ANTI-INFECTIVE THERAPY/ 2 Aminoglycosides often rise before a significant rise in serum cre Tables 1.8 and 1.9, together with Figure 1.5, summarize nine can be detected the characteristics of the various aminoglycosides 2. Ototoxicity. Aminoglycosides enter the inner ear CHEMISTRY AND MECHANISM OF ACTION Auid and damage outer hair cells important to the Aminoglycosides were originally derived from detection of high-frequency sound. Loss of high Streptomyces species. These agents have a characteristic equency hearing occurs in 3% to 14% of patients treated with aminoglycosides. The risk of 6-member ring with amino-group substitutions, and they are highly soluble in water. At neutral ph, they are hearing loss is greater after prolonged treatment, with most cases developing after 9 or more days e con of therapy. Hearing loss is irreversible and can to their antibacterial activity. At a low pH, the charge is reduced, impairing antimicrobial activity. Their positive ter therapy has been discontinue ion has been observed with charge also causes aminoglycosides to bind to and become inactivated by B-lactam antibiotics. Therefore certain families having a high incidence of deaf- aminoglycosides should never be in the same solution ness after receiving aminoglycosides. The risk of with B-lactam antibiotics hearing loss depends on the specific aminoglyco- the bacterium, the antibiotic molecules side. Neomycin has the highest risk of toxicity, nteract with and ate dna and other anionic followed in order of decreasing frequency by gen components. Aminoglycosides also bind to the 30S sub- amicin, tobramycin, amikacin, and netilmicin Concomitant use of furosemide or vancomycin unit of bacterial 16S ribosomal rna and interfere with and exposure to loud noises increase the risk. As ranslation. These combined effects are bactericidal compared with dosing at 8-hour intervals, once- ToxICITY ly dosing reduces the toxic risk. The aminoglycosides have a narrow ratio of therapeutic ess commonly, cosides can cause neuro effect to toxic side effect, and monitoring serum levels generally required to prevent toxicity. These agents are thenia gravis. Given the high risk of toxicity,amino among the most toxic drugs prescribed today, and they glycosides should be used only when alternative should be avoided whenever safer alternative antibiotics are available(table 1. 10). required, the duration of therapy should be as brief as Two major toxicities are observed possible. Pretreatment and periodic testing of high frequency hearing should be performed, and serum 1. Nephrotoxicity. Injury to the proximal convo- creatinine and aminoglycoside serum levels should be luted tubules of the kidney leads to a reduction in monitored creatinine clearance. The brush border cells of the roximal tubule take up aminoglycosides PHARMACOKINETICS endocytosis, and intracellular entry is associated Following intravenous infusion, aminoglycosides take with cell necrosis. Aminoglycosides cause sign 15 to 30 minutes to distribute throughout the body cant reductions of glomerular filtration in 5% to Therefore, to determine peak serum level, blood samples 25% of patients. Patient characteristics associated should be drawn 30 minutes after completion of the with an increased risk of nephrotoxicity include intravenous infusion. The half-life of aminoglycosides is older age, pre-existing renal disease, hepatic dys- 2 to 5 hours, and these agents are cleared by the kidneys function, volume depletion, and hypotension. Re- Proper dosing of aminoglycosides is more compli exposure to aminoglycosides increases risk, as do cated than for most other antibiotics, and these agents the use of larger doses, more frequent dos In ais, a tervals, and treatment for more than cist is consulted to assist in dose management For daily 3 days. The risk of renal failure is also associated multiple-dose therapy, a loading dose is first given to with co-administration of vancomycin, ampho- rapidly achieve a therapeutic serum level; maintenance tericin B, clindamycin, piperacillin, cephalon- doses are then administered Doses are calculated based porins, foscarnet, or furosemide. Because renal on ideal body weight. In the setting of renal dysfunc tubular cells have regenerative power, renal dys- tion, dosing must be carefully adjusted, and peak and the aminoglycoside. Because aminoglycosides are worsens, the dosage interval should be extended arment function usually reverses on discontinuation of trough serum levels monitored. As renal impai primarily renally cleared, aminoglycoside serum Once-daily aminoglycoside dosing is now the pre- evels are actin orsinI ferred the ap unction gh aminoglycoside serum levels multidose therapy, once-daily administration reduces
Aminoglycosides Tables 1.8 and 1.9, together with Figure 1.5, summarize the characteristics of the various aminoglycosides. CHEMISTRY AND MECHANISM OF ACTION Aminoglycosides were originally derived from Streptomyces species. These agents have a characteristic 6-member ring with amino-group substitutions, and they are highly soluble in water. At neutral pH, they are positively charged, and this positive charge contributes to their antibacterial activity. At a low pH, the charge is reduced, impairing antimicrobial activity. Their positive charge also causes aminoglycosides to bind to and become inactivated by -lactam antibiotics. Therefore aminoglycosides should never be in the same solution with -lactam antibiotics. Upon entering the bacterium, the antibiotic molecules interact with and precipitate DNA and other anionic components. Aminoglycosides also bind to the 30S subunit of bacterial 16S ribosomal RNA and interfere with translation. These combined effects are bactericidal. TOXICITY The aminoglycosides have a narrow ratio of therapeutic effect to toxic side effect, and monitoring serum levels is generally required to prevent toxicity. These agents are among the most toxic drugs prescribed today, and they should be avoided whenever safer alternative antibiotics are available (Table 1.10). Two major toxicities are observed: 1. Nephrotoxicity. Injury to the proximal convoluted tubules of the kidney leads to a reduction in creatinine clearance. The brush border cells of the proximal tubule take up aminoglycosides by endocytosis, and intracellular entry is associated with cell necrosis. Aminoglycosides cause signifi- cant reductions of glomerular filtration in 5% to 25% of patients. Patient characteristics associated with an increased risk of nephrotoxicity include older age, pre-existing renal disease, hepatic dysfunction, volume depletion, and hypotension. Reexposure to aminoglycosides increases risk, as do the use of larger doses, more frequent dosing intervals, and treatment for more than 3 days. The risk of renal failure is also associated with co-administration of vancomycin, amphotericin B, clindamycin, piperacillin, cephalosporins, foscarnet, or furosemide. Because renal tubular cells have regenerative power, renal dysfunction usually reverses on discontinuation of the aminoglycoside. Because aminoglycosides are primarily renally cleared, aminoglycoside serum levels are useful for detecting worsening renal function. Trough aminoglycoside serum levels often rise before a significant rise in serum creatinine can be detected. 2. Ototoxicity. Aminoglycosides enter the inner ear fluid and damage outer hair cells important to the detection of high-frequency sound. Loss of highfrequency hearing occurs in 3% to 14% of patients treated with aminoglycosides. The risk of hearing loss is greater after prolonged treatment, with most cases developing after 9 or more days of therapy. Hearing loss is irreversible and can occur weeks after therapy has been discontinued. A genetic predisposition has been observed, with certain families having a high incidence of deafness after receiving aminoglycosides. The risk of hearing loss depends on the specific aminoglycoside. Neomycin has the highest risk of toxicity, followed in order of decreasing frequency by gentamicin, tobramycin, amikacin, and netilmicin. Concomitant use of furosemide or vancomycin, and exposure to loud noises increase the risk. As compared with dosing at 8-hour intervals, oncedaily dosing reduces the toxic risk. Less commonly, aminoglycosides can cause neuromuscular blockade; they should be avoided in myasthenia gravis. Given the high risk of toxicity, aminoglycosides should be used only when alternative antibiotics are unavailable. When aminoglycosides are required, the duration of therapy should be as brief as possible. Pretreatment and periodic testing of highfrequency hearing should be performed, and serum creatinine and aminoglycoside serum levels should be monitored. PHARMACOKINETICS Following intravenous infusion, aminoglycosides take 15 to 30 minutes to distribute throughout the body. Therefore, to determine peak serum level, blood samples should be drawn 30 minutes after completion of the intravenous infusion. The half-life of aminoglycosides is 2 to 5 hours, and these agents are cleared by the kidneys. Proper dosing of aminoglycosides is more complicated than for most other antibiotics, and these agents require close monitoring. In many hospitals, a pharmacist is consulted to assist in dose management. For daily multiple-dose therapy, a loading dose is first given to rapidly achieve a therapeutic serum level; maintenance doses are then administered. Doses are calculated based on ideal body weight. In the setting of renal dysfunction, dosing must be carefully adjusted, and peak and trough serum levels monitored. As renal impairment worsens, the dosage interval should be extended. Once-daily aminoglycoside dosing is now the preferred therapy in nearly all instances. As compared with multidose therapy, once-daily administration reduces ANTI-INFECTIVE THERAPY / 23
24/ CHAPTER 1 Table 1.8. Aminoglycosides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose for reduced Cost (trade name creatinine clearance 2 mg/kg load, 0.03 mg/kg X Crcl q8h, bramycin (Garamycin and q8h; or 5-\0 Ygh1-2ug/mL;or and tre Nebcin 5 mg/kg g24h 60-79:4mg/kgq24 50:3.5mg/kgq24h 40: 2.5 mg/kg g24h <30: Conventional dosing, adjusting trough to <0.5 ug/mL 8 mg/kg load 0.12mg/kg×crdq8h trough 5-10 5 mg/kg daily 60-79:12mg/kgq24h 50: 7.5 mg/kg q24h 40:4.0mg/kgq24h <30: Conventional dosing. justing trough to <5μg/mL Netilmicin mg/kg load, Same as gentamicin and tobramycin 2 mg/kg q8h 50-80:15mg/kgq24-72h Narrow 40:15mg/kgq72-9h 7.5 mg/kg q12h <10:75mg/kgq72-96h 15-25μgmL and trough to 5-10 ug/mL Intravenous preparations (daily cost dollars):$=20-70: $5=71-110: $$=111-150: $$=150-200: SSSS$ 2200. Includes costs of monitoring and tox Table 1.9. Organisms That May Be Susceptible to Aminoglycosides Gentamicin Amikacin Most Enterobacteriaceae Most enterobacteriaceae Most Enterobacteriaceae Yersinia pestis see Figure 1.5) Francisella tularense Francisella tularensis Pseudomonas aeruginosa Mycobacterium avium Brucella spp Brucella spp (combined with doxy (combined with doxycycline) anti-Pseudomonas penicillin cycline) Synergy with penicillins, cephalosporins M tuberculosis mycin, and ceftriaxone for S viridans Synergy with penicillins vancomycin for Enterococ
24 / CHAPTER 1 Table 1.8. Aminoglycosides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Gentamicin 2 2 mg/kg load, 0.03 mg/kg CrCl q8h, $$$$– Narrow and then adjusting peak to $$$$$ tobramycin 1.7–2 mg/kg 5–10 g/mL (Garamycin and q8h; or and trough 1–2 g/mL; or Nebcin) 5 mg/kg q24h 60–79: 4 mg/kg q24h 50: 3.5 mg/kg q24h 40: 2.5 mg/kg q24h <30: Conventional dosing, adjusting trough to <0.5 g/mL Amikacin 2 8 mg/kg load, 0.12 mg/kg CrCl q8h, $$$$– Narrow (Amikin) then adjusting peak to $$$$$ 7.5–8 mg/kg 20–40 g/mL, and q8h, or trough 5–10 g/mL, or 15 mg/kg daily 60–79: 12 mg/kg q24h 50: 7.5 mg/kg q24h 40: 4.0 mg/kg q24h <30: Conventional dosing, adjusting trough to <5 g/mL Netilmicin 2.5 2 mg/kg load, Same as gentamicin $$$$– Narrow then and tobramycin $$$$$ 2 mg/kg q8h Streptomycin 2–5 7.5 mg/kg load, 50–80: 15 mg/kg q24–72h $$$$– Narrow then 10–40: 15 mg/kg q72–96h $$$$$ 7.5 mg/kg q12h <10: 7.5 mg/kg q72–96h, adjusting peak to 15–25 g/mL and trough to 5–10 g/mL Intravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200. Includes costs of monitoring and toxicity. Table 1.9. Organisms That May Be Susceptible to Aminoglycosides Gentamicin Tobramycin Amikacin Streptomycin Most Enterobacteriaceae Most Enterobacteriaceae Most Enterobacteriaceae Yersinia pestis (see Figure 1.5) (see Figure 1.5) (see Figure 1.5) Francisella tularensis Francisella tularensis Pseudomonas aeruginosa Mycobacterium avium Brucella spp. Brucella spp. (synergy with complex (combined with doxy (combined with doxycycline) anti-Pseudomonas penicillin cycline) Synergy with penicillins, or cephalosporins) M. tuberculosis vancomycin, and ceftriaxone for S. viridans Synergy with penicillins and vancomycin for Enterococcus
ANTI-INFECTIVE THERAPY/ 25 Table 1. 10. Toxicities of miscellaneous antibiotics Clinical symptom Antibiotic 且 Allergic skin ras Steven-Johnson Diarrhea(Clost difficile) Gastrointestinal intolerance Dizziness Neurotoxicity Phlebitis Laboratory tests: Creatinine Cytopenias Eosinophilia AST/ALT个 QT prolonged Glucose↑or↓ Amylase↑ "Red man syn common, but not a true allergic reaction (see text) Gemifloxacin is associated with frequent skin rash in women under 40 years of age. evere and occasionally fatal hepatitis associated with talithromycin Black principle side effect; dark gray less common side effect; light gray = rare side effect; white= not reported or very rare; T= rise; AST/ALT= aspartate aminotransferase/alanine transaminase the concentration of the aminoglycoside that accumu- adjust for renal impairment, the daily dose should be lates in the renal cortex and lowers the incidence of reduced nephrotoxicity. Because aminoglycosides demonstrate Monitoring of serum levels is recommended for concentration-dependent killing, the high peak levels both multidose and once-daily regimens. With multi- achieved with this regimen increase the bactericidal rate dose therapy, blood for a peak level determination and prolong the post-antibiotic effect. In addition, a should be drawn 30 minutes after intravenous infu- once-daily regimen is simpler and less expensive to sion is complete, and for a trough level, 30 minutes administer. This regimen has not been associated with a before the next dose. Blood for peak and trough deter higher incidence of neuromuscular dysfunction. To minations should be drawn after the third dose of
ANTI-INFECTIVE THERAPY / 25 Table 1.10. Toxicities of Miscellaneous Antibiotics Clinical symptom Antibiotic Allergic skin rash a b c Steven–Johnson Diarrhea (Clost. difficile) Gastrointestinal intolerance Hearing loss Dizziness Neurotoxicity Seizure Musculoskeletal Phlebitis Laboratory tests: Coagulation Creatinine↑ Cytopenias Eosinophilia AST/ALT↑ d Bilirubin↑ QT prolonged Glucose↑ or ↓ Amylase↑ a “Red man syndrome” common, but not a true allergic reaction (see text). b Also photosensitivity. c Gemifloxacin is associated with frequent skin rash in women under 40 years of age. d Severe and occasionally fatal hepatitis associated with talithromycin. Black = principle side effect; dark gray less common side effect; light gray rare side effect; white not reported or very rare; ↑ rise; AST/ALT aspartate aminotransferase/alanine transaminase. Aminoglycosides Vancomycin Macrolides Clindamycin Tetracyclines Chloramphenicol Quinolons Linezolid Quinu/dalfopristin Daptomycin Meronidazole Sulfas the concentration of the aminoglycoside that accumulates in the renal cortex and lowers the incidence of nephrotoxicity. Because aminoglycosides demonstrate concentration-dependent killing, the high peak levels achieved with this regimen increase the bactericidal rate and prolong the post-antibiotic effect. In addition, a once-daily regimen is simpler and less expensive to administer. This regimen has not been associated with a higher incidence of neuromuscular dysfunction. To adjust for renal impairment, the daily dose should be reduced. Monitoring of serum levels is recommended for both multidose and once-daily regimens. With multidose therapy, blood for a peak level determination should be drawn 30 minutes after intravenous infusion is complete, and for a trough level, 30 minutes before the next dose. Blood for peak and trough determinations should be drawn after the third dose of
26/ CHAPTER 1 KEY POINTS advantage of this characteristic. Aminoglycosides also demonstrate persistent suppression of bacterial growth for I to 3 hours after the antibiotic is no longer present About Aminoglycoside Toxicity The higher the concentration of the aminoglycoside the longer the post-antibiotic effect. Aminoglycosides 1. Very low ratio of therapeutic benefit to toxic also demonstrate synergy with antibiotics that act on the cell wall(B-lactam antibiotics and glycopeptides) 2. Monitoring of serum levels usually required The effect of these combinations is greater than the sum of the anti-microbial effects of each individual 3. Nephrotoxicity commonly occurs (usually agent. Synergy has been achieved in the treatment of reversible). Incidence is higher in enterococci,S. viridans, S. aureus, coagulase-negativ a) elderly individuals staphylococci, P aeruginosa, L. monocytogenes, and JK b) patients with pre-existing renal disease, corynebacteria. c) patients with volume depletion and hypoten- An aminoglycoside in combination with other sion, and antibiotics is generally recommended for treatment of d) patients with liver disease the severely ill patients with sepsis syndrome to assure 4. Higher incidence with co-administration of broad coverage for gram-negative bacilli. An amino ancomycin, cephalosporins, clindamycin, pipe- glycoside combined with penicillin is recommende racillin, foscarnet or furosemide r empiric coverage acterial endocarditis 5.The loss of high-frequency hearing and vestibular Tobramycin combined with an anti-pseudomonal dysfunction resulting from ototoxicity is often icillin or an anti-pseudomonal cephalosporin is devastating for elderly individuals. recommended as primary treatment of p aeruginosa. 6. Neuromuscular blockade is rare Streptomycin or gentamicin is the treatment of choice 7. Once-daily therapy may be less toxic. KEY POINTS antibiotic to assure full equilibration within the dis- tribution volume. In the critically ill patient, blood for a peak level determination should be drawn after About Dosing and Serum the first dose to assure achievement of an adequate Monitoring of Aminoglycosides For once-daily do gh levels need to be moni- red to assure adequate clearance. Serum level at 18 hours 1. Aminoglycosides take 15 to 30 minutes to equi- librate in the b should be <l ug/mL. Alternatively, blood for a level deter- mination can be drawn between 6 and 14 hours, and the 2. For multidose therapy, blood for a peak serum level determination should be drawn 30 min- alue applied to a nomogram to help decide on subs utes after infusion quent doses. In the seriously ill patient, blood for a peak level determination should also be drawn 30 minutes after 3. Blood for trough serum level determinations ompletion of the infusion to assure that a therapeutic should be drawn just before the next dose el is being achieved( for gentamicin-tobramycin, a tai 4. Conventionally, aminoglycosides are given get concentration of 16 to 24 ug/mL should be achieved). times daily Dosing should be based on lean Once-daily dosing is not recommended for the treatmen ody weight of enterococcal endocarditis and has not been sufficiently 5. Once-daily dosing takes advantage of studied in pregnancy or in patients with osteomyelitis or ncentration-dependent killing and the post-antibiotic effects of ar 6. Once-daily dosing reduces, but does not elimi- SPECTRUM OF ACTIVITY AND TREATMENT RECOMMENDATIONS 7. In most cases, trough serum levels need to be The aminoglycosides are cidal for most aerobic gram monitored only during once-daily dosing Toxicity egative ding Pseudomonas species. These correlates with high trough levels. agents kill rapidly, and the killing is concentration Ince-daily dosing is not recommended for dependent-that is, the rate increases as the concentra enterococcal endocarditis or pregnant women. tion of the antibiotic increases Once-daily dosing takes
antibiotic to assure full equilibration within the distribution volume. In the critically ill patient, blood for a peak level determination should be drawn after the first dose to assure achievement of an adequate therapeutic level. For once-daily dosing, trough levels need to be monitored to assure adequate clearance. Serum level at 18 hours should be <1 g/mL. Alternatively, blood for a level determination can be drawn between 6 and 14 hours, and the value applied to a nomogram to help decide on subsequent doses. In the seriously ill patient, blood for a peak level determination should also be drawn 30 minutes after completion of the infusion to assure that a therapeutic level is being achieved (for gentamicin–tobramycin, a target concentration of 16 to 24 g/mL should be achieved). Once-daily dosing is not recommended for the treatment of enterococcal endocarditis and has not been sufficiently studied in pregnancy or in patients with osteomyelitis or cystic fibrosis. SPECTRUM OF ACTIVITY AND TREATMENT RECOMMENDATIONS The aminoglycosides are cidal for most aerobic gramnegative bacilli, including Pseudomonas species. These agents kill rapidly, and the killing is concentrationdependent—that is, the rate increases as the concentration of the antibiotic increases. Once-daily dosing takes advantage of this characteristic. Aminoglycosides also demonstrate persistent suppression of bacterial growth for 1 to 3 hours after the antibiotic is no longer present. The higher the concentration of the aminoglycoside, the longer the post-antibiotic effect. Aminoglycosides also demonstrate synergy with antibiotics that act on the cell wall (-lactam antibiotics and glycopeptides). The effect of these combinations is greater than the sum of the anti-microbial effects of each individual agent. Synergy has been achieved in the treatment of enterococci, S. viridans, S. aureus, coagulase-negative staphylococci, P. aeruginosa, L. monocytogenes, and JK corynebacteria. An aminoglycoside in combination with other antibiotics is generally recommended for treatment of the severely ill patients with sepsis syndrome to assure broad coverage for gram-negative bacilli. An aminoglycoside combined with penicillin is recommended for empiric coverage of bacterial endocarditis. Tobramycin combined with an anti-pseudomonal penicillin or an anti-pseudomonal cephalosporin is recommended as primary treatment of P. aeruginosa. Streptomycin or gentamicin is the treatment of choice for tularemia and Yersinia pestis, and either agent can 26 / CHAPTER 1 1. Very low ratio of therapeutic benefit to toxic side effect. 2. Monitoring of serum levels usually required. 3. Nephrotoxicity commonly occurs (usually reversible). Incidence is higher in a) elderly individuals, b) patients with pre-existing renal disease, c) patients with volume depletion and hypotension, and d) patients with liver disease. 4. Higher incidence with co-administration of vancomycin, cephalosporins, clindamycin, piperacillin, foscarnet, or furosemide. 5. The loss of high-frequency hearing and vestibular dysfunction resulting from ototoxicity is often devastating for elderly individuals. 6. Neuromuscular blockade is rare. 7. Once-daily therapy may be less toxic. KEY POINTS About Aminoglycoside Toxicity 1. Aminoglycosides take 15 to 30 minutes to equilibrate in the body. 2. For multidose therapy, blood for a peak serum level determination should be drawn 30 minutes after infusion. 3. Blood for trough serum level determinations should be drawn just before the next dose. 4. Conventionally, aminoglycosides are given 3 times daily. Dosing should be based on lean body weight. 5. Once-daily dosing takes advantage of concentration-dependent killing and the post-antibiotic effects of aminoglycosides. 6. Once-daily dosing reduces, but does not eliminate, nephrotoxicity. 7. In most cases, trough serum levels need to be monitored only during once-daily dosing.Toxicity correlates with high trough levels. 8. Once-daily dosing is not recommended for enterococcal endocarditis or pregnant women. KEY POINTS About Dosing and Serum Monitoring of Aminoglycosides
ANTI-INFECTIVE THERAPY/ 27 KEY POINTS KEY POINTS About Aminoglycoside Antibacterial Activity About Glycopeptide Antibacterial Activity 1. 6-Member ring, soluble in water, positively 1. Act on the cell wall of gram-positive bacteria by charged; never with cephalosporins or acidic binding to the D-alanine-D-alanine peptidogly- solutions can precursor 2. Cause temporary holes in bacterial membranes, 2. Require active bacterial growth ind to ribosomal rNa and interfere with trans- 3. Also interfere with RNA synthesis 4. Have a 2-hour post-antibiotic effect 3. Killing is concentration-dependent. 4. The higher the concentration, the longer the post-antibiotic effect. 5. Excellent gram-negative coverage; strepto- cus, and pseudomonas aeruginosa infections. apid infusion is uncommon. Ototoxicity has been reported also be used to treat brucella Gentamicin combined The half-lives of vancomycin (4 to 6 hours) and with penicillin is the treatment of choice for both teicoplanin(40 to 70 hours)are prolonged Table 1.11) S. viridans and Enterococcus faecalis in the anuric patient, the half-life of vancomycin Glycopeptide Antibiotics increases to 7 to 9 days. For vancomycin, peak levels should reach 20 to 50 ug/mL, with trough levels b Table 1. 11, together with Figure 1.5, summarizes the char- maintained at 10 to 12 ug/mL Vancomycin penetrates most tissue spaces, but does not cross the blood-brain barrier in the absence of inflammation. The CHEMISTRY AND MECHANISM OF ACTION cerebrospinal levels are achieved in patients with Vancomycin and teicoplanin are complex glycopeptides meningitis. Unlike vancomycin, which is minimally of approximately 1500 Da molecular weight. These bound to protein, teicoplanin is 90% protein-bound, agents act primarily at the cell wall of gram-positive accounting for its slow renal clearance. Tissue penetra- organisms by binding to the D-alanine-D-alanine tion has not been extensively studied, and little data are precursor and preventing it from being incorporated available on penetration of bone, peritoneal, or cere- into the peptidoglycan. The binding of vancomycin to brospinal fluid his cell wall precursor blocks the transpeptidase and transglycolase enzymes, interfering with cell wall for mation and increasing permeability of the cell. These agents may also interfere with RNA synthesis. The bind rapidly and tightly to bacteria and rapidly kill KEY POINTS actively growing organisms. They also have a 2-hour effect About Vancomycin Toxicity The most common side effect of the glycopeptide. Rapid infusion associated with "red man syn. antibiotics is "red man syndrome, " which occurs mos often when vancomycin is infused rapidly(Table 2. Phlebitis is common 1.10).The patient experiences flushing of the face, 3. Ototoxicity leading to deafness uncommon, neck, and upper thorax. This reaction is thought to be preceeded by tinnitus aused by sudden histamine release secondary to local yperosmolality and not to be a true hypersensitivity reaction. Infusing vancomycin over
also be used to treat Brucella. Gentamicin combined with penicillin is the treatment of choice for both S. viridans and Enterococcus faecalis. Glycopeptide Antibiotics Table 1.11, together with Figure 1.5, summarizes the characteristics of the glycopeptide antibiotics. CHEMISTRY AND MECHANISM OF ACTION Vancomycin and teicoplanin are complex glycopeptides of approximately 1500 Da molecular weight. These agents act primarily at the cell wall of gram-positive organisms by binding to the D-alanine–D-alanine precursor and preventing it from being incorporated into the peptidoglycan. The binding of vancomycin to this cell wall precursor blocks the transpeptidase and transglycolase enzymes, interfering with cell wall formation and increasing permeability of the cell. These agents may also interfere with RNA synthesis. They bind rapidly and tightly to bacteria and rapidly kill actively growing organisms. They also have a 2-hour post-antibiotic effect. TOXICITY The most common side effect of the glycopeptide antibiotics is “red man syndrome,” which occurs most often when vancomycin is infused rapidly (Table 1.10). The patient experiences flushing of the face, neck, and upper thorax. This reaction is thought to be caused by sudden histamine release secondary to local hyperosmolality and not to be a true hypersensitivity reaction. Infusing vancomycin over a 1-hour period usually prevents this reaction. There is less experience with teicoplanin; however, this agent does not cause significant thrombophlebitis, and skin flushing after rapid infusion is uncommon. Ototoxicity has been reported. PHARMACOKINETICS The half-lives of vancomycin (4 to 6 hours) and teicoplanin (40 to 70 hours) are prolonged Table 1.11). Both drugs are excreted primarily by the kidneys, and in the anuric patient, the half-life of vancomycin increases to 7 to 9 days. For vancomycin, peak levels should reach 20 to 50 g/mL, with trough levels being maintained at 10 to 12 g/mL. Vancomycin penetrates most tissue spaces, but does not cross the blood–brain barrier in the absence of inflammation. Therapeutic cerebrospinal levels are achieved in patients with meningitis. Unlike vancomycin, which is minimally bound to protein, teicoplanin is 90% protein-bound, accounting for its slow renal clearance. Tissue penetration has not been extensively studied, and little data are available on penetration of bone, peritoneal, or cerebrospinal fluid. ANTI-INFECTIVE THERAPY / 27 1. 6-Member ring, soluble in water, positively charged; never with cephalosporins or acidic solutions. 2. Cause temporary holes in bacterial membranes, bind to ribosomal RNA, and interfere with translation. 3. Killing is concentration-dependent. 4. The higher the concentration, the longer the post-antibiotic effect. 5. Excellent gram-negative coverage; streptomycin for tularemia and plague. 6. Synergy with penicillins in S. viridans, Enterococcus, and Pseudomonas aeruginosa infections. KEY POINTS About Aminoglycoside Antibacterial Activity 1. Act on the cell wall of gram-positive bacteria by binding to the D-alanine–D-alanine peptidoglycan precursor. 2. Require active bacterial growth. 3. Also interfere with RNA synthesis. 4. Have a 2-hour post-antibiotic effect. KEY POINTS About Glycopeptide Antibacterial Activity 1. Rapid infusion associated with “red man syndrome.” 2. Phlebitis is common. 3. Ototoxicity leading to deafness uncommon, preceeded by tinnitus 4. Rarely nephrotoxic, potentiates aminoglycoside nephrotoxicity KEY POINTS About Vancomycin Toxicity