《传染病学 Infectious Disease》课程教学资源（MBBS）课程参考书籍教材：Infectious Diseases, A Clinical Short Course, Second Edition

28/ CHAPTER 1 Table 1.11. Glycopeptides, Macrolides, Clindamycin, Tetracyclines, and Chloramphenicol: Half-Life Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose for reduced Costa (h) creatinine clearance 5mg/kgⅣq12h 40-60:1gq12-24h Narrow (Vancocin (usual dose: 1 g q12h) 20-40: q24-48h 10-20:q48-72h <10q3-7d on levels. trough:10-12μg/mL Teicoplanin 40-70 6 mg/kg IV or IM 10-50: Half the dose Not sold in Narrow <10: One third the dose United States 1. 2-1.6 250-500 mg PO q6h No change required 1gⅣq6h 250-500 mg Po q12h<10:250-500mgq24hs-5 (Biaxin, Biaxin XL) (Zithromax) 10 800 mg PO q24h <30:600mgq24h Narrow Clindamycin 150-300mgPo No change required PO: SSSSs Narrow 300-900mgⅣ Tetracycline 250-500mgPo 50-80:q12h 10-50:q12-24h <10:q24 200 mg PO No change required Minocin, Dynacin twice daily Tigecycline For severe hepatic 50 mg Iv q12h dysfunction 25 mg Iv q12h 025-1gⅣq6h Broad enous preparations( daily cost dollars): $=20-70: $s571-110: SSS =111-150: SSSS=150-200: SSSS$> 200; oral preparations(10- day course cost dollars):5=10-5055=51-100555=101-140:5555=141-180;5552180

28 / CHAPTER 1 Table 1.11. Glycopeptides, Macrolides, Clindamycin, Tetracyclines, and Chloramphenicol: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Vancomycin 4–6 15 mg/kg IV q12h 40–60: 1 g q12–24h $ Narrow (Vancocin) (usual dose: 1 g q12h) 20–40: q24–48h 10–20: q48–72h <10: q3–7d Exact dose based on levels: peak: 25–50 g/mL; trough: 10–12 g/mL Teicoplanin 40–70 6 mg/kg IV or IM 10–50: Half the dose Not sold in Narrow (Targocid) followed by <10: One third the dose United 3 mg/kg q24h States Erythromycin 1.2–1.6 250-500 mg PO q6h No change required $ Narrow 1 g IV q6h Clarithromycin 4 250–500 mg PO q12h <10: 250–500 mg q24h $–$$ Narrow (Biaxin, Biaxin XL) XL: 1 g PO q24h Azithromycin 68 500 mg PO, Probably no change $ Narrow (Zithromax) followed by required 250 mg PO q24h, or <10: Not studied 500 mg IV q24h Talithromycin 10 800 mg PO q24h <30: 600 mg q24h $$ Narrow (Ketek) Clindamycin 2.5 150–300 mg PO q6h No change required PO: $$$$$ Narrow (Cleocin) 300–900 mg IV q6–8h IV: $ Tetracycline 8 250–500 mg PO 50–80: q12h $ Broad twice daily 10–50: q12–24h <10: q24h Doxycycline 18 100 mg PO No change required $ Broad (Vibramycin, Doxy) twice daily Minocycline 16 200 mg PO No change required $ Broad (Minocin, Dynacin) twice daily Tigecycline 42 100 mg IV, No change required. $$ Very (Tygecil) followed by For severe hepatic broad 50 mg IV q12h dysfunction, maintenance dose: 25 mg IV q12h Chloramphenicol 4 0.25–1 g IV q6h No change required. $ Broad (Chloromycetin) Serum levels should be monitored in hepatic failure. a Intravenous preparations (daily cost dollars): $ = 20–70; $$ 5 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oral preparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180

ANTI-INFECTIVE THERAPY/ 29 ANTIMICROBIAL SPECTRUM AND TREATMENT RECOMMENDATIONS KEY POINTS Vancomycin and teicoplanin both cover MRSA and MSSA, and they are the recommended treatment for About the treatment recommendations MRSA. These agents also kill most strains of coagulase- for Vancomycin negative staphylococci (S epidermidis), which are usually methicillin-resistant. They are recommended for the and bacterial endocarditis. For th phylococcal line sepsis 1. Treatment of choice for methicillin-resistant glycopeptide antibiotic should be combined with one or strains have been reported more additional antibiotics(see Chapter 7). Vancomycin 2. Treatment of choice for coagulase-negative ntermediately-resistant strains of S. aureus were first staphylococci. scovered in Japan and have also 3. Excellent activity against high-level penicillin- Europe and the United States. These strains have MICs of resistant Streptococcus pneumoniae 8 to 16 ug/mL and are cross-resistant to teicoplanin. The illin-allergic patient, vancomycin is increasing use of vancomycin has selected for these recommended for Strep pyogenes, Gp B strepto- and warns us that the indiscriminant use of the glycopep- occi, Strep viridans, and Strep bovis. tide antibiotics must be avoided 5. Excellent activity against some strains of Ente ancomycin and teicoplanin not only have exceller rococcus;however, van a gene-mediated ctivity against Staphylococcus, but also against penicillin vancomycin-resistant enterococci (VRE)are resistant and tible strains of S pneumoniae, and th increasing in frequency are recommended for empiric treatment of the seriously ill 6. Vancomycin use must be restricted to reduce patient with pneumococcal meningitis to cover for highly the likelihood of selecting for VRE and van resistant strains. The glycopeptide antibiotI comycin-tolerant Staph aureus. also effectively treat S. pyogenes, GpB streptococci, S viridans, and S. bovis, and they are recommended for treatment of these infections in the penicillin-all patient. Corynebacterium jeikeium(previously called JK CHEMISTRY AND MECHANISM OF ACTION diphtheroids)is sensitive to vancomycin, and that antibi- The founding member of the macrolide family, ery- tic is recommended for its atment. Oral hromycin, was originally purified from a soil bac clears C dificile from the bowel, and in the past it was terium. It has a complex 14-member macrocyclic recommended for C difficile toxin-associated diarrhea. lactone ring(which gives rise to the class name However, because of the increased risk of developing VRE "macrolides")attached to two sugars. Azithromycin has following oral vancomycin, this regimen is recommended a 15-member lactone ring and a nitrogen substitution only for cases that are refractory to metronidazole or for Clarithromycin has a methoxy group modification at atients who are very carbon 6 of the erythromycin molecule. These modifi Vancomycin is frequently used to treat Enterococcus cations enhance oral absorption and broaden the faecalis and faecium, however, an increasing number of antimicrobial spectrum strains have become resistant. Three gene complexes The newest class of macrolide- like agents are the transfer resistance. The van A gene cluster directs peptide semisynthetic derivatives of erythromycin called glycan cell wall synthesis and coverts D-alanine-D-alanine ketolides. The ketolides, represented by talithro the site of vancomycin action)to D-alanine-D-lactate, mycin, have a 14-member macrolactone ring with a markedly reducing vancomycin and teicoplanin binding keto group at position 3, with the hydroxyls at The other two resistance gene clusters, van B and van C, positions d 12 replaced by cyclic carbam result in vancomycin resistance, but do not impair These agents all inhibit protein biosynthesis by block- teicoplanin activity. ing the passage of nascent proteins through the Macrolides and ketolides ribosome exit tunnel. in the case of conventional macrolides, inhibition is accomplished by binding to Tables 1 11 and 1.12, together with Figure 1.5, summa- a single domain of the 50S ribosomal subunit rizes the chracteristics of the macrolides and ketolides. (domain V of the 23 rRNA molecule). As compared

ANTIMICROBIAL SPECTRUM AND TREATMENT RECOMMENDATIONS Vancomycin and teicoplanin both cover MRSA and MSSA, and they are the recommended treatment for MRSA. These agents also kill most strains of coagulase￾negative staphylococci (S. epidermidis), which are usually methicillin-resistant. They are recommended for the treatment of coagulase-negative staphylococcal line sepsis and bacterial endocarditis. For the latter infection, the glycopeptide antibiotic should be combined with one or more additional antibiotics (see Chapter 7). Vancomycin￾intermediately-resistant strains of S. aureus were first discovered in Japan and have also been identified in Europe and the United States. These strains have MICs of 8 to 16 g/mL and are cross-resistant to teicoplanin. The increasing use of vancomycin has selected for these strains and warns us that the indiscriminant use of the glycopep￾tide antibiotics must be avoided. Vancomycin and teicoplanin not only have excellent activity against Staphylococcus, but also against penicillin￾resistant and susceptible strains of S. pneumoniae, and they are recommended for empiric treatment of the seriously ill patient with pneumococcal meningitis to cover for highly penicillin-resistant strains. The glycopeptide antibiotics also effectively treat S. pyogenes, GpB streptococci, S. viridans, and S. bovis, and they are recommended for treatment of these infections in the penicillin-allergic patient. Corynebacterium jeikeium (previously called JK diphtheroids) is sensitive to vancomycin, and that antibi￾otic is recommended for its treatment. Oral vancomycin clears C. difficile from the bowel, and in the past it was recommended for C. difficile toxin–associated diarrhea. However, because of the increased risk of developing VRE following oral vancomycin, this regimen is recommended only for cases that are refractory to metronidazole or for patients who are very seriously ill. Vancomycin is frequently used to treat Enterococcus faecalis and faecium; however, an increasing number of strains have become resistant. Three gene complexes transfer resistance. The van A gene cluster directs peptido￾glycan cell wall synthesis and coverts D-alanine–D-alanine (the site of vancomycin action) to D-alanine–D-lactate, markedly reducing vancomycin and teicoplanin binding. The other two resistance gene clusters, van B and van C, result in vancomycin resistance, but do not impair teicoplanin activity. Macrolides and Ketolides Tables 1.11 and 1.12, together with Figure 1.5, summa￾rizes the chracteristics of the macrolides and ketolides. CHEMISTRY AND MECHANISM OF ACTION The founding member of the macrolide family, ery￾thromycin, was originally purified from a soil bac￾terium. It has a complex 14-member macrocyclic lactone ring (which gives rise to the class name “macrolides”) attached to two sugars. Azithromycin has a 15-member lactone ring and a nitrogen substitution. Clarithromycin has a methoxy group modification at carbon 6 of the erythromycin molecule. These modifi- cations enhance oral absorption and broaden the antimicrobial spectrum. The newest class of macrolide-like agents are the semisynthetic derivatives of erythromycin called ketolides. The ketolides, represented by talithro￾mycin, have a 14-member macrolactone ring with a keto group at position 3, with the hydroxyls at positions 11 and 12 replaced by a cyclic carbamate. These agents all inhibit protein biosynthesis by block￾ing the passage of nascent proteins through the ribosome exit tunnel. In the case of conventional macrolides, inhibition is accomplished by binding to a single domain of the 50S ribosomal subunit (domain V of the 23 rRNA molecule). As compared ANTI-INFECTIVE THERAPY / 29 1. Treatment of choice for methicillin-resistant Staphylococcus aureus; vancomycin-tolerant strains have been reported. 2. Treatment of choice for coagulase-negative staphylococci. 3. Excellent activity against high-level penicillin￾resistant Streptococcus pneumoniae. 4. In the penicillin-allergic patient, vancomycin is recommended for Strep. pyogenes, Gp B strepto￾cocci, Strep. viridans, and Strep. bovis. 5. Excellent activity against some strains of Ente￾rococcus; however,van A gene–mediated vancomycin-resistant enterococci (VRE) are increasing in frequency. 6. Vancomycin use must be restricted to reduce the likelihood of selecting for VRE and van￾comycin-tolerant Staph. aureus. KEY POINTS About the Treatment Recommendations for Vancomycin

CHAPTER 1 Table 1. 12. Organisms That May Be Susceptible to Macrolides and Ketolides Azithromycin Streptococcus pyogenes More active against Less active against Most active against S pyogenes S pyogenes S pyogenes S pneumoniae More active against Less active against Active against some PCN-sensitive PCN-sensitive erythromycin-resistant strains Mouth flora includin anaerobes, but not Active against multiresistant Bacteroides fragil All pathogens covered all pathogens covered Neisseria gonorrhoeae by erythromycin, plus by erythromycin, plus All pathogens covered more active against by erythromycin, plus: H influenzae Moraxella catarrhalis Most active against Moraxella catarrhalis Borrelia burgdorfer Most active against Good activity against Mycoplasma pneumoniae Mycobacterium avium M avium complex Ureaplasma ureal Helicobacter pylori but not enterococcus faecium Chlamydia trachomatis Toxoplasma gondii Plasmodium falciparum H influenzae Corynebacterium diphtheriae M. avium Bartonella quintana with the macro-lides, telithromycin binds to the 50s ally fatal hepatitis. All patients receiving this agent should ubunit with higher affinity, binding to two regions of therefore be warned of this potential side effect, and the the 23S rRNA molecule(domains II and V) rather drug should be prescribed only for cases of pneumonia in than one region. This unique binding mode explains which the incidence of penicillin-resistant S. pneumoniae the enhanced antimicrobial activity of ketolides is high. Under these circumstance a Huoroqu nst macrolide-resistant pathogens gram-positive coverage may be preferred ToxICITY Macrolides and ketolides may exacerbate myasthenia gravis and should be avoided in patients with that ill Macrolides and ketolides are among the safer classes ness. Macrolides prolong the QT interval, and ery- of antibiotics(Table 1. 10). The primary adverse reac- thromycin administration has, on rare occasions, b bowel motility. In fact, erythromycin can be used to associated with ventricular tachycardia. These agents are metabolized by the cytochro treat gastric paresis. Particularly in younger patients, P450 3A4 system, and they cause an increase in serun abdominal cramps, nausea, vomiting, diarrhea, and levels of other drugs metabolized by that system, includ gas are common with erythromycin. These symptoms ing many of the statins, short-acting benzodiazepi are dose-related and are more common with oral such as midazolam(Versed), cisapride(Propulsid) preparations, but can als o occur with intravenous ritonavir(Norvir), and tacrolimus(Progr administration. Gastrointestinal toxicity can be debil- ting, forcing the drug to be discontinued. PHARMACOKINETICS Azithromycin and clarithromycin at the usual recom- The stearate, ethylsuccinate, and estolate forms of ery- mended doses are much less likely to cause these thromycin are reasonably well absorbed on an empty dverse reactions stomach, reaching peak serum levels 3 hours after inge alithromycin administration has been accompany tion. Clarithromycin, azithromycin, and telithromycin Ity with accommodation, resulting in blurred are better absorbed orally than erythromycin is, result vision. Patients have also experienced diplopia following k concentrations within I hour. Erythromycin administration of this agent. Talithromycin treatment has and azithromycin should be taken on an empty stom- also resulted in the sudden onset of severe and occasion ach. If cost is not a primary issue, the improved

with the macro-lides, talithromycin binds to the 50S subunit with higher affinity, binding to two regions of the 23S rRNA molecule (domains II and V) rather than one region. This unique binding mode explains the enhanced antimicrobial activity of ketolides against macrolide-resistant pathogens. TOXICITY Macrolides and ketolides are among the safer classes of antibiotics (Table 1.10). The primary adverse reac￾tions are related to these agents’ ability to stimulate bowel motility. In fact, erythromycin can be used to treat gastric paresis. Particularly in younger patients, abdominal cramps, nausea, vomiting, diarrhea, and gas are common with erythromycin. These symptoms are dose-related and are more common with oral preparations, but can also occur with intravenous administration. Gastrointestinal toxicity can be debil￾itating, forcing the drug to be discontinued. Azithromycin and clarithromycin at the usual recom￾mended doses are much less likely to cause these adverse reactions. Talithromycin administration has been accompanied by difficulty with accommodation, resulting in blurred vision. Patients have also experienced diplopia following administration of this agent. Talithromycin treatment has also resulted in the sudden onset of severe and occasion￾ally fatal hepatitis. All patients receiving this agent should therefore be warned of this potential side effect, and the drug should be prescribed only for cases of pneumonia in which the incidence of penicillin-resistant S. pneumoniae is high. Under these circumstance a fluoroquinolone with gram-positive coverage may be preferred. Macrolides and ketolides may exacerbate myasthenia gravis and should be avoided in patients with that ill￾ness. Macrolides prolong the QT interval, and ery￾thromycin administration has, on rare occasions, been associated with ventricular tachycardia. These agents are metabolized by the cytochrome P450 3A4 system, and they cause an increase in serum levels of other drugs metabolized by that system, includ￾ing many of the statins, short-acting benzodiazepines, such as midazolam (Versed), cisapride (Propulsid), ritonavir (Norvir), and tacrolimus (Prograf). PHARMACOKINETICS The stearate, ethylsuccinate, and estolate forms of ery￾thromycin are reasonably well absorbed on an empty stomach, reaching peak serum levels 3 hours after inges￾tion. Clarithromycin, azithromycin, and talithromycin are better absorbed orally than erythromycin is, result￾ing in peak concentrations within 1 hour. Erythromycin and azithromycin should be taken on an empty stom￾ach. If cost is not a primary issue, the improved 30 / CHAPTER 1 Table 1.12. Organisms That May Be Susceptible to Macrolides and Ketolides Erythromycin Clarithromycin Azithromycin Talithromycin Streptococcus pyogenes Penicillin (PCN)–sensitive S. pneumoniae Mouth flora including anaerobes, but not Bacteroides fragilis Neisseria gonorrhoeae Neisseria meningitides Campylobacter jejuni Bordetella pertussis Legionella pneumophilia Mycoplasma pneumoniae Ureaplasma urealyticum Chlamydia trachomatis Chlamydophila pneumoniae Corynebacterium diphtheriae Bartonella quintana More active against S. pyogenes More active against PCN-sensitive S. pneumoniae All pathogens covered by erythromycin, plus: Haemophilus influenzae Moraxella catarrhalis Borrelia burgdorferi Mycoplasma leprae Mycobacterium avium complex Toxoplasma gondii Helicobacter pylori Less active against S. pyogenes Less active against PCN-sensitive S. pneumoniae all pathogens covered by erythromycin, plus: more active against H. influenzae Moraxella catarrhalis Most active against Legionella pneumophilia M. avium complex Helicobacter pylori Plasmodium falciparum Most active against S. pyogenes Active against some erythromycin-resistant strains Active against multiresistant S. pneumoniae All pathogens covered by erythromycin, plus: Most active against erythromycin-sensitive S. aureus Good activity against Enterococcus faecalis, but not Enterococcus faecium H. influenzae Moraxella catarrhalis Poor activity against M. avium complex

ANTI-INFECTIVE THERAPY/ 3 KEY POINTS acteria. Erythromycin can be bacteriostatic or bacteric- dal. Cidal activity increases when antibiotic concentra- tions are high and bacteria are growing rapidly About Macrolide Chemistry, Mechanism These drugs are recommended for the treatment of of Action, and Toxicity community-acquired pneumonia(see Chapter 4).How ever. pneumoniae resistance to macrolides has steadily increased and now ranges between 10% and 15% 1. Complex 14-to 15-member lactone ring struc. Resistance is more likely in intermediately penic resistant strains(40% macrolide resistant)and 2. Inhibit RNA-dependent protein synthesis, bind penicillin-resistant strains(60% macrolide resistance to 50S ribosomal subunit; telithromycin binds Multiresistant S. pneumoniae can be treated with ta with higher affinity, binding to two sites rather ithromycin as a consequence of that agents different than just one ribosomal binding sites 3. Can be bacteriostatic or cidal In most countries, including the United States, 95% 4. Gastrointestinal irritation, particularly with ery. of S. pyogenes are sensitive to macrolides.However,in hromycin, is the major toxicity Japan, where macrolides are commonly used, 60%are 5. Hypersensitivity reactions can occur. resistant. Because S. aureus can develop resistance after a 6. Transient hearing loss with high doses, mainly single mutation, macrolides are generally not recom- in elderly individuals mended in their treatment. The macrolides and 7. Talithromycin can cause blurred vision and ketolides are effective against mouth fora, including diplopia. Also can result in fatal hepatitis. anaerobes,but they do not cover the bowel anaerobe 8. Can exacerbate myasthenia gravis. B. fragilis. The macrolides are also the treatment of choice for Legionella pneumophilia, with telithromycin, 9. Prolonged QT interval; occasionally causes ven tricular tachycardia azithromycin, and clarithromycin being more potent than erythromycin 10. Metabolized by the cytochrome P450 3A4 sys- em: increase serum concentrations of other Macrolides are the primary antibiotics used to treat drugs metabolized by that system e two major pathogens associat monia: Mycoplasma pneumoniae and chlamydophila pneumoniae(see Chapter 4). Talith approved for acute bacterial sinusitis. In many instances he erythromycins can be used as an alternative to peni absorption and lower incidence of gastrointestinal toxi- cillin in the penicil i-allergic patient mary antibio se city make the three newer agents preferable to ery. Clarithromycin is one of the hromycin in most instances(Table 1. 11) used for the treatment of atypical mycobacterial Most of the macrolides and ketolides are metabolized tions, particularly MAl complex. Azithromycin in com- nd cleared primarily by the liver. Azithromycin bination with other antibiotics is also recommended for metabolized, being excreted unchanged in the bile the treatment of MAI complex, and it can be used alone percentages of these drugs are also excreted in the urine. for MAI prophylaxis in HIV-infected patients with These agents are widely distributed in tissues, achieving CD4 cell counts below 100 cells/mL. concentrations that are several times the peak concentra- In combination with antacid therapy, effective regi tion achieved in serum in most areas the body, including mens for curing peptic ulcer disease caused by Heli- the prostate and middle ear Clarithromycin levels in cobacter pylori include azithromycin or clarithromycin middle ear fluid have been shown to be nearly 10 times combined with bismuth salts and either amoxicillin serum levels. Azithromycin concentrations in tissue metronidazole, or tetracycline. Single high-dose ceed serum levels by a factor of 10 to 100, and its aver thromycin(I g) effectively treats chancroid, as well as age half-life in tissues is 2 to 4 days. Therapeutic levels of Chlamydia trachomatis urethritis and cervicitis. Single azithromycin have been estimated to persist for 5 days dose therapy also cures male Ureaplasma urealyticum after the completion of a 5-day treatment course. With urethritis. the exception of intravenous erythromycin, these agents fail to achieve significant levels in the cerebrospinal auid Clindamycin SPECTRUM OF ACTIVITY AND CHEMISTRY AND MECHANISM OF ACTION TREATMENT RECOMMENDATIONS Although clindamycin is structurally different Macrolides demonstrate excellent activity against erythromycin, many of its biologic characterist most some

absorption and lower incidence of gastrointestinal toxi￾city make the three newer agents preferable to ery￾thromycin in most instances (Table 1.11). Most of the macrolides and ketolides are metabolized and cleared primarily by the liver. Azithromycin is not metabolized, being excreted unchanged in the bile. Small percentages of these drugs are also excreted in the urine. These agents are widely distributed in tissues, achieving concentrations that are several times the peak concentra￾tion achieved in serum in most areas the body, including the prostate and middle ear. Clarithromycin levels in middle ear fluid have been shown to be nearly 10 times serum levels. Azithromycin concentrations in tissue exceed serum levels by a factor of 10 to 100, and its aver￾age half-life in tissues is 2 to 4 days. Therapeutic levels of azithromycin have been estimated to persist for 5 days after the completion of a 5-day treatment course. With the exception of intravenous erythromycin, these agents fail to achieve significant levels in the cerebrospinal fluid. SPECTRUM OF ACTIVITY AND TREATMENT RECOMMENDATIONS Macrolides demonstrate excellent activity against most gram-positive organisms and some gram-negative bacteria. Erythromycin can be bacteriostatic or bacterici￾dal. Cidal activity increases when antibiotic concentra￾tions are high and bacteria are growing rapidly. These drugs are recommended for the treatment of community-acquired pneumonia (see Chapter 4). How￾ever S. pneumoniae resistance to macrolides has steadily increased and now ranges between 10% and 15%. Resistance is more likely in intermediately penicillin￾resistant strains (40% macrolide resistant) and highly penicillin-resistant strains (60% macrolide resistance). Multiresistant S. pneumoniae can be treated with tal￾ithromycin as a consequence of that agent’s different ribosomal binding sites. In most countries, including the United States, 95% of S. pyogenes are sensitive to macrolides. However, in Japan, where macrolides are commonly used, 60% are resistant. Because S. aureus can develop resistance after a single mutation, macrolides are generally not recom￾mended in their treatment. The macrolides and ketolides are effective against mouth flora, including anaerobes, but they do not cover the bowel anaerobe B. fragilis. The macrolides are also the treatment of choice for Legionella pneumophilia, with talithromycin, azithromycin, and clarithromycin being more potent than erythromycin. Macrolides are the primary antibiotics used to treat the two major pathogens associated with atypical pneu￾monia: Mycoplasma pneumoniae and Chlamydophila pneumoniae (see Chapter 4). Talithromycin is also approved for acute bacterial sinusitis. In many instances the erythromycins can be used as an alternative to peni￾cillin in the penicillin-allergic patient. Clarithromycin is one of the primary antibiotics used for the treatment of atypical mycobacterial infec￾tions, particularly MAI complex. Azithromycin in com￾bination with other antibiotics is also recommended for the treatment of MAI complex, and it can be used alone for MAI prophylaxis in HIV-infected patients with CD4 cell counts below 100 cells/mL. In combination with antacid therapy, effective regi￾mens for curing peptic ulcer disease caused by Heli￾cobacter pylori include azithromycin or clarithromycin combined with bismuth salts and either amoxicillin, metronidazole, or tetracycline. Single high-dose azithromycin (1 g) effectively treats chancroid, as well as Chlamydia trachomatis urethritis and cervicitis. Single￾dose therapy also cures male Ureaplasma urealyticum urethritis. Clindamycin CHEMISTRY AND MECHANISM OF ACTION Although clindamycin is structurally different from erythromycin, many of its biologic characteristics are similar. Clindamycin consists of an amino acid linked ANTI-INFECTIVE THERAPY / 31 1. Complex 14- to 15-member lactone ring struc￾ture. 2. Inhibit RNA-dependent protein synthesis, bind to 50S ribosomal subunit; talithromycin binds with higher affinity, binding to two sites rather than just one, 3. Can be bacteriostatic or cidal. 4. Gastrointestinal irritation, particularly with ery￾thromycin, is the major toxicity. 5. Hypersensitivity reactions can occur. 6. Transient hearing loss with high doses, mainly in elderly individuals. 7. Talithromycin can cause blurred vision and diplopia. Also can result in fatal hepatitis. 8. Can exacerbate myasthenia gravis. 9. Prolonged QT interval; occasionally causes ven￾tricular tachycardia. 10.Metabolized by the cytochrome P450 3A4 sys￾tem; increase serum concentrations of other drugs metabolized by that system. KEY POINTS About Macrolide Chemistry, Mechanism of Action, and Toxicity

32/ CHAPTER 1 KEY POINTS ANTIMICROBIAL SPECTRUM AND TREATMENT RECOMMENDATIONS lar to e About the Spectrum and Treatment Indications against streptococci and staphylococci(Figure 1.5) for Macrolides and Ketolides Moderately penicillin-resistant S. pneumoniae are often sensitive to clindamycin. In the penicillin-allergi 1. Gram-positive coverage, plus mouth anaerobes. patient, clindamycin is a reasonable alternative for 2. Recommended for treatment of comm S. pyogenes pharyngitis. Because its activity agains acquired pneumonia H. influenzae is limited, clindamycin is not recom- mended for the treatment of otitis media 3. Increased use of macrolides selects for resistant strains of Streptococcus pyogenes and S pneu- Clindamycin distinguishes itself from the macrolides by moniae Penicillin-resistant strains of S pneumo possessing excellent activity against most anaerobic bacte niae are often resistant to macrolides ria. It is used effectively in combination with an aminogly coside, aztreonam, or a third-generation cephalosporin to mycin is effective treat fecal soilage of the peritoneum. However, other less- toxic regimens have proved to be equally effective. Clin 5. Recommended for treatment of legionella damycin in combination with a first-ge cephalosporin can be used to block toxin production in 6. Recommended for Mycoplasma, Ureaplasma severe cellulitis and necrotizing fasciitis caused by mSsa or and chlamydi S pyogenes. It is also effective for the treatment of anaerobic 7. Clarithromycin or azithromycin can used for pulmonary and pleural infections. Clindamycin also has treatment of Helicobacter pylor significant activity against Toxoplasma gondii and is recom 8. Clarithromycin is a primary drug for treatment mended as alternative therapy in the sulfa-allergic patient of Mycobacterium avium intracellulare(MAl). and azithromycin is useful for MAl prophylaxis Tetrac nes in Hiv patients with low CD4 cell counts. CHEMISTRY AND MECHANISMS OF ACTION The tetracyclines consist of four 6-member rings with substitutions at the 4, 5, 6, and 7 positions that alter to an amino sugar, and it was derived by modifyin neomycin. It binds to the same 50S ribosomal bind ng site used by the macrolides, blocking bacterial KEY POINTS Tox About Clindamycin Diarrhea is a major problem seen in 20% of patients est with oral administration. In up to half of the affected 1. Binds to the 5oS ribosomal binding site used by patients, the cause of diarrhea is pseudomembranous colitis, a disease caused by overgrowth of the anaerobi 2. Diarrhea is a common side effect, with Clostrid- bacteria C difficile(see Chapter 8) ium difficile toxin found in half of cases 3. Pseudomembranous colitis can lead to toxic PHARMACOKINETICS megacolon and death. If C. difficile toxin Clindamycin is well absorbed orally; however, the detected, clindamycin should be discontinued. drug can also be administered intravenously and the intravenous route can achieve higher peak serum including MSSA; covers many intermediate levels. Clindamycin penetrates most tissues, but it penicillin-resistant Streptococcus pneumoniae, does not enter the cerebrospinal fuid Clindamycin i but is not a first-line therapy. metabolized primarily by the liver and is excreted in 5. Excellent anaerobic coverage, including Be the bile. Therapeutic concentrations of clindamycin sist in the stool for 5 or more days after the antibi- 6. Used to reduce toxin production by S pyogene otic is discontinued, and the reduction of clin and Staphylococcus aureus. damycin-sensitive flora persists for up to 14 da 7. Used to treat anaerobic lung abscesses and Small percentages of clindamycin metabolites are also toxoplasmosis in the sulfa-allergic patient excreted in the urine

to an amino sugar, and it was derived by modifying lincomycin. It binds to the same 50S ribosomal bind￾ing site used by the macrolides, blocking bacterial protein synthesis. TOXICITY Diarrhea is a major problem seen in 20% of patients taking clindamycin (Table 1.10). The incidence is high￾est with oral administration. In up to half of the affected patients, the cause of diarrhea is pseudomembranous colitis, a disease caused by overgrowth of the anaerobic bacteria C. difficile (see Chapter 8). PHARMACOKINETICS Clindamycin is well absorbed orally; however, the drug can also be administered intravenously and the intravenous route can achieve higher peak serum levels. Clindamycin penetrates most tissues, but it does not enter the cerebrospinal fluid. Clindamycin is metabolized primarily by the liver and is excreted in the bile. Therapeutic concentrations of clindamycin persist in the stool for 5 or more days after the antibi￾otic is discontinued, and the reduction of clin￾damycin-sensitive flora persists for up to 14 days. Small percentages of clindamycin metabolites are also excreted in the urine. ANTIMICROBIAL SPECTRUM AND TREATMENT RECOMMENDATIONS Clindamycin is similar to erythromycin in its activity against streptococci and staphylococci (Figure 1.5). Moderately penicillin-resistant S. pneumoniae are often sensitive to clindamycin. In the penicillin-allergic patient, clindamycin is a reasonable alternative for S. pyogenes pharyngitis. Because its activity against H. influenzae is limited, clindamycin is not recom￾mended for the treatment of otitis media. Clindamycin distinguishes itself from the macrolides by possessing excellent activity against most anaerobic bacte￾ria. It is used effectively in combination with an aminogly￾coside, aztreonam, or a third-generation cephalosporin to treat fecal soilage of the peritoneum. However, other less￾toxic regimens have proved to be equally effective. Clin￾damycin in combination with a first-generation cephalosporin can be used to block toxin production in severe cellulitis and necrotizing fasciitis caused by MSSA or S. pyogenes. It is also effective for the treatment of anaerobic pulmonary and pleural infections. Clindamycin also has significant activity against Toxoplasma gondii and is recom￾mended as alternative therapy in the sulfa-allergic patient. Tetracyclines CHEMISTRY AND MECHANISMS OF ACTION The tetracyclines consist of four 6-member rings with substitutions at the 4, 5, 6, and 7 positions that alter 32 / CHAPTER 1 1. Gram-positive coverage, plus mouth anaerobes. 2. Recommended for treatment of community￾acquired pneumonia. 3. Increased use of macrolides selects for resistant strains of Streptococcus pyogenes and S. pneu￾moniae. Penicillin-resistant strains of S. pneumo￾niae are often resistant to macrolides. 4. Talithromycin is effective against multi-resistant S. pneumoniae. 5. Recommended for treatment of Legionella pneumophilia. 6. Recommended for Mycoplasma, Ureaplasma, and Chlamydia. 7. Clarithromycin or azithromycin can used for treatment of Helicobacter pylori. 8. Clarithromycin is a primary drug for treatment of Mycobacterium avium intracellulare (MAI), and azithromycin is useful for MAI prophylaxis in HIV patients with low CD4 cell counts. KEY POINTS About the Spectrum and Treatment Indications for Macrolides and Ketolides 1. Binds to the 50S ribosomal binding site used by the macrolides. 2. Diarrhea is a common side effect, with Clostrid￾ium difficile toxin found in half of cases. 3. Pseudomembranous colitis can lead to toxic megacolon and death. If C. difficile toxin is detected, clindamycin should be discontinued. 4. Active against most gram-positive organisms including MSSA; covers many intermediate penicillin-resistant Streptococcus pneumoniae, but is not a first-line therapy. 5. Excellent anaerobic coverage, including Bac￾teroides fragilis. 6. Used to reduce toxin production by S. pyogenes and Staphylococcus aureus. 7. Used to treat anaerobic lung abscesses and toxoplasmosis in the sulfa-allergic patient. KEY POINTS About Clindamycin