimicrobial therapy
• Streptococcus pyogenes has predictable susceptibility patterns to certain antibiotics
• Gram-negative bacilli and staphylococcal species display unpredictable patterns, needing susceptibility testing

Bacteriostatic vs. Bactericidal Drugs

• Bacteriostatic drugs arrest bacterial growth and replication, allowing the immune system to attack
• Bactericidal drugs kill bacteria at achievable serum levels, thus being the choice for seriously ill and immunocompromised patients
• Linezolid is bacteriostatic against Staphylococcus aureus and enterococci but bactericidal against most S. pneumoniae strains

Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC)

• MIC is the lowest antimicrobial concentration preventing visible organism growth after 24 hours of incubation
• MBC is the lowest antimicrobial concentration resulting in a 99.9% decline in colony count overnight

Effect of the Site of Infection on Therapy

• Adequate antibiotic levels must reach the infection site for effective eradication
• Capillaries with varying permeability carry drugs to body tissues
• Brain capillaries forming the blood-brain barrier (BBB) impede entry of most molecules, except small and lipophilic ones
• Drug properties affecting BBB penetration include lipid solubility, weight, and protein binding
• Lipid-soluble drugs, like chloramphenicol and metronidazole, penetrate the CNS significantly
• Beta-lactam antibiotics, like penicillin, have limited penetration through an intact BBB
• Low molecular weight compounds cross the BBB easier, whereas high molecular weight compounds (e.g., vancomycin) penetrate poorly
• High protein binding restricts a drug's entry into the CSF

Patient Factors in Antibiotic Selection

• Patient condition is important, including immune system status, kidneys, liver, circulation, and age
• Pregnancy and breastfeeding affect antimicrobial agent selection
• Alcoholism, diabetes, advanced age, and immunosuppressive drugs can affect immunocompetence
• High doses of bactericidal agents or longer treatments may be needed
• Renal dysfunction can cause drug accumulation, necessitating dosage adjustments
• Direct monitoring of serum levels of vancomycin and aminoglycosides helps prevent toxicities in patients with renal dysfunction
• Liver dysfunction requires caution when using antibiotics concentrated or eliminated by the liver, for example, erythromycin and doxycycline
• Poor perfusion reduces antibiotic amount reaching the affected area, making infections difficult to treat Elderly patients with decreased renal or liver function may have altered drug pharmacokinetics
• Many antibiotics cross the placental barrier or enter breast milk, potentially causing detrimental effects, even at low concentrations

Safety and Cost of Agents

• Penicillins are among the least toxic antibiotics as they interfere with functions unique to microorganisms
• Chloramphenicol has less specificity and is reserved for life-threatening infections due to potential toxicity
• Drugs may have similar efficacy but widely vary in cost

Route of Administration

• Oral administration is suitable for mild outpatient infections
• Parenteral administration treats serious infections and drugs poorly absorbed in the GI tract
• Vancomycin and aminoglycosides are so poorly absorbed from the GI tract that serum levels cannot be attained by oral administration

Determinants of Rational Dosing

• Rational dosing of antimicrobial agents is based on pharmacodynamics and pharmacokinetic properties
• Concentration-dependent killing, time-dependent killing, and post-antibiotic effect (PAE) influence dosing frequency

Concentration-Dependent Killing

• Aminoglycosides and daptomycin show increased bacterial killing with increased antibiotic concentration
• Once-a-day bolus infusion achieves high peak levels, rapidly killing infecting pathogens
• Beta-lactams, macrolides, and clindamycin do not exhibit concentration-dependent killing

Time-Dependent Killing

• Clinical efficacy is predicted by the duration that blood concentrations remain above the MIC
• Antimicrobial drugs with a long PAE (e.g. aminoglycosides) often require only one dose per day, mainly against gram-negative bacteria

Antimicrobial Spectra

• Narrow-spectrum antibiotics act on a single or limited group of microorganisms
• Isoniazid is active only against Mycobacterium tuberculosis
• Extended-spectrum antibiotics are effective against Gram-positive organisms and a significant number of Gram-negative bacteria
• Ampicillin is considered to have an extended spectrum because it acts against Gram-positive and some Gram-negative bacteria
• Broad-spectrum antibiotics such as tetracycline, fluoroquinolones, and carbapenems affect a wide variety of microbial species
• Broad-spectrum antibiotics can drastically alter normal bacterial flora and precipitate superinfection due to organisms such as Clostridium difficile

Combinations of Antimicrobial Drugs

• It is best to treat patients with a single agent specific to the infecting organism to reduce superinfections, resistance, and toxicity
• Certain situations require combinations of antimicrobial drugs, for example, tuberculosis treatment
• Beta-lactams and aminoglycosides show synergism, making the combination more effective than either drug alone

Disadvantages of Drug Combinations

• Some antibiotics can cause bacteriostasis, which can interfere with bactericidal agents
• Tetracycline drugs can interfere with the bactericidal effects of penicillins and cephalosporins
• Unnecessary combination therapy can lead to antibiotic resistance

Drug Resistance

• Bacteria are considered resistant if the maximum tolerated antibiotic level does not halt their growth

Prophylactic Use of Antibiotics

• Certain situations, such as dental procedures and surgeries, require antibiotics for prevention
• Indiscriminate antimicrobial agent use results in bacterial resistance and superinfection
• Prophylactic use is restricted to situations where benefits outweigh risks with duration closely observed

Complications of Antibiotic Therapy

• Antibiotics don't protect against adverse effects
• Drugs may produce allergic reactions or be toxic in ways unrelated to antimicrobial activity
• Hypersensitivity or immune reactions to antimicrobial drugs is a frequent occurrence
• Penicillins can cause serious hypersensitivity problems, ranging from urticaria to anaphylactic shock
• High antibiotic serum levels may cause toxicity by directly affecting cellular processes, such as aminoglycosides causing ototoxicity
• Broad-spectrum antimicrobials or combinations can alter the normal microbial flora, leading to overgrowth of opportunistic organisms, especially fungi or resistant bacteria

Cell Wall Inhibitors (Part 1)

• Some antimicrobials interfere with bacterial cell wall synthesis
• Inhibitors of cell wall synthesis require actively proliferating microorganisms
• Beta-lactam antibiotics, vancomycin, and daptomycin are major members of this group

Penicillins

• Penicillins share chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitors
• Hydrolysis of the beta-lactam ring by bacterial beta-lactamases yields penicilloic acid, which lacks antibacterial activity
• Penicillins interfere with the last step of bacterial cell wall synthesis, resulting in cell lysis and drugs are bactericidal and work in a time-dependent fashion
• Penicillins only work against bacteria that synthesize a peptidoglycan cell wall and are ineffective against organisms lacking this structure such as mycobacteria and viruses

Resistance to Penicillins and Other Beta-Lactams

• Resistance is due to:
  • Inactivation by beta-lactamase
  • Modification of target PBPs (penicillin-binding protein)
  • Impaired penetration of drug to target PBPs
  • Antibiotic efflux
• Beta-lactamase production is the most common
• Altered target PBPs are the basis of methicillin resistance in staphylococci and penicillin resistance in pneumococci and most resistant enterococci
• Resistance due to impaired penetration of antibiotic occurs only in Gm-ve species
• Beta-lactam antibiotics cross the outer membrane and enter Gm-ve organisms via outer membrane protein channels called porins

Penicillin Pharmacokinetics

• Route of administration is determined by the drug's stability to gastric acid and infection severity
• Ampicillin with sulbactam, ticarcillin with clavulanic acid, nafcillin, and oxacillin must be administered intravenously (IV) or intramuscularly (IM)
• Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations
• Procaine penicillin G and benzathine penicillin G are depot forms and administered IM - slowly absorbed into circulation, persisting at low levels
• Most penicillins are incompletely absorbed after oral administration
• Food decreases the absorption of penicillinase-resistant penicillins
• Penicillins cross the placental barrier, but none have teratogenic effects
• Penetration into bone or cerebrospinal fluid (CSF) is insufficient unless sites are inflamed
• Primary route of excretion is by kidneys
• Patients with impaired renal function require dosage adjustments.
• Nafcillin and oxacillin are metabolized in the liver and do not require dose adjustment for renal insufficiency
• Penicillins are also excreted in breast milk

Penicillin Clinical Use

• Oral penicillins, except amoxicillin, should be administered 1-2 hours before or after a meal
• Blood levels of all penicillins can be raised by simultaneous administration of probenecid
• Penicillins should only be prescribed when there is reasonable suspicion of, or documented infection with, susceptible organisms

Types of Penicillin

• Penicillin G is a drug of choice for infections caused by streptococci, some enterococci, penicillin-susceptible pneumococci, staphylococci, and non-beta-lactamase producing organisms
• Effective doses intravenously depend on the organism, the site, and infection severity and High-dose penicillin G can also be given as a continuous intravenous infusion
• Penicillin V is only for minor infections because of its poor bioavailability, four-times-daily dosing, and narrow antibacterial spectrum
• Semisynthetic penicillins (Methicillin, Nafcillin) are indicated for infections caused by beta-lactamase producing staphylococci, and are acid-stable with reasonable bioavailability
• Extended-spectrum penicillins (Amoxicillin, Aminopenicillins, Carboxypenicillins) have greater activity against Gm-ve bacteria because of their enhanced ability to penetrate the Gm-ve outer membrane and are inactivated by beta-lactamases
• Aminopenicillins, ampicillin and amoxicillin, have similar spectrums of activity, but amoxicillin is better absorbed orally
• Amoxicillin is given orally to treat bacterial sinusitis, otitis, and lower respiratory tract infections
• Ampicillin (not amoxicillin) is effective for shigellosis
• At dosages of 4-12 g/d intravenously, ampicillin is useful for treating serious infections caused by susceptible anaerobes and enterococci but not Klebsiella, Enterobacter, P aeruginosa, and other Gm-ve aerobes commonly encountered in hospital-acquired infections
• Organisms intrinsically produce beta-lactamases that inactivate ampicillin
• Carboxypenicillins, carbenicillin and ticarcillin broaden the spectrum of penicillins against gram negative pathogens, including P aeruginosa but Piperacillin is active against many Gm-ve bacilli
• Ampicillin and amoxicillin may be available in combination with beta-lactamase inhibitors such as clavulanic acid and sulbactam that extend the activity of the penicillins

Adverse Reactions to Penicillins

• Penicillins are among the safest drugs, and blood levels are not monitored; however, adverse reactions may occur:
• Hypersensitivity: Approximately 5% of patients have some kind of reaction, ranging from rashes to angioedema and anaphylaxis, and cross-allergic reactions occur among the beta-lactam antibiotics
• Diarrhea is a common problem, specifically with antimicrobials that have an extended antibacterial spectrum, and pseudomembranous colitis may occur is rare
• Nephritis: Can cause acute interstitial nephritis, and methicillin is therefore no longer used clinically
• Neurotoxicity: Can provoke seizures when injected intrathecally or if very high blood levels reached, and epileptic patients are particularly at risk
• Hematologic toxicities: Decreased coagulation may be observed with high doses of some penicillins (piperacillin and ticarcillin) with cytopenias associated with therapy of greater than 2 weeks

Cell Wall Inhibitors (Part 2) - Cephalosporins (CPS)

• Closely related structurally and functionally to penicillins
• Same mode of action and resistance mechanisms as penicillins
• More resistant than penicillins to certain beta-lactamases

Cephalosporin Antibacterial Spectrum

• Classified as 1st, 2nd, 3rd, 4th, and advanced generation based on bacterial susceptibility patterns and resistance to beta-lactamases
• 1st generation (FG): act as penicillin G (PnG) substitutes and are resistant to staphylococcal penicillinase with modest activity against Gram- rod like E. coli, and K. pneumoniae and Most oral cavity anaerobes are sensitive, but the B. fragilis group is resistant
• 2nd generation (SG): show greater activity against H. influenzae, Enterobacter aerogenes, and some Neisseria with weaker activity against gram-positive and antimicrobial coverage includes anaerobes such as B. fragilis but neither drug is first line because of resistance among B. fragilis
• 3rd generation (TG): Used in treatment of infectious diseases but are are less potent than FG CPs against MSSA; have enhanced activity against gram-negative bacilli
• Ceftriaxone and cefotaxime have become agents of choice in the treatment of meningitis
• Ceftazidime has activity against P. aeruginosa, but resistance is increasing
• TG CPs are associated with significant “collateral damage,” that is the induction and spread of antimicrobial resistance
• 4th generation (FRG): Cefepime is classified as a FRG CP and is administered parenterally where spectrum includes streptococci and staphylococci and aerobic gram organisms
• Advanced generation: Ceftaroline is administered IV as a prodrug and has activity against MRSA where indications include complicated skin infections, or community-acquired pneumonia
• In addition to gram-positive activity, it has similar gram-negative activity to ceftriaxone
• Twice-daily dosing limits use outside of an institutional setting

Cephalosporin Pharmacokinetics

• Poor oral absorption, thus many must be administered IV or IM
• All CPs distribute well into body fluids, but few achieve adequate CSF levels
• Ceftriaxone and cefotaxime are effective in treating neonatal and childhood meningitis caused by H. influenzae
• Cefazolin is commonly used as a single prophylaxis dose
• Crosses the placenta
• Eliminated through tubular secretion or glomerular filtration and doses must be adjusted in cases of renal dysfunction
• Exception is ceftriaxone, which is excreted through the bile and employed in patients with renal insufficiency

Cephalosporin Adverse Effects

• Allergic reactions are a concern
• Patients who have had an anaphylactic response, Stevens-Johnson syndrome, or toxic epidermal necrolysis to penicillins should not receive CPs
• CPs should be avoided or used with caution in individuals with penicillin allergy
• The highest rate of allergic cross-sensitivity is between penicillin and first-generation CPs

Other Beta-Lactam Antibiotics

• Cell wall inhibitors, vancomycin and daptomycin, are summarised in table 1
• Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan with a time dependent Bactericidal
• Limited to gram-positive organisms that include Staphylococcus aureus , Streptococcus pyogenes, penicillin-resistant, S. pneumoniae, vancomycin-susceptibleEnterococcus faecalis, and E. faecium
• Given IV or PO (only for Clostridium difficile) with Renal elimination and half life of 6-10 hrs
• Daptomycin inhibits cell wall synthesis with a Concentration dependent Bactericidal with vancomycin-resistant E. faecalis and E. faecium (VRE) and it is given IV and also has Renal elimination withDose adjusted based on renal function
• Infusion related reactions ( due to histamine release), Ototoxicity and nephrotoxicity with Vancomycin and Myalgias, elevated hepatic transaminases and creatine phosphokinases with Daptomycin
• Vancomycin is drug of choice for severe MRSA infections or orally can be used for C. difficile. and daptomycin is inactivated by pulmonary surfactants so should not be used in pneumonia

Antimicrobial drugs treat infections through selective toxicity, targeting microorganisms while being tolerated by the host. Selection of antimicrobial agents requires knowing the organism's identity and susceptibility. Empiric therapy involves immediate drug administration before bacterial identification.