4/ CHAPTER 1 leading to the loss of porins can reduce antibiotic pene- Ribosomal resistance to gentamicin, tobramycin, and tration and lead to antibiotic resistance amikacin is less common because these aminoglyco PRODUCTION OF EFFLUX PUMPS ides have several binding sites on the bacterial ribo- some and require multiple bacterial Transposons have been found that encode for an their binding is blocked el tetracycline out of bacteria. Active efflux of antibi CONCLUSIONS has been observed in m bacteria,and this mechanism is used to resist Bacteria can readily transfer antibiotic resistance acrolide, and fluoroquinolone Bacteria have multiple mechanisms to destroy antibiotic treatment. S. aureus, S. epidermidis, otics, lower the antibiotic concentration, and interfere Pyogenes, group B streptococci, and S. pneumoniae with antibiotic binding. Under the selective pressures of also can utilize energy-dependent efflux pumps to prolonged antibiotic treatment, the qu stion Is not resist antibiotics whether, but when resistant bacteria will take over Modification of the Antibiotic Target ALTERATIONS OF CELL WALL PRECURSORS ANTI-INFECTIVE AGENT DOSING Vancomycin and teicoplanin binding requires that D- The characteristics that need to be considered when alanine-D-alanine be at the end of the peptidoglycan cell administering antibiotics include absorption(when deal- strains of Enterococcus faecium and Enterococcus faecalis os with oral antibiotics), volume of distribution, metab- wall precursors of gram-positive bacteria. Resistant m and excretion. These factors determine the dose of contain the vanA plasmid, which encodes a protein that each drug and the time interval of administration. To synthesizes D-alanine-D-lactate instead of D-alanine-D- effectively clear a bacterial infection, serum levels of the alanine at the end of the peptidoglycan precursor Loss antibiotic need to be maintained above the minimul of the terminal D-alanine markedly reduces vancomy inhibitory concentration(MIC) for a significant period. and teicoplanin binding, allowing the mutant bac- For each pathogen, the MIC is determined by serially terium to survive and grow in the presence of these diluting the antibiotic into liquid medium containing 101 bacteria per milliliter. Inoculated tubes are incubated overnight until broth without added antibiotic ha CHANGES IN TARGET ENZYMES become cloudy or turbid as a result of bacterial growth ial cell wall. Penicillin-resistant S. pneumoniae demon- clear-constitutes the MIC(Figure 1.2). Automated strate decreased numbers of PBPs or PBPs that bind analyzers can now quickly determine, for individual penicillin with lower affinity, or both. Decreased peni- pathogens, the MICs for multiple antibiotics, and these cillin binding reduces the ability of the antibiotic to kill data serve to guide the physician's choice of antibiotics the targeted bacteria The mean bactericidal concentration(MBC) is deter The basis for antibiotic resistance in MRSA is pro- mined by taking each clear tube and inoculating a plate duction of a low affinity PBP encoded by the meca of solid medium with the solution. Plates are then incu gene.Mutations in the target enzymes dihydropteroate bated to allow colonies to form. The lowest concentra- amide and trimethoprim resistance respectively. Single is, no colonies on solid medium-represents me MB c synthetase and dihydrofolate reductase cause sulfon- tion of antibiotic that blocks all growth of bacteria--th amino-acid mutations that alter dNa gyrase function Successful cure of an infection depends on multiple can result in resistance to fluoroquinolones host factors in addition to serum antibiotic concentration ALTERATIONS IN RIBOSOMAL BINDING SITE However, investigators have attempted to predict succe ful treatment by plotting serum antibiotic levels against Tetracyclines, macrolides, lincosamides, and amino- time. Three parameters can be assessed(Figure 1.3):time glycosides all act by binding to and disrupting the above the MIC (T>MIC), ratio of the peak antibiotic con of individual antibiotics later in this chapter). A num- area under the curve(AUC)to the MIC (AUCMC% nction of bacterial ribosomes(see the descriptions centration to the MIC(Cmax/MIC), and the ratio ber of resistance genes encode for enzymes that Cure rates for B-lactam antibiotics are maximized demethylate adenine residues on bacterial ribosomal maintaining serum levels above the MIC for >50% of RNA, inhibiting antibiotic binding to the ribosome. the time. Peak antibiotic concentrations are of less
leading to the loss of porins can reduce antibiotic penetration and lead to antibiotic resistance. PRODUCTION OF EFFLUX PUMPS Transposons have been found that encode for an energy-dependent pump that can actively pump tetracycline out of bacteria. Active efflux of antibiotics has been observed in many enteric gram-negative bacteria, and this mechanism is used to resist tetracycline, macrolide, and fluoroquinolone antibiotic treatment. S. aureus, S. epidermidis, S. pyogenes, group B streptococci, and S. pneumoniae also can utilize energy-dependent efflux pumps to resist antibiotics. Modification of the Antibiotic Target ALTERATIONS OF CELL WALL PRECURSORS Alteration of cell wall precursors is the basis for VRE. Vancomycin and teicoplanin binding requires that Dalanine-D-alanine be at the end of the peptidoglycan cell wall precursors of gram-positive bacteria. Resistant strains of Enterococcus faecium and Enterococcus faecalis contain the vanA plasmid, which encodes a protein that synthesizes D-alanine-D-lactate instead of D-alanine-Dalanine at the end of the peptidoglycan precursor. Loss of the terminal D-alanine markedly reduces vancomycin and teicoplanin binding, allowing the mutant bacterium to survive and grow in the presence of these antibiotics. CHANGES IN TARGET ENZYMES Penicillins and cephalosporins bind to specific proteins called penicillin-binding proteins (PBPs) in the bacterial cell wall. Penicillin-resistant S. pneumoniae demonstrate decreased numbers of PBPs or PBPs that bind penicillin with lower affinity, or both. Decreased penicillin binding reduces the ability of the antibiotic to kill the targeted bacteria. The basis for antibiotic resistance in MRSA is production of a low affinity PBP encoded by the mecA gene. Mutations in the target enzymes dihydropteroate synthetase and dihydrofolate reductase cause sulfonamide and trimethoprim resistance respectively. Single amino-acid mutations that alter DNA gyrase function can result in resistance to fluoroquinolones. ALTERATIONS IN RIBOSOMAL BINDING SITE Tetracyclines, macrolides, lincosamides, and aminoglycosides all act by binding to and disrupting the function of bacterial ribosomes (see the descriptions of individual antibiotics later in this chapter). A number of resistance genes encode for enzymes that demethylate adenine residues on bacterial ribosomal RNA, inhibiting antibiotic binding to the ribosome. Ribosomal resistance to gentamicin, tobramycin, and amikacin is less common because these aminoglycosides have several binding sites on the bacterial ribosome and require multiple bacterial mutations before their binding is blocked. CONCLUSIONS Bacteria can readily transfer antibiotic resistance genes. Bacteria have multiple mechanisms to destroy antibiotics, lower the antibiotic concentration, and interfere with antibiotic binding. Under the selective pressures of prolonged antibiotic treatment, the question is not whether, but when resistant bacteria will take over. ■ ANTI-INFECTIVE AGENT DOSING The characteristics that need to be considered when administering antibiotics include absorption (when dealing with oral antibiotics), volume of distribution, metabolism, and excretion. These factors determine the dose of each drug and the time interval of administration. To effectively clear a bacterial infection, serum levels of the antibiotic need to be maintained above the minimum inhibitory concentration (MIC) for a significant period. For each pathogen, the MIC is determined by serially diluting the antibiotic into liquid medium containing 104 bacteria per milliliter. Inoculated tubes are incubated overnight until broth without added antibiotic has become cloudy or turbid as a result of bacterial growth. The lowest concentration of antibiotic that prevents active bacterial growth—that is, the liquid media remains clear—constitutes the MIC (Figure 1.2). Automated analyzers can now quickly determine, for individual pathogens, the MICs for multiple antibiotics, and these data serve to guide the physician’s choice of antibiotics. The mean bactericidal concentration (MBC) is determined by taking each clear tube and inoculating a plate of solid medium with the solution. Plates are then incubated to allow colonies to form. The lowest concentration of antibiotic that blocks all growth of bacteria—that is, no colonies on solid medium—represents the MBC. Successful cure of an infection depends on multiple host factors in addition to serum antibiotic concentration. However, investigators have attempted to predict successful treatment by plotting serum antibiotic levels against time. Three parameters can be assessed (Figure 1.3): time above the MIC (T>MIC), ratio of the peak antibiotic concentration to the MIC (Cmax/MIC), and the ratio of the area under the curve (AUC) to the MIC (AUC/MIC). Cure rates for -lactam antibiotics are maximized by maintaining serum levels above the MIC for >50% of the time. Peak antibiotic concentrations are of less 4 / CHAPTER 1
ANTI-INFECTIVE THERAPY 5 MIC mbc exceed the MIC. High peak levels of these antibiotics may be more effective than low peak levels at curing inf Inoculate all tubes with 104 bacteria incubate 38C X 12 hrs tions. Therefore, for treatment with aminoglycosides and Clea fluoroquinolones Cmax/MIC and AUC/MIC are more helpful for maximizing effectiveness. In the rested to achieve maximal effectiveness when Cmax/MIC is 10 to 12. For fluoroquinolones, best outcomes in com- munity-acquired pneumonia may be achieved when the AUC/MIC is >34. To prevent the development of Auc roquinolone resistance to S pneumoniae, in vitro studies have suggested that AUC/MIC should be >50. For ug/ml p aeruginosa, an AUC/MIC Minimal Inhibitory Concentration( MIC)=2uIgml In vitro studies also demonstrate that aminoglycosides when the antibiotic is removed, a delay in the recovery of th ccurs ram-negative bacteria demon strate a delay of 2 to 6 hours in the recovery of active no delay after penicillins and cephalosporins. But per cillin and cephalosporins generally cause a 2-hour delay in the recovery of gram-positive or Figure 1-2. Understanding the minimum inhibitory effect can be dosed less frequently; those with no post concentration and the minimal bactericidal antibiotic effect should be administered by constant therapeutic approaches, it must be kept in mind that con- centration-dependent killing and post-antibiotic effect are importance for these antibiotics, and serum concentra- both in vitro phenomena, and treatment strategies based e s times to enhance penetration into less permeable body sites. human clinical trials oroquinolones demonstrate concentration-dei killing. In vitro studies show that these antibiotics demonstrate greater killing the more thei r concentrations KEY POINTS About Antibiotic Dosing 1. Absorption, volume of distribution, metabolism, and excretion all affect serum antibiotic levels the Curve 2. Mean inhibitory concentration(MIC)is helpf in guiding antibiotic choice. 3. To maximize success with B-lactam antibiotics serum antibiotic levels should be above the mic for at least 50% of the time (t>mic >50%6) 4. To maximize success with aminoglycosides and fluoroquinolones, high peak concentration, Time above MIc Cmax/MIC, and high AUC/MIC ratio are recom- mended Drug dependent killing and post-antibiotic effect for minoglycosides and fluoroquinolones remain to be proven by dinical trials. Figure 1-3. Pharmacokinetics of a typical antibiotic
importance for these antibiotics, and serum concentrations above 8 times the MIC are of no benefit other than to enhance penetration into less permeable body sites. Unlike -lactam antibiotics, aminoglycosides and fluoroquinolones demonstrate concentration-dependent killing. In vitro studies show that these antibiotics demonstrate greater killing the more their concentrations exceed the MIC. High peak levels of these antibiotics may be more effective than low peak levels at curing infections. Therefore, for treatment with aminoglycosides and fluoroquinolones Cmax/MIC and AUC/MIC are more helpful for maximizing effectiveness. In the treatment of gram-negative bacteria, aminoglycosides have been suggested to achieve maximal effectiveness when Cmax/MIC is 10 to 12. For fluoroquinolones, best outcomes in community-acquired pneumonia may be achieved when the AUC/MIC is 34. To prevent the development of fluoroquinolone resistance to S. pneumoniae, in vitro studies have suggested that AUC/MIC should be 50. For P. aeruginosa, an AUC/MIC of 200 is required. In vitro studies also demonstrate that aminoglycosides and fluoroquinolones demonstrate a post-antibiotic effect: when the antibiotic is removed, a delay in the recovery of bacterial growth occurs. Gram-negative bacteria demonstrate a delay of 2 to 6 hours in the recovery of active growth after aminoglycosides and fluoroquinolones, but no delay after penicillins and cephalosporins. But penicillins and cephalosporins generally cause a 2-hour delay in the recovery of gram-positive organisms. Investigators suggest that antibiotics with a significant post-antibiotic effect can be dosed less frequently; those with no postantibiotic effect should be administered by constant infusion. Although these in vitro effects suggest certain therapeutic approaches, it must be kept in mind that concentration-dependent killing and post-antibiotic effect are both in vitro phenomena, and treatment strategies based on these effects have not been substantiated by controlled human clinical trials. ANTI-INFECTIVE THERAPY / 5 Figure 1–2. Understanding the minimum inhibitory concentration and the minimal bactericidal concentration. 1. Absorption, volume of distribution, metabolism, and excretion all affect serum antibiotic levels. 2. Mean inhibitory concentration (MIC) is helpful in guiding antibiotic choice. 3. To maximize success with -lactam antibiotics, serum antibiotic levels should be above the MIC for at least 50% of the time (T>MIC 50%). 4. To maximize success with aminoglycosides and fluoroquinolones, high peak concentration, Cmax/MIC, and high AUC/MIC ratio are recommended. 5. The clinical importance of concentrationdependent killing and post-antibiotic effect for aminoglycosides and fluoroquinolones remain to be proven by clinical trials. KEY POINTS About Antibiotic Dosing Figure 1–3. Pharmacokinetics of a typical antibiotic.
6/ CHAPTER 1 BASIC STRATEGIES FOR ANTIBIOTIC THERAPY Does the patient have a The choice of antibiotics should be carefully consi- WBC with Differential dered. A step-by-step logical approach is helpful Assess Severity of iness 1. Decide Whether The Patient Has a Observe Closely One test that has traditionally been used to differentiate Obtain culture an acute systemic bacterial infection from a viral illness the peripheral white blood cell (WBC)count. In patients with serious systemic bacterial infections, the peripheral Obtain Cul If Patient worsens WBC count may be elevated and may demonstrate an including bl clinically ncreased percentage of neutrophils. On occasion, less mature neutrophils such as band forms and, less com- monly, metamyelocyte are observed on peripheral blood smear. Most viral infections fail to induce a neutrophil response. Viral infections, particularly Epstein-Barr virus Probable site of an increase in lymphocytes monocytes(or ection& Begin both)and may induce the for Empiric Therapy cytes. Unfortunately, the peripheral WBC count is only a Recently, serum procalcitonin concentration has been found to be a far more accurate test for differen bacterial from viral infection. In response to bacterial fection, this precursor of calcitonin is synthesized and released into the serum by many organs of the body; pro- Stain Results duction of interferon in response to viral infection inhibits its synthesis. The serum procalcitonin test may also be of prognostic value, serum procalcitonin levels nlarly high in severe sepsis(see Chapter 2) nsistent with Infection Negative or Colonization Review sensitivities and 2. Make a Reasonable statistical Guess streamline antibiotics as to the Possible Pathogens (narrowest spectrum and fewest drugs possible) Based on the patient's symptoms and signs, as well as on laboratory tests, the anatomic site of the possible infec- Figure 1. 4. Algorithm for the initial use of tion can often be determined. For example, burning on anti-infective therapy urination, associated with pyuria on urinalysis, suggests tract infection The bowel fora. They include E coli, Klebsiella, and Proteus. flora associated with the hospital and the floor where the Antibiotic treatment needs to cover thes tient became ill. Many hospitals have a high incidence antibiotic treatment for monly associated with infections at specific anatomic a possible staphylococcal infection must include van- sites and the large percentage of pseudomonas to gentamicin, eliminating that antibiotic from consid 3. Be aware of the Antibiotic Susceptibility Patterns eration as empiric treatment of possible gram-negative in Your Hospital and Community sepsis. In many communities, individuals who have never been hospitalized are today presenting with soft In patients that develop infection while in hospital tissue infections caused by cMRSA, and physicians in ("nosocomial infection), empiric therapy needs to take these communities must adjust their empiric antibiotic into account the antibiotic susceptibility patterns of the selection(see Chapter 10
BASIC STRATEGIES FOR ANTIBIOTIC THERAPY The choice of antibiotics should be carefully considered. A step-by-step logical approach is helpful (Figure 1.4). 1. Decide Whether The Patient Has a Bacterial Infection One test that has traditionally been used to differentiate an acute systemic bacterial infection from a viral illness is the peripheral white blood cell (WBC) count. In patients with serious systemic bacterial infections, the peripheral WBC count may be elevated and may demonstrate an increased percentage of neutrophils. On occasion, less mature neutrophils such as band forms and, less commonly, metamyelocytes are observed on peripheral blood smear. Most viral infections fail to induce a neutrophil response. Viral infections, particularly Epstein–Barr virus, induce an increase in lymphocytes or monocytes (or both) and may induce the formation of atypical monocytes. Unfortunately, the peripheral WBC count is only a rough guideline, lacking both sensitivity and specificity. Recently, serum procalcitonin concentration has been found to be a far more accurate test for differentiating bacterial from viral infection. In response to bacterial infection, this precursor of calcitonin is synthesized and released into the serum by many organs of the body; production of interferon in response to viral infection inhibits its synthesis. The serum procalcitonin test may also be of prognostic value, serum procalcitonin levels being particularly high in severe sepsis (see Chapter 2). 2. Make a Reasonable Statistical Guess as to the Possible Pathogens Based on the patient’s symptoms and signs, as well as on laboratory tests, the anatomic site of the possible infection can often be determined. For example, burning on urination, associated with pyuria on urinalysis, suggests a urinary tract infection. The organisms that cause uncomplicated urinary tract infection usually arise from the bowel flora. They include E. coli, Klebsiella, and Proteus. Antibiotic treatment needs to cover these potential pathogens. Later chapters review the pathogens commonly associated with infections at specific anatomic sites and the recommended antibiotic coverage for those pathogens. 3. Be aware of the Antibiotic Susceptibility Patterns in Your Hospital and Community In patients that develop infection while in hospital (“nosocomial infection), empiric therapy needs to take into account the antibiotic susceptibility patterns of the flora associated with the hospital and the floor where the patient became ill. Many hospitals have a high incidence of MRSA and therefore empiric antibiotic treatment for a possible staphylococcal infection must include vancomycin, pending culture results. Other hospitals have a large percentage of Pseudomonas strains that are resistant to gentamicin, eliminating that antibiotic from consideration as empiric treatment of possible gram-negative sepsis. In many communities, individuals who have never been hospitalized are today presenting with softtissue infections caused by cMRSA, and physicians in these communities must adjust their empiric antibiotic selection (see Chapter 10). 6 / CHAPTER 1 Figure 1.4. Algorithm for the initial use of anti-infective therapy. Does the Patient have a Bacterial Infection? WBC with Differential Assess Severity of Illness Yes No, Observe Closely Obtain Cultures. Obtain Cultures including blood Decide on Probable Site of Infection & Begin Empiric Therapy At 3 Days Review Culture and Gram Stain Results Positive & Gram stain consistent with Infection Review sensitivities and streamline antibiotics (narrowest spectrum and fewest drugs possible) Negative or Colonization Return to top If Patient worsens clinically
ANTI-INFECTIVE THERAPY/ 7 4. Take into Account Previous Antibiotic Treatment tic. The use of rifampin combined with oxacillin is The remarkable adaptability of bacteria makes it antagonistic in some strains of S. aureus for exam- highly likely that a new pathogen will be resistant to ple. Many combination regimens have not been previously administered antibiotics. If the onset of the completely studied, and the natural assumption that new infection was preceded by a significant interval nore antibiotics lead to more killing power often does not apply when antibiotics were not given, the resident fora may b. Use of multiple antibiotics increases the risk of re-establishment of normal fora can take weeks, and adverse reactions. Drug allergies are common patients in hospital are likely to recolonize with highly When a patient re than one antibiotic devel resistant hospital ps an allergic reaction, all antibiotics become itial offenders, and these 5. Take into Consideration Important Host Factors be used. In some instances, combination therapy a. Penetration into the site of infection. For example, can increase the risk of toxicity. The combination of patients with bacterial meningitis should not be gentamicin and vancomycin increases the risk of treated with antibiotics that fail to cross the nephrotoxicity, for example blood-brain barrier(examples include 1st-generation Use of multiple antibiotics often increases costs cep losporins, gentamicin, and clindamycin) and the risk of administration errors. Administra on of two or more intravenous antibiotics requires b. Peripheral WBC count. Patients with neutropenia have a high mortality rate from sepsis. Immediate multiple intravenous reservoirs, lines, and pumps Nurses and pharmacists must dispense each antibi broad-spectrum, high-dose intravenous antibiotic otic dose, increasing labor costs. The more drugs a treatment is recommended py for patient receives, the higher the probability of an these patients administration error. Use of two or more drugs usu- c. Age and underlying diseases(hepatic and renal ally increases the acquisition costs dysfunction). Elderly patients tend to metabolize d. Use of multiple antibiotics the risk of and excrete antibiotics more slowly; longer dosing intervals are therefore often required. Agents with infection with highly resistant organisms. Pro- significant toxicity (such as aminoglycosides longed use of broad-spectrum antibiotic coverage increases the risk of infection with MRSA, vre should generally be avoided in elderly patients because they exhibit greater toxicity. Antibiotics multiresistant gram-negative bacilli, and fungi When multiple antibiotics are used, the spectrum metabolized primarily by the liver should generally of bacteria killed increases. Killing most of the be avoided or reduced in patients with significant rrhosis. In renal dy normal fora in the pharynx and gastrointestinal function, antibiotic doses need to be modified ract is harmful to the host. The normal flora ompete for nutrients, occupy binding sites that d. Duration of hospitalization Patients who have could otherwise be used by pathe bacteria and produce agents that inhibit the growth of community-acquired pat patients who have ompetitors. Loss of the normal fora allows resis- been in the hospital for prolonged periods and have tant pathogens to overgrow received several courses of antibiotics tend to be col- onized with highly resistant bacteria and with fungi. 7. Switch to Narrower-Spectrum Antibiotic Coverage e. Severity of the patient's illness. The severely ill Within 3 Days patient who is toxic and hypotensive requires broad-(Table 1. 1, Figure 1.5 ). Within 3 days following the new fever without other serious can usually be observed off antibiotic nic complaints mouth flora reveal that the numbers and types of bac- teria begin to change significantly. The normal Aora 6. Use the Fewest Drugs Possible die, and resistant gram-negative rods, gram-positive cocci,and fungi begin to predominate. The more Multiple drugs may lead to antagonism rather quickly the selective pressures of broad-spectrum than synergy. Some regi ens, such as overage can be discontinued, the lower the and an aminoglycoside for Enterococcus, have been risk of selecting for highly resistant pathogens.Broad shown to result in synergy-that is, the combined coverage is reasonable as initial empiric therapy until effects are greater than simple addition of the MBCs cultures are available. By the 3rd day, the microbiology of the two agents would suggest. In other instances, laboratory can generally identify the pathogen or certain C have proved to be antagonis- pathogens, and a narrower-spectrum, specific antibiotic
4. Take into Account Previous Antibiotic Treatment The remarkable adaptability of bacteria makes it highly likely that a new pathogen will be resistant to previously administered antibiotics. If the onset of the new infection was preceded by a significant interval when antibiotics were not given, the resident flora may have recolonized with less resistant flora. However, the re-establishment of normal flora can take weeks, and patients in hospital are likely to recolonize with highly resistant hospital flora. 5. Take into Consideration Important Host Factors a. Penetration into the site of infection. For example, patients with bacterial meningitis should not be treated with antibiotics that fail to cross the blood–brain barrier (examples include 1st-generation cephalosporins, gentamicin, and clindamycin). b. Peripheral WBC count. Patients with neutropenia have a high mortality rate from sepsis. Immediate broad-spectrum, high-dose intravenous antibiotic treatment is recommended as empiric therapy for these patients. c. Age and underlying diseases (hepatic and renal dysfunction). Elderly patients tend to metabolize and excrete antibiotics more slowly; longer dosing intervals are therefore often required. Agents with significant toxicity (such as aminoglycosides) should generally be avoided in elderly patients because they exhibit greater toxicity. Antibiotics metabolized primarily by the liver should generally be avoided or reduced in patients with significant cirrhosis. In patients with significant renal dysfunction, antibiotic doses need to be modified. d. Duration of hospitalization. Patients who have just arrived in the hospital tend to be colonized with community-acquired pathogens; patients who have been in the hospital for prolonged periods and have received several courses of antibiotics tend to be colonized with highly resistant bacteria and with fungi. e. Severity of the patient’s illness. The severely ill patient who is toxic and hypotensive requires broadspectrum antibiotics; the patient who simply has a new fever without other serious systemic complaints can usually be observed off antibiotics. 6. Use the Fewest Drugs Possible a. Multiple drugs may lead to antagonism rather than synergy. Some regimens, such as penicillin and an aminoglycoside for Enterococcus, have been shown to result in synergy—that is, the combined effects are greater than simple addition of the MBCs of the two agents would suggest. In other instances, certain combinations have proved to be antagonistic. The use of rifampin combined with oxacillin is antagonistic in some strains of S. aureus, for example. Many combination regimens have not been completely studied, and the natural assumption that more antibiotics lead to more killing power often does not apply. b. Use of multiple antibiotics increases the risk of adverse reactions. Drug allergies are common. When a patient on more than one antibiotic develops an allergic reaction, all antibiotics become potential offenders, and these agents can no longer be used. In some instances, combination therapy can increase the risk of toxicity. The combination of gentamicin and vancomycin increases the risk of nephrotoxicity, for example. c. Use of multiple antibiotics often increases costs and the risk of administration errors. Administration of two or more intravenous antibiotics requires multiple intravenous reservoirs, lines, and pumps. Nurses and pharmacists must dispense each antibiotic dose, increasing labor costs. The more drugs a patient receives, the higher the probability of an administration error. Use of two or more drugs usually increases the acquisition costs. d. Use of multiple antibiotics increases the risk of infection with highly resistant organisms. Prolonged use of broad-spectrum antibiotic coverage increases the risk of infection with MRSA, VRE, multiresistant gram-negative bacilli, and fungi. When multiple antibiotics are used, the spectrum of bacteria killed increases. Killing most of the normal flora in the pharynx and gastrointestinal tract is harmful to the host. The normal flora compete for nutrients, occupy binding sites that could otherwise be used by pathogenic bacteria, and produce agents that inhibit the growth of competitors. Loss of the normal flora allows resistant pathogens to overgrow. 7. Switch to Narrower-Spectrum Antibiotic Coverage Within 3 Days (Table 1.1, Figure 1.5). Within 3 days following the administration of antibiotics, sequential cultures of mouth flora reveal that the numbers and types of bacteria begin to change significantly. The normal flora die, and resistant gram-negative rods, gram-positive cocci, and fungi begin to predominate. The more quickly the selective pressures of broad-spectrum antibiotic coverage can be discontinued, the lower the risk of selecting for highly resistant pathogens. Broad coverage is reasonable as initial empiric therapy until cultures are available. By the 3rd day, the microbiology laboratory can generally identify the pathogen or pathogens, and a narrower-spectrum, specific antibiotic ANTI-INFECTIVE THERAPY / 7
8/ CHAPTER 1 Table 1. 1. Classification of Antibiotics by spectrum of Activity Narrow Moderately Broad Broad Very Broad Penicillin Ampicillin Ampicillin-sulbactam Ticarcillin -clavulanate Oxacillin/Nafcillin Amoxicillin-clavulanate Piperacillin-tazobactam Cefazolin Ceftriaxone Cephalexin/ Cephradine Ceftizoxime Aminoglycoside Cefuroxime-axetil Ceftazidime Vancomycin Cefaclor Cefixime Gatifloxacin Macrolides Ciprofloxacin Cefpodoxime proxetil Moxifloxacin Clindamycin Telithromycin Chlo Trimethoprim Levofloxacin sulfamethoxazole Metronidazole regimen can be initiated. Despite the availability of cul- amicin is low, but when blood-level monitoring, ture results, clinicians too often continue the same requirement to closely follow blood urea nitrogen empiric broad-spectrum antibiotic regimen, and that infections with highly resistant superbugs. Figure 1.5 antI KEY POINTS otics as a guide to the antibiotic choice Obey the 3-day rule. Continuing broad-spectrum About the Steps Required to Design antibiotics beyond 3 days drastically alters the host's an antibiotic Regimen resident fora and selects for resistant organisms. After 3 days, streamline antibiotic coverage. Use narrower- spectrum antibiotics to treat the specific pathogens 1. Assess the probability of bacterial infection identified by culture and Gram stain (Antibiotics should be avoided in viral infections 2. Be familiar with the pathogens primarily 8. All Else Being Equal, Choose The Least responsible for infection at each anatomic site. pensive Drug 3. Be familiar with the bacterial flora in the local As is discussed in later chapters, more than one antib hospital and community otic regimen can often be used to successfully treat a 4. Take into account previous antibiotic treatment. cific infection. Given the strong economic forces dri- 5. Take into account the specific host factors(age, ving medicine today, the physician needs to consider the cost of therapy whenever possible. Too often, new, more duration of hospitalization, severity of illness) expensive antibiotics are chosen over older generic 6. Use the minimum number and narrowest spec- antibiotics that are equally effective. In this book, the trum of antibiotics possible review of each specific antibiotic tries to classify that 7. Switch to a narrower-spectrum antibiotic regi- antibiotics cost range to assist the clinician in making nen based on culture results cost-effective decisions 8. Take into account acquisition cost and the costs However, in assessing cost, factoring in toxicity is of toxicity also important. For example, the acquisition cost of
8 / CHAPTER 1 regimen can be initiated. Despite the availability of culture results, clinicians too often continue the same empiric broad-spectrum antibiotic regimen, and that behavior is a critical factor in explaining subsequent infections with highly resistant superbugs. Figure 1.5 graphically illustrates the spectrum of available antibiotics as a guide to the antibiotic choice. Obey the 3-day rule. Continuing broad-spectrum antibiotics beyond 3 days drastically alters the host’s resident flora and selects for resistant organisms. After 3 days, streamline antibiotic coverage. Use narrowerspectrum antibiotics to treat the specific pathogens identified by culture and Gram stain. 8. All Else Being Equal, Choose The Least Expensive Drug As is discussed in later chapters, more than one antibiotic regimen can often be used to successfully treat a specific infection. Given the strong economic forces driving medicine today, the physician needs to consider the cost of therapy whenever possible. Too often, new, more expensive antibiotics are chosen over older generic antibiotics that are equally effective. In this book, the review of each specific antibiotic tries to classify that antibiotic’s cost range to assist the clinician in making cost-effective decisions. However, in assessing cost, factoring in toxicity is also important. For example, the acquisition cost of Table 1.1. Classification of Antibiotics by Spectrum of Activity Narrow Moderately Broad Broad Very Broad Penicillin Ampicillin Ampicillin–sulbactam Ticarcillin–clavulinate Oxacillin/Nafcillin Ticarcillin Amoxicillin–clavulanate Piperacillin–tazobactam Cefazolin Piperacillin Ceftriaxone, Cefepime Cephalexin/Cephradine Cefoxitin Cefotaxime Imipenem Aztreonam Cefotetan Ceftizoxime Meropenem Aminoglycosides Cefuroxime–axetil Ceftazidime Ertapenem Vancomycin Cefaclor Cefixime Gatifloxacin Macrolides Ciprofloxacin Cefpodoxime proxetil Moxifloxacin Clindamycin Azithromycin Tetracycline Tigecycline Linezolid Clarithromycin Doxycycline Quinupristin/dalfopristin Talithromycin Chloramphenicol Daptomycin Trimethoprim– Levofloxacin sulfamethoxazole Metronidazole gentamicin is low, but when blood-level monitoring, the requirement to closely follow blood urea nitrogen 1. Assess the probability of bacterial infection. (Antibiotics should be avoided in viral infections.) 2. Be familiar with the pathogens primarily responsible for infection at each anatomic site. 3. Be familiar with the bacterial flora in the local hospital and community. 4. Take into account previous antibiotic treatment. 5. Take into account the specific host factors (age, immune status, hepatic and renal function, duration of hospitalization, severity of illness). 6. Use the minimum number and narrowest spectrum of antibiotics possible. 7. Switch to a narrower-spectrum antibiotic regimen based on culture results. 8. Take into account acquisition cost and the costs of toxicity. KEY POINTS About the Steps Required to Design an Antibiotic Regimen