ANTI-INFECTIVE THERAPY 3 KEY POINTS B-lactamase activity occurs primarily through plasmids and Multiple classes of B-lactamases exist. Some preferen- About antibiotic resistance tially break down penicillins; others preferentially destroy 1. Bacteria can quickly alter their genetic makeup by trum B-lactamases(ESBLS) readily destroy most cp a)point mutation losporins. Another class of B-lactamase is resistant to b) transfer of dna by plasmid conjugation. clavulanate, an agent added to numerous antibiotics to inhibit B-lactamase activity. Some bacteria are able to pro- c) transfer of dna by bacteriophage trans duce B-lactamases called carbapenemases that are capable inactivating imipenem and meropenem. d) transfer of naked DNA by transposon trans- Gram-negative bacilli produce a broader spectrum formation of B-lactamases than do gram-positive organisms, and pility of bacteria to share DNA therefore infections with gram-negative urvival advantage, allowing them to quickly more commonly arise in patients treated for pro apt to antibiotic ex longed periods with broad-spectrum antibiotics. Ir 3. Biochemical alterations leading to antibiotic some instances, B-lactamase activity is low before the resistance include bacterium is exposed to antibiotics; however, follow a) degradation or modification of the antibiotic. re,B-lactamase activity is induced b)reduction of the bacterial antibiotic concen- Enterobacter is a prime example. This gram-negative tration by inhibiting entry or by efflux bacterium may appear sensitive to cephalosporins on initial testing. Following cephalosporin treatment c) modification of the antibiotic target. B-lactamase activity increases, resistance develops and the patient's infection relapses. For this reason, uestion is not whether, but when resistant third-generation cephalosporins are not recom- bacteria will take over. mended for serious Enterobacter infections OTHER ENZYME MODIFICATIONS OF ANTIBIOTICS Erythromycin is readily inactivated by an esterase than hydrolyzes the lactone ring of the antibiotic. This Thus bacteria possess multiple ways to transfer their esterase has been identified in Escherichia coli. Other lasmid-mediated erythromycin inactivating enzymes DNA, and they promiscuously share genetic informa- have been discovered in Streptococcus species and tion. This promiscuity provides a survival advantage, S. aureus. Chloramphenicol is inactivated by chloram- allowing bacteria to quickly adapt to their environment. phenicol acetyltransferase, which has been isolated from BIOCHEMICAL MECHANISMS FOR and gram-negative bacteria. Simi- larly, aminoglycosides can be inactivated by acetyltrans- ANTIMICROBIAL RESISTANCE ferases. Bacteria also inactivate this class of antibiotics by What are some of the proteins that these resistant gene phosphorylation and adenylation encode for, and how do they work? These resistance enzymes are found in many gram The mechanisms by which bacteria resist antibiotics negative strains and are increasingly detected in entero- can be classified into three major groups cocci, S. aureus and S epidermidis. of the antib Reduction of the bacterial Reduction of the bacterial antibiotic concentration Antibiotic Concentration Modification of the antibiotic target INTERFERENCE WITH ANTIBIOTIC ENTRY For an antibiotic to work, it must be able to penetrate Degradation or Modification the bacterium and reach its biochemical target. gram- of the Antibiotic negative bacteria contain an outer lipid coat that β- LACTAMASES neration by hydrophobic reagents( most antibiotics). The passage of hydrophobic antibi Many bacteria synthesize one or more enzymes called otics is facilitated by the presence of porins-small B-lactamases that inactivate antibiotics by breaking the channels in the cell walls of gram-negative I bacteria that amide bond on the B-lactam ring. Transfer of allow the passage of charged molecules. Mutations
Thus bacteria possess multiple ways to transfer their DNA, and they promiscuously share genetic information. This promiscuity provides a survival advantage, allowing bacteria to quickly adapt to their environment. BIOCHEMICAL MECHANISMS FOR ANTIMICROBIAL RESISTANCE What are some of the proteins that these resistant genes encode for, and how do they work? The mechanisms by which bacteria resist antibiotics can be classified into three major groups: • Degradation or modification of the antibiotic • Reduction of the bacterial antibiotic concentration • Modification of the antibiotic target Degradation or Modification of the Antibiotic -LACTAMASES Many bacteria synthesize one or more enzymes called -lactamases that inactivate antibiotics by breaking the amide bond on the -lactam ring. Transfer of -lactamase activity occurs primarily through plasmids and transposons. Multiple classes of -lactamases exist. Some preferentially break down penicillins; others preferentially destroy specific cephalosporins or carbenicillin. Extended-spectrum -lactamases (ESBLs) readily destroy most cephalosporins. Another class of -lactamase is resistant to clavulanate, an agent added to numerous antibiotics to inhibit -lactamase activity. Some bacteria are able to produce -lactamases called carbapenemases that are capable of inactivating imipenem and meropenem. Gram-negative bacilli produce a broader spectrum of -lactamases than do gram-positive organisms, and therefore infections with gram-negative organisms more commonly arise in patients treated for prolonged periods with broad-spectrum antibiotics. In some instances, -lactamase activity is low before the bacterium is exposed to antibiotics; however, following exposure, -lactamase activity is induced. Enterobacter is a prime example. This gram-negative bacterium may appear sensitive to cephalosporins on initial testing. Following cephalosporin treatment, -lactamase activity increases, resistance develops, and the patient’s infection relapses. For this reason, third-generation cephalosporins are not recommended for serious Enterobacter infections. OTHER ENZYME MODIFICATIONS OF ANTIBIOTICS Erythromycin is readily inactivated by an esterase that hydrolyzes the lactone ring of the antibiotic. This esterase has been identified in Escherichia coli. Other plasmid-mediated erythromycin inactivating enzymes have been discovered in Streptococcus species and S. aureus. Chloramphenicol is inactivated by chloramphenicol acetyltransferase, which has been isolated from both gram-positive and gram-negative bacteria. Similarly, aminoglycosides can be inactivated by acetyltransferases. Bacteria also inactivate this class of antibiotics by phosphorylation and adenylation. These resistance enzymes are found in many gramnegative strains and are increasingly detected in enterococci, S. aureus and S. epidermidis. Reduction of the Bacterial Antibiotic Concentration INTERFERENCE WITH ANTIBIOTIC ENTRY For an antibiotic to work, it must be able to penetrate the bacterium and reach its biochemical target. Gramnegative bacteria contain an outer lipid coat that impedes penetration by hydrophobic reagents (such as most antibiotics). The passage of hydrophobic antibiotics is facilitated by the presence of porins—small channels in the cell walls of gram-negative bacteria that allow the passage of charged molecules. Mutations ANTI-INFECTIVE THERAPY / 3 1. Bacteria can quickly alter their genetic makeup by a) point mutation. b) transfer of DNA by plasmid conjugation. c) transfer of DNA by bacteriophage transduction. d) transfer of naked DNA by transposon transformation. 2. The ability of bacteria to share DNA provides a survival advantage, allowing them to quickly adapt to antibiotic exposure. 3. Biochemical alterations leading to antibiotic resistance include a) degradation or modification of the antibiotic. b) reduction of the bacterial antibiotic concentration by inhibiting entry or by efflux pumps. c) modification of the antibiotic target. 4. Under the selection pressure of antibiotics, the question is not whether, but when resistant bacteria will take over. KEY POINTS About Antibiotic Resistance
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