Cell Wall Inhibitors PDF

Cell Wall Inhibitors Dr. Thaer Abdelghani  Penicillins Cephalosporins Carbapenems Monobactams  PENICILLINS Basic structure consists of a core four-membered β- lactam ring, which is attached to a thiazolidine ring and an R side chain. Differ from one another in the R substit...

Cell Wall Inhibitors Dr. Thaer Abdelghani  Penicillins Cephalosporins Carbapenems Monobactams  PENICILLINS Basic structure consists of a core four-membered β- lactam ring, which is attached to a thiazolidine ring and an R side chain. Differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue (Figure 29.2). Nature of side chain affects the antimicrobial spectrum, stability to stomach acid, cross- hypersensitivity, and susceptibility to (β -lactamases).  Mechanism of Action Interfere with the last step of bacterial cell wall synthesis by a process known as transpeptidation. Structurally resemble terminal portion of peptidoglycan. They compete for and bind to enzymes (PBPs), which catalyze transpeptidase and facilitate cross-linking of the cell wall (Fig. 29.3). → formation of a weakened cell wall → cell death. Penicillins are regarded as bactericidal and work in a time- dependent fashion.  Antibacterial Spectrum Factors determining PBP susceptibility to these antibiotics include size, charge, and hydrophobicity of the particular β -lactam antibiotic. Gram-positive microorganisms = have cell walls that are easily traversed by penicillins → susceptible to drugs. Gram-negative microorganisms = have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. Porins - act as water-filled channels to permit transmembrane entry.  1. Natural penicillins: Penicillin G and penicillin V are obtained from fermentations of the fungus Penicillium chrysogenum. Penicillin G (benzylpenicillin) has activity against a variety of gram-positive organisms, gram-negative organisms, and spirochetes (Figure 29.4). Potency of penicillin G is (5-10) times greater than that of penicillin V against Neisseria spp. and anaerobes. Most streptococci are very sensitive to penicillin G, but penicillin-resistant viridans streptococci and S. pneumoniae isolates are emerging.  1. Natural penicillins: Majority of S. aureus are now penicillinase producing and therefore resistant to penicillin G. Penicillin remains the drug of choice for the treatment of gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum). Penicillin V, only available in oral formulation, has a spectrum similar to that of penicillin G, but it is not used for treatment of severe infections. Penicillin V is more acid stable than penicillin G (oral agent).  2. Semisynthetic penicillins: Ampicillin and amoxicillin. Also known as aminopenicillins or extended spectrum penicillins. Created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Addition of R groups extends the gram-negative antimicrobial activity of aminopenicillins to include E. coli, H. influenzae, and P. mirabilis (Fig. 29.5A). Ampicillin (with or without the addition of gentamicin) is the drug of choice for the gram-positive bacillus Listeria monocytogenes and susceptible enterococcal species.  Also widely used in the treatment of respiratory infections. Amoxicillin is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis. These drugs are co-formulated with β -lactamase inhibitors, such as clavulanic acid or sulbactam, to combat infections caused by β -lactamase - producing organisms. For example, without the β -lactamase inhibitor, methicillin- sensitive S. aureus (MSSA) is resistant to ampicillin and amoxicillin. 3. Antistaphylococcal penicillins: Methicillin, nafcillin, oxacillin, and dicloxacillin are β- lactamase (penicillinase) - resistant penicillins. Use - restricted to the treatment of infections caused by penicillinase-producing staphylococci, including MSSA. Because of its toxicity, methicillin is not used clinically in the US except in laboratory tests to identify MRSA. MRSA is resistant to most commercially available β - lactam antibiotics. Penicillinase-resistant penicillins have minimal to no activity against gram-negative infections. 4. Antipseudomonal penicillin: Piperacillinis - activity against P. aeruginosa (Fig. 29.5B). Formulation of piperacillin with tazobactam extends the antimicrobial spectrum to include penicillinase-producing organisms (most Enterobacteriaceae and Bacteroides). Figure 29.6  Resistance Resistance to β-lactam antibiotics occurs due to the following:- 1. β -Lactamase production 2. Decreased permeability to the drug 3. Altered PBPs 1. β -Lactamase production: They hydrolyzes cyclic amide bond of the β -lactam ring, → loss of bactericidal activity (Fig. 29.2). Major cause of resistance to the penicillins:- 1.Constitutive, produced by bacterial chromosome, or 2.Acquired (more commonly) by the transfer of plasmids. Some β -lactam antibiotics are poor substrates for β - lactamases and resist hydrolysis. Gram-positive secrete β -lactamases extracellularly, whereas gram-negative inactivate β -lactam drugs in the periplasmic space. 2. Decreased permeability to the drug: Decreased penetration - prevents drug from reaching target PBPs. Gram-positive - peptidoglycan layer is near the surface and there are few barriers for drug to reach its target. Gram-negative organisms - have a complex cell wall includes porins, e.g., P. aeruginosa. Also, efflux pump, actively removes antibiotics from site of action, reduce the amount of intracellular drug e.g., K. pneumoniae.  3. Altered PBPs: PBPs are bacterial enzymes involved in the synthesis of cell wall. Number of PBPs varies with the type of organism. Modified PBPs have a lower affinity for β -lactam antibiotics, requiring clinically unattainable concentrations of drug to inhibit bacterial growth. This explains MRSA resistance to most commercially available β -lactams. D. Pharmacokinetics 1. Administration 2. Routes of administration 3. Depot forms 4. Absorption 5. Distribution 6. Metabolism 7. Excretion 1. Administration: Route of administration of a β-lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. 2. Routes of administration: Combination of ampicillin with sulbactam, piperacillin with tazobactam, and the antistaphylococcal penicillins nafcillin and oxacillin must be administered IV or IM. Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations. Others are effective by oral, IV, or IM routes. Combination of amoxicillin with clavulanic acid is only available in an oral formulation in the US. 3. Depot forms: Procaine penicillin G and benzathine penicillin G are administered IM and serve as depot forms. 4. Absorption: Acidic environment within the intestinal tract is unfavorable for the absorption of penicillins. In the case of penicillin V, only one-third of an oral dose is absorbed under the best of conditions. Food decreases the absorption of the penicillinase resistant penicillin dicloxacillin because as gastric emptying time increases, the drug is destroyed by stomach acid → should be taken on an empty stomach. Conversely, amoxicillin is stable in acid and is readily absorbed from the GIT. 5. Distribution: β-lactam antibiotics distribute well throughout the body. All penicillins cross placental - no teratogenic effects. However, penetration into bone or CSF is insufficient for therapy unless these sites are inflamed (Fig. 29.7 and 29.8). Penicillin levels in the prostate are insufficient to be effective against infections. 6. Metabolism: Metabolism of the β-lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function. Nafcillin and oxacillin are exceptions and are primarily metabolized in the liver. 7. Excretion: Primary route of excretion is through the organic acid (tubular) secretory system as well as by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted. Nafcillin and oxacillin are primarily metabolized in the liver, they do not require dose adjustment for renal insufficiency. Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter and, thus, can increase blood levels. Penicillins are also excreted in breast milk.  E. Adverse Reactions Penicillins are among the safest drugs. 1. Hypersensitivity: Approximately 10 % of patients report allergy to penicillin. Reactions range from rashes to anaphylaxis. Cross-allergic reactions occur among β-lactam antibiotics. 2. Diarrhea: Diarrhea is a common problem. Pseudomembranous colitis from C. difficile. 3. Nephritis: Penicillins, particularly methicillin, cause acute nephritis. [Methicillin is no longer used clinically] 4. Neurotoxicity: Seizures - if injected intrathecally or if very high blood levels are reached. 5. Hematologic toxicities: Decreased coagulation may be observed with high doses of piperacillin, nafcillin, and to some extent, with penicillin G. Cytopenias have been associated with therapy of greater than 2 weeks, and therefore, blood counts should be monitored weekly for such patients.  Cephalosporins β-lactam antibiotics closely related both structurally and functionally to penicillins. Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7 aminocephalosporanic acid. Structural changes on the acyl side chain at the 7-position alter antibacterial activity and variations at the 3-position modify the pharmacokinetic profile (Figure 29.10). Cephalosporins have same mode of action as penicillins, and they are affected by the same resistance mechanisms. More resistant than penicillins to certain β -lactamases. A. Antibacterial spectrum Classified based largely on their bacterial susceptibility patterns and resistance to β - lactamases (Fig. 29.11). 1. First generation 2. Second generation 3. Third generation 4. Fourth generation 5. Advanced generation 1. First generation: Act as penicillin G substitutes. Resistant to the staphylococcal penicillinase (MSSA). S. pneumoniae resistant to penicillin & first- generation cephalosporins. Modest activity against Proteus mirabilis, E. coli, and K. pneumoniae. Most oral cavity anaerobes (Peptostreptococcus) are sensitive, but Bacteroides fragilis is resistant. 2. Second generation: Greater activity against gram - negative organisms, whereas activity against gram - positive organisms is weaker. Antimicrobial coverage of the cephamycins (cefotetan and cefoxitin) includes anaerobes (Bacteroides fragilis). 3. Third generation: Assumed an important role in the treatment of infectious diseases. Less potent than first-generation against MSSA. Enhanced activity against gram-negative bacilli, including β -lactamase producing strains of H. influenzae and N. gonorrhoeae. Spectrum of activity includes enteric organisms, such as Serratia marcescens and Providencia species. 3. Third generation: Ceftriaxone and cefotaxime have become agents of choice in the treatment of meningitis. Ceftazidime has activity against P. aeruginosa; however, resistance is increasing and use should be evaluated on a case-by-case basis. Caution - associated with development of C. difficile infection. 4. Fourth generation: Cefepime - must be administered parenterally. Cefepime has a wide antibacterial spectrum activity against streptococci and staphylococci (but only those that are methicillin susceptible). Cefepime is also effective against aerobic gram- negative organisms, such as Enterobacter species, E. coli, K pneumoniae, P. mirabilis, and P. aeruginosa. 5. Advanced generation: Ceftaroline is a broad spectrum, advanced-generation. It is the only β -lactam in the US with activity against MRSA, and it is indicated for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. Unique structure - bind to PBPs found in MRSA and penicillin-resistant S. pneumoniae. Broad gram-positive activity, also has similar gram- negative activity to the third-generation ceftriaxone. Twice-daily dosing regimen also limits use outside of an institutional setting. B. Resistance Resistance to the cephalosporins is either due to the hydrolysis of the β-lactam ring by β-lactamases or reduced affinity for PBPs.  C. Pharmacokinetics 1. Administration: Many cephalosporins must be administered IV or IM because of their poor oral absorption (Fig. 29.12). Exceptions noted in (Fig. 29.13). 2. Distribution: All cephalosporins distribute very well into body fluids. Adequate therapeutic levels in the CSF, regardless of inflammation, achieved with only few cephalosporins. For example, ceftriaxone and cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by H. influenzae. Cefazolin is commonly used for surgical prophylaxis due to its activity against penicillinase-producing S. aureus, along with its good tissue & fluid penetration. 3. Elimination: Eliminated through tubular secretion and/or glomerular filtration (Fig. 29.12). Doses must be adjusted in renal dysfunction to guard against accumulation and toxicity. One exception is ceftriaxone, which is excreted through the bile into the feces and, therefore, is frequently employed in patients with renal insufficiency. D. Adverse effects Cephalosporins are generally well tolerated like penicillins. Allergic reactions are a concern. Cephalosporins should be avoided or used with caution in individuals with penicillin allergy. Cross-reactivity between penicillin and cephalosporins is around 3% - 5% and is determined by the similarity in the side chain, not the β –lactam structure. Other β-Lactam Antibiotics A. Carbapenems B. Monobactams A. Carbapenems Carbapenems are synthetic β -lactam antibiotics. Differ in structure from the penicillins in that the sulfur atom of the thiazolidine ring (Fig. 29.2) has been replaced by a carbon atom (Fig. 29.14). Imipenem, meropenem, doripenem, and ertapenem. 1. Antibacterial spectrum: Imipenem resists hydrolysis by most β -lactamases, but not the metallo- β -lactamases. Drug plays a role in empiric therapy because it is active against β -lactamase-producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa (Fig. 29.15). Meropenem and doripenem have antibacterial activity similar to that of imipenem. Ertapenem (unlike other carbapenems), lacks coverage against P. aeruginosa, Enterococcus species, and Acinetobacter species. 2. Pharmacokinetics: Imipenem, meropenem, and doripenem are administered IV, penetrate well body tissues and fluids, including CSF when the meninges are inflamed. Meropenem - reach therapeutic levels in bacterial meningitis even without inflammation. Excreted by glomerular filtration. Imipenem undergoes cleavage by a dehydropeptidase of the proximal renal tubule. Compounding imipenem with cilastatin protects it from renal dehydropeptidase → prolongs its activity in body. Other carbapenems do not require coadministration of cilastatin. Ertapenem is administered IV once daily.  3. Adverse effects: 1. Imipenem / cilastatin can cause nausea, vomiting, and diarrhea. 2. Eosinophilia and neutropenia are less common than with other β -lactams. 3. High levels of imipenem may provoke seizures. 4. Cross - reactivity of carbapenems and penicillin (less than 1%).  B. Monobactams Monobactams, also disrupt bacterial cell wall synthesis, are unique because the β -lactam ring is not fused to another ring (Fig. 29.14). Aztreonam, is the only commercially available one. Antimicrobial activity directed primarily against gram-negative pathogens, including the Enterobacteriaceae and P. aeruginosa. Lacks activity against gram-positive and anaerobes. Aztreonam is administered either IV or IM and can accumulate in patients with renal failure.  Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash, and, occasionally, abnormal liver function tests. Has a low immunogenic potential, and it shows little cross-reactivity with antibodies induced by other β -lactams. Thus, this drug may offer a safe alternative for treating patients who are allergic to other penicillins, cephalosporins, or carbapenems.  V. β -Lactamase inhibitors Hydrolysis of β -lactam ring, either by enzymatic cleavage with β -lactamase or by acid, destroys the antimicrobial activity. β -Lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam), contain β -lactam ring, by themselves, do not have significant antibacterial activity. Avibactam and vaborbactam are also β - lactamase inhibitors; however, their structures lack the core β -lactam ring. β -Lactamase inhibitors function by inactivating β -lactamases → protecting the antibiotics.  β -lactamase inhibitors, therefore, formulated in combination with β -lactamase - sensitive antibiotics, such as amoxicillin, ampicillin, and piperacillin (Fig. 29.1). Effect of clavulanic acid and amoxicillin on the growth of β -lactamase - producing E. coli are shown in (Fig. 29.16).  A. Cephalosporin and β - lactamase inhibitor combinations Ceftolozane is 3rd - generation cephalosporin combined with the β -lactamase inhibitor, tazobactam. Only available IV formulation. Main use is the treatment of resistant Enterobacteriaceae and multidrug resistant P. aeruginosa. Has activity against some β -lactamase-producing bacteria (strains of ESBLs). This combination has narrow gram-positive and very limited anaerobic activity.  Ceftazidime, 3rd - generation cephalosporin is combined with the β -lactamase inhibitor avibactam. Ceftazidime-avibactam, available only in IV formulation. Has broad gram-negative activity including Enterobacteriaceae and P. aeruginosa. Has minimal activity against Acinetobacter as well as anaerobic and gram-positive organisms.  Both of these combinations are indicated for the treatment of intra-abdominal infections (in combination with metronidazole) and for the management of complicated UTI. Given the extensive antimicrobial activity, ceftolozane - tazobactam and ceftazidime – avibactam are reserved for the treatment of infections due to multidrug-resistant pathogens.  B. Carbapenem / β- lactamase inhibitor combination Meropene - vaborbactam is a combination of a carbapenem and a β - lactamase inhibitor. It is approved for the treatment of complicated UTI including pyelonephritis. This combination agent has activity against Enterobacteriaceae producing a broad spectrum of β -lactamases, except metallo- β -lactamases.  VANCOMYCIN Tricyclic glycopeptide active against aerobic and anaerobic gram-positive bacteria, including MRSA, MRSE, Enterococcus spp., and C. difficile (Fig. 29.17). Binds to peptidoglycan precursors, disrupting polymerization and cross - linking required for maintenance of cell wall integrity. Bactericidal activity.  Vancomycin is commonly used in patients with skin and soft tissue infections, infective endocarditis, and nosocomial pneumonia. Frequency of administration is dependent on renal function. Monitoring of creatinine clearance is required to optimize exposure and minimize toxicity. Common adverse events include nephrotoxicity, infusion-related reactions (red man syndrome and phlebitis), and ototoxicity.  Emergence of resistance is uncommon within Streptococcus and Staphylococcus spp., but frequently observed in Enterococcus faecium infections. Resistance is driven by alterations in binding affinity to peptidoglycan precursors. Vancomycin has poor absorption after oral administration. Use of oral formulation is limited to the management of C. difficile infection in the colon. LIPOGLYCOPEPTIDES Telavancin, oritavancin, and dalbavancin are bactericidal concentration-dependent semisynthetic lipoglycopeptide antibiotics with activity against gram-positive bacteria. Lipoglycopeptides maintain a spectrum of activity similar to vancomycin. Because of structural differences, they are more potent than vancomycin and may have activity against vancomycin- resistant isolates. Like vancomycin, they inhibit bacterial cell wall synthesis. Additionally, telavancin and oritavancin disrupt membrane potential.  In combination, these actions improve activity and minimize selection of resistance. Telavancin is considered an alternative to vancomycin in treating acute bacterial skin and skin structure infections (ABSSSIs) and hospital-acquired pneumonia caused by resistant gram-positive organisms, including MRSA. Use of telavancin in clinical practice may be limited by its adverse effect profile, which includes nephrotoxicity, and interactions with medications known to prolong the OTC interval (fluoroquinolones, macrolides).  Oritavancin and dalbavancin (in contrast to telavancin), have prolonged half-lives (245 - 187 hrs, respectively), allowing for single-dose of ABSSSI. Oritavancin and telavancin are known to interfere with phospholipid reagents used in assessing coagulation. Alternative therapy should be considered with concomitant heparin use.  DAPTOMYCIN Bactericidal concentration-dependent cyclic lipopeptide antibiotic. Alternative to other agents, such as vancomycin or linezolid, for treating infections caused by resistant gram- positive organisms, including MRSA and VRE (Fig. 29.18).  Indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus, including endocarditis. It is inactivated by pulmonary surfactants; thus, it should never be used in the treatment of pneumonia. Daptomycin is dosed IV once daily. Fig. 29.19 provides a comparison of important characteristics of vancomycin, daptomycin, and lipoglycopeptides.  FOSFOMYCIN Fosfomycin is a bactericidal synthetic derivative of phosphonic acid. It blocks cell wall synthesis by inhibiting the enzyme enolpyruvyl transferase, a key step in peptidoglycan synthesis. Indicated for UTI caused by E. coli or E. faecalis and is considered first-line therapy for acute cystitis. Due to its unique structure and mechanism of action, cross-resistance with other antimicrobials is unlikely.  Rapidly absorbed after oral administration and distributes well to the kidneys, bladder, and prostate. Excreted in its active form in the urine and maintains high concentrations over several days, allowing for a one-time dose. (Parenteral formulation is available in select countries). Most commonly reported adverse effects include diarrhea, vaginitis, nausea, and headache.  POLYMYXINS Cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria. They have a detergent-like effect that disrupts cell membrane integrity, leading to leakage of cellular components and cell death. Polymyxins are concentration- dependent bactericidal agents. Activity against most clinically important gram-negative bacteria, including P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter spp., and Enterobacter spp.  Only two forms of polymyxin are in clinical use today, polymyxin B and colistin (polymyxin E). Polymyxin B is available in parenteral, ophthalmic, otic, and topical preparations. Colistin is only available as a prodrug, colistimethate sodium, which is administered IV or inhaled. Use of these drugs has been limited due to the increased risk of nephrotoxicity and neurotoxicity (slurred speech, muscle weakness) when used systemically. Increasing gram-negative resistance intrinsically. THANK YOU