- Email: [email protected]
Empiric antibiotic use—aztreonam as a model
Empiric Antibiotic STUART
LEVIN,M.D. Chicago,
Use-Aztreonam
as a Model
///inois
Empiric antibiotic therapy, which accounts for over 90 percent of in-hospital therapeutic antibiotic decisions, may be defined as tentative therapy designed to decrease morbidity and mortality associated with severe infection due to unidentified bacterial pathogens. In the 4% to 72-hour interim between presentation and the availability of reliable culture and sensitivity data that allow for definitive therapy, empiric therapy is extremely important. Aztreonam, the first member of the monobactam class of monocyclic betalactam antibiotics, is highly active against most gram-negative aerobic bacteria, including Pseudomonas aeruginosa. Its spectrum of activity is similar to that of the aminoglycosides but without the toxicity associated with those agents. For this reason, aztreonam may play an important role in empiric therapy. Currently, it can be recommended as single-agent empiric therapy only for severe urinary tract infections, but in combination with a variety of other agents, it has proved useful against a wide range of bacterial infections, and in certain subgroups, such as penicillin-allergic patients, it may represent the treatment of choice. It is not yet clear whether aztreonam is superior to other relatively nontoxic agents, such as the third-generation cephalosporins or carbapenems, but there is little doubt that this new agent is a generally safe and effective drug for the treatment of suspected gram-negative sepsis.
From Rush Medical College, and Department of Internal Medicine, Section of Infectious Disease, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois. Requests for reprints should be addressed to Stuart Levin, M.D., Department of Internal Medicme, Rush-Presbyterian-Saint Luke’s Medical Center, 1753 West Congress Parkway. Chlcago, llllnois 60612.
n 1983, Dr. Maxwell Finland defined empiric antibiIpresentation, otic therapy as “tentative” therapy, initiated on before reliable culture and sensitivity information becomes available. In contrast to empiric therapy is definitive therapy, termed such because it comprises treatment administered after useful culture and sensitivity information becomes available; definitive therapy is generally not possible until 48 to 72 hours (Day 3 decision) after empiric therapy (Day 1 decision) has been initiated [l]. It is interesting that although greater than 90 percent of all therapeutic antibiotic decisions made in the hospital setting are empiric, most of the medical literature focuses on drugs of choice for the treatment of infections for which the pathogens have been identified. ROLE OF EMPIRIC THERAPY IN INFECTIOUS DISEASE The obvious aim of empiric therapy is to decrease the morbidity and mortality associated with infection by suspected but not yet proved or precisely identified bacterial pathogens while being selective enough to minimize drug toxicity, drug costs, and bacterial superinfection [21. Naturally, empiric antibiotic therapy often must be continued beyond the third day, as, for example, when an improved clinical response has occurred but no definite pathogen has been identified. In a majority of such cases, it is usually possible to modify the initial empiric regimen, which often includes expensive and potentially toxic agents, to one involving drugs with a narrower spectrum, lower cost, and less toxicity [3]. Specifically, in most nonleukopenic, relatively stable patients who have responded to empiric therapy but whose specific pathogens have not been identified by 48 to 72 hours, physicians can stop administration of aminoglycosides, vancomycin, imipenem, and third-generation cephalosporins, as well as specialized antibiotics active mainly against Pseudomonas aeruginosa such as ceftazidime and broadspectrum penicillins. Less expensive antibiotics with reasonable gram-positive and anaerobic and more limited gram-negative coverage, such as the first-generation cephalosporins, can be continued. As long as appropriate cultures were obtained before antibiotic treatment was initiated, the subsequent absence of positive cultures for P. aeruginosa, methicillin-resistant Staphylococcus aureus, and antibiotic-resistant gram-negative rods in nonleukopenic patients suggests that the overall toxicity and financial cost of continuing initial broad-spectrum antibiotic coverage considerably outweigh any potential efficacy [3]. Empiric broad-spectrum therapy may be more appropriately decreased on the third or fourth day of therapy by the average prudent physician who has been giving daily care and then makes a treatment decision based on available culture information than can be done by the most expert and experienced infectious disease specialist on Day 1. Of course, it must be kept in mind that such initial broad-spectrum therapy
March 23, 1990
The American Journal of Medicine
Volume 88 (suppl 3C)
3C-21s
SYMPOSIUM
ON AZTREONAM
/ LEVIN
is only indicated for patients who are in great need, e.g., extremely toxic patients, immunocompromised patients, or patients with hospital-acquired infections. As envisioned by Dr. Finland, the accuracy of Day 1 therapy might approach that of definitive therapy through use of a computer; general knowledge of bacterial sensitivities; specific clinical information pertaining to individual patients; pharmacologic information related to the patient’s age and liver and renal function; and specific local and regional information about bacterial antibiotic sensitivities. Eventually, computers will be capable of generating antibiotic decisions with probability and standard-deviation information and then aiding in the formulation of diagnostic and therapeutic decisions [l]. Until such reliable computer-generated information is available, however, empiric antibiotic decisions remain dependent on human judgment, which is based on local and universal experience, the apparent severity of the underlying disease before infection, the severity and speed of onset of the suspected infection, the importance of the organ system involved, as well as on rapidly available etiologic-agent tests, such as the underused Gram stain, and antigen tests such as counterimmunoelectrophoresis and latex agglutination. Clinical judgment must be refined as much as possible in order to limit the overuse of drugs, toxicity, and selection of antibiotic-resistant bacteria in the environment. Empiric choices therefore must be specific for patients: a narcotic abuser with signs of serious sepsis, for example, must always be treated with empiric therapy for S. aureus, often for methicillin-resistant S. aureus, and not uncommonly for P. aeruginosa. Similarly, it would be inappropriate to use ciprofloxacin alone to treat a foul-smelling abdominal abscess, since foul odor indicates the presence of anaerobes and the quinolones are not active against anaerobes.
AZTREONAMAS A MODELFOREMPIRICTHERAPY Aztreonam is the first member of a new class of monocyclic agents-the monobactams-to become available for clinical use. These unique agents bind only to the penicillin-binding protein 3 of gram-negative aerobic bacteria and thus do not exert activity against gram-positive or anaerobic bacteria. Aztreonam is extremely active against a majority of aerobic and facultative gram-negative bacilli, such as the Enterobacteriaceae, including Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Proteus, Salmonella, and Shigella spp. It also has significant activity against P. aemginosa, being more active than
most third-generation cephalosporins although slightly less active than imipenem and ceftazidime. The mechanism of action of aztreonam is similar to that of beta-lactam agents in its inhibition of synthesis of the bacterial cell wall. It does not induce bacterial chromosomal beta-lactamases, and most beta-lactamases produced by gram-negative rods will not inactivate this drug [4]. Initially susceptible bacteria can, however, develop resistance secondary to membraneprotein changes that inhibit antibiotic penetration, and such resistant bacteria are often cross-resistant with the third-generation cephalosporins. Aztreonam is also similar to other beta-lactams in its toxicity profile, but it differs in that it has little if any crossimmunogenicity with the other beta-lactam agents
3G22S
March 23, 1990
The American Journal of Medicine
and has not been found to cause coagulation abnormalities such as those produced by carboxypenicillins and the methylthiotetrazide cephalosporins. It is neither nephrotoxic nor ototoxic [5,6]. The decision to use aztreonam is based on its proved efficacy against gram-negative bacilli and its spectrum of activity, which is similar to that of the aminoglycosides. Aztreonam can be considered as alternative therapy for any gram-negative infection for which an aminoglycoside might have been used. Since aztreonam is often synergistic and never antagonistic with aminoglycosides against gram-negative bacilli, it also can be used in combination with an aminoglycoside, rather than as a substitute, to broaden the spectrum against gram-negative bacilli and possibly obtain synergy. Aztreonam also can be used with other betalactams to extend the spectrum of activity, but such combinations may not yield synergy [4]. Single-Drug Empiric Therapy with Aztreonam
Aztreonam can be justified for single-agent empiric therapy only in the treatment of hospital- or community-acquired urinary tract infections, especially if the infection is serious enough to require intravenous or intramuscular therapy 17-91. Biliary tract sepsis is another relatively common infection that is primarily due to gram-negative bacilli; gram-positive bacteria and anaerobes are relatively infrequent causes unless there has been longstanding obstruction. However logical the use of aztreonam in biliary tract disease, there are not sufficient studies to strongly support its solitary empiric use in these infections [lo]. Additionally, enterococcal bacteremia can occasionally complicate biliary tract sepsis. Aztreonam in Empiric Combination Therapy
Aztreonam has proved effective in combination with different antibiotics for treatment of a wide range of clinical syndromes. Used alone, it has been found to be equal to aminoglycosides in the treatment of serious urinary tract infections [81, and used in combination with gram-positive agents, it has been as effective as aminoglycoside combinations in the empiric treatment of lower respiratory tract infection [ll-131, skin and soft tissue infection [141, and gynecologic and intraabdominal infection [15-171. Gram-negative bacteremia, including that due to P. aeruginosa, also has been successfully treated with aztreonam [4,18-201. In addition, this agent has been combined with clindamycin to treat lower respiratory tract, intra-abdominal, and gynecologic infection, and it has been combined with vancomycin for treatment of sepsis in granulocytopenic cancer patients [21,221. Host Factors Indicative of Aztreonam as Treatment of Choice
In patients who are strongly penicillin allergic, aztreonam may be considered the drug of choice in empiric therapy for gram-negative sepsis, since such allergy contraindicates the use of cephalosporins, carbapenems, and penicillins, and aztreonam is less toxic than aminoglycosides. Other host characteristics also strongly suggest the use of aztreonam. These include advanced age, underlying central nervous system defects, gastrointestinal bleeding, and high risk of neph-
Volume 88 (suppl 3C)
SYMPOSIUM
rotoxicity from aminoglycosides, as in liver- and renaltransplant patients. Aztreonam might also be useful for treatment of patients receiving beta-lactam therapy for a known or suspected infection who nevertheless continue to have fever and in whom the possibility of beta-la&am fever is suspected. For these patients, there is a theoretic benefit to switching to aztreonam, which is not immunologically cross-reactive with other beta-la&am antibiotics. Although not prospectively proved, this approach has been used by the author with apparent success and allows lysis of fever within a few days while continuing to provide relatively safe beta-la&am therapy. Comparison of Aztreonam with Other Beta-Lactams
The potential benefit of aztreonam over other relatively nontoxic drugs, such as the third-generation cephalosporins and carbapenems, has yet to be determined. Imipenem, however, despite its broad-spectrum activity against gram-positive and anaerobic bacteria and its excellent gram-negative coverage, becomes less desirable as empiric therapy in the presence of advanced age and prior neurologic disease or azotemia. Similarly, except for ceftazidime, the thirdgeneration cephalosporins do not exert adequate activity against P. aeruginosa compared with aztreonam. Nevertheless, there is no proved superiority of aztreonam compared with ceftazidime, except in penicillin-allergic patients, for whom aztreonam would be the better choice. A decision between these two agents might be made on the basis of acquisition cost of the drugs. Despite its inclusion in the familiar betalactam class of drugs, aztreonam is currently underutilized in many situations due to a lack of familiarity with the drug by the practicing physician.
COMMENTS There is little question that aztreonam is a safe and effective drug to use for the treatment of suspected gram-negative sepsis in most clinical situations. Unless the source of the infection is the urinary tract, however, aztreonam must always be combined with a second agent such as an aminoglycoside or an agent with gram-positive activity.
ON AZTREONAM I LEVIN
REFERENCES 1. Finland M: Empiric therapy for bacterial infections: the historical perspective. Rev infect Dis 1983; 5 (suppl): SZ-S8.~ 2. Donowitz GR, Mandell GL: Empiric therapy for pneumonia. Rev Infect Dis 1983; 5 (suppl): s40-s54. 3. Briceland LL, Nightingale CH, Quintiliani R, eta/: Antibiotic streamlining from combrnation therapy to monotherapy utilizing an interdisciplinary approach. Arch Intern Med 1988; 148: 2019-2022. 4. Scully BE, Neu HC: Use of aztreonam in the treatment of serrous infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa. Am J Med 1985; 78: 251-261. 5. Adkinson NF Jr, Saxon A, Spence MR, et a/; Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985: 7 ~SUDDI4): S613-S621. 6. Saxon A, Beall GN, Rohr AS, et a/; Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107: 204-215. 7. Childs SJ: Aztreonam in the treatment of urinary tract Infection. Am J Med 1985; 78 (suppl 2A): 44-46. 8. Sattler FS, Moyer JE, Schramm M, et at Aztreonam compared with gentamicin for treatment of serious urinary tract infections. Lancet 1984; I: 1315-1318. 9. Cox CE: Aztreonam therapy for complicated urinary tract infections caused by multidrug-resistant bacteria. Rev Infect Dis 1985; 7 (suppl 4): S767-S777. 10. Condon RE. Friedhoff LT. Edmiston CE. ef al: Aztreonam concentration in abdominal tissues and bile. Antimicrob’Agents Chemother 1986; 29: 1101-1103. 11. Schentag JJ, Vari Al, Winslade NE, et at Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia. Am J Med 1985; 78 (suppl 2A): 34-41. 12. Nolen TM, Phillips HL, Hall HJ: Comparison of aztreonam and tobramycrn in the treatment of lower respiratory tract infections caused by gram-negative bacilli. Rev Infect Dis 1985; 7 (suppl 4): S666-S668. 13. Greenberg RN, Reilly PM, Luppen KL, et at Aztreonam therapy for gram-negative oneumonia. Am J Med 1985: 78 lsu~ol 2AI: 31-33. i4. Simons WJ, Lee TJ: Treatment’of’gram-negative infections with aztreonam. Am J Med 1985; 78 (suppl 2A): 27-30. 15. Birolini D, Moraes MF, deSouza OS: Aztreonam plus clindamycin vs. tobramycin plus clindamycin for the treatment of intraabdominal infections. Rev Infect Dis 1985; 7 (suppl 41: S724-S761. lb. Henry SA: Overall clinical experience with aztreonam In the treatment of obstetricgynecologic infections. Rev Infect Dis 1985; 7 (suppl 4): S703-S708. 17. Pastorek JG II, Cole C, Aldridge KE, et al: Aztreonam plus ckndamycin as therapy for pelvic infections in women. Am J Med 1985: 78 ISUDDI2AI: 47-50. 18. LeFrock JL, Smith BR, Chandrasekar P, et al: Efficacy and safety of aztreonam in the treatment of serious gram-negative bacterial infections. Arch Int Med 1987; 147: 325328. 19. Cone LA, Woodard DR: Aztreonam therapy for serious gram-negative bacillary infections. Rev Infect Dis 1985: 7 lsuo~l 41: S794-S802. 20. McKellar PP: Clinical evaluation of aztreonam therapy for serious infections due to gram-negative bacteria. Rev Infect Dis 1985; 7 (suppl 4): S803-5809. 21. Jones P, Rolston K, Fainstein V, et at Aztreonam plus vancomycin (plus amikacin) vs. moxalactam plus ticarcillin for the empiric treatment of febrile eprsodes in neutropenic cancer patients. Rev Infect Dis 1985; 7 (suppl 4): S741-S746. 22. Lagast H, Kiastersky J, Kains JP, et at Empiric antimicrobial therapy with aztreonam or ceftazidime in gram-negative septicemia. Am J Med 1986; 80 (suppl 5C): 7984.
March 23, 1990
The American Journal of Medicine
Volume 88 (suppl 3C)
3G23S
LEVIN,M.D. Chicago,
Use-Aztreonam
as a Model
///inois
Empiric antibiotic therapy, which accounts for over 90 percent of in-hospital therapeutic antibiotic decisions, may be defined as tentative therapy designed to decrease morbidity and mortality associated with severe infection due to unidentified bacterial pathogens. In the 4% to 72-hour interim between presentation and the availability of reliable culture and sensitivity data that allow for definitive therapy, empiric therapy is extremely important. Aztreonam, the first member of the monobactam class of monocyclic betalactam antibiotics, is highly active against most gram-negative aerobic bacteria, including Pseudomonas aeruginosa. Its spectrum of activity is similar to that of the aminoglycosides but without the toxicity associated with those agents. For this reason, aztreonam may play an important role in empiric therapy. Currently, it can be recommended as single-agent empiric therapy only for severe urinary tract infections, but in combination with a variety of other agents, it has proved useful against a wide range of bacterial infections, and in certain subgroups, such as penicillin-allergic patients, it may represent the treatment of choice. It is not yet clear whether aztreonam is superior to other relatively nontoxic agents, such as the third-generation cephalosporins or carbapenems, but there is little doubt that this new agent is a generally safe and effective drug for the treatment of suspected gram-negative sepsis.
From Rush Medical College, and Department of Internal Medicine, Section of Infectious Disease, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois. Requests for reprints should be addressed to Stuart Levin, M.D., Department of Internal Medicme, Rush-Presbyterian-Saint Luke’s Medical Center, 1753 West Congress Parkway. Chlcago, llllnois 60612.
n 1983, Dr. Maxwell Finland defined empiric antibiIpresentation, otic therapy as “tentative” therapy, initiated on before reliable culture and sensitivity information becomes available. In contrast to empiric therapy is definitive therapy, termed such because it comprises treatment administered after useful culture and sensitivity information becomes available; definitive therapy is generally not possible until 48 to 72 hours (Day 3 decision) after empiric therapy (Day 1 decision) has been initiated [l]. It is interesting that although greater than 90 percent of all therapeutic antibiotic decisions made in the hospital setting are empiric, most of the medical literature focuses on drugs of choice for the treatment of infections for which the pathogens have been identified. ROLE OF EMPIRIC THERAPY IN INFECTIOUS DISEASE The obvious aim of empiric therapy is to decrease the morbidity and mortality associated with infection by suspected but not yet proved or precisely identified bacterial pathogens while being selective enough to minimize drug toxicity, drug costs, and bacterial superinfection [21. Naturally, empiric antibiotic therapy often must be continued beyond the third day, as, for example, when an improved clinical response has occurred but no definite pathogen has been identified. In a majority of such cases, it is usually possible to modify the initial empiric regimen, which often includes expensive and potentially toxic agents, to one involving drugs with a narrower spectrum, lower cost, and less toxicity [3]. Specifically, in most nonleukopenic, relatively stable patients who have responded to empiric therapy but whose specific pathogens have not been identified by 48 to 72 hours, physicians can stop administration of aminoglycosides, vancomycin, imipenem, and third-generation cephalosporins, as well as specialized antibiotics active mainly against Pseudomonas aeruginosa such as ceftazidime and broadspectrum penicillins. Less expensive antibiotics with reasonable gram-positive and anaerobic and more limited gram-negative coverage, such as the first-generation cephalosporins, can be continued. As long as appropriate cultures were obtained before antibiotic treatment was initiated, the subsequent absence of positive cultures for P. aeruginosa, methicillin-resistant Staphylococcus aureus, and antibiotic-resistant gram-negative rods in nonleukopenic patients suggests that the overall toxicity and financial cost of continuing initial broad-spectrum antibiotic coverage considerably outweigh any potential efficacy [3]. Empiric broad-spectrum therapy may be more appropriately decreased on the third or fourth day of therapy by the average prudent physician who has been giving daily care and then makes a treatment decision based on available culture information than can be done by the most expert and experienced infectious disease specialist on Day 1. Of course, it must be kept in mind that such initial broad-spectrum therapy
March 23, 1990
The American Journal of Medicine
Volume 88 (suppl 3C)
3C-21s
SYMPOSIUM
ON AZTREONAM
/ LEVIN
is only indicated for patients who are in great need, e.g., extremely toxic patients, immunocompromised patients, or patients with hospital-acquired infections. As envisioned by Dr. Finland, the accuracy of Day 1 therapy might approach that of definitive therapy through use of a computer; general knowledge of bacterial sensitivities; specific clinical information pertaining to individual patients; pharmacologic information related to the patient’s age and liver and renal function; and specific local and regional information about bacterial antibiotic sensitivities. Eventually, computers will be capable of generating antibiotic decisions with probability and standard-deviation information and then aiding in the formulation of diagnostic and therapeutic decisions [l]. Until such reliable computer-generated information is available, however, empiric antibiotic decisions remain dependent on human judgment, which is based on local and universal experience, the apparent severity of the underlying disease before infection, the severity and speed of onset of the suspected infection, the importance of the organ system involved, as well as on rapidly available etiologic-agent tests, such as the underused Gram stain, and antigen tests such as counterimmunoelectrophoresis and latex agglutination. Clinical judgment must be refined as much as possible in order to limit the overuse of drugs, toxicity, and selection of antibiotic-resistant bacteria in the environment. Empiric choices therefore must be specific for patients: a narcotic abuser with signs of serious sepsis, for example, must always be treated with empiric therapy for S. aureus, often for methicillin-resistant S. aureus, and not uncommonly for P. aeruginosa. Similarly, it would be inappropriate to use ciprofloxacin alone to treat a foul-smelling abdominal abscess, since foul odor indicates the presence of anaerobes and the quinolones are not active against anaerobes.
AZTREONAMAS A MODELFOREMPIRICTHERAPY Aztreonam is the first member of a new class of monocyclic agents-the monobactams-to become available for clinical use. These unique agents bind only to the penicillin-binding protein 3 of gram-negative aerobic bacteria and thus do not exert activity against gram-positive or anaerobic bacteria. Aztreonam is extremely active against a majority of aerobic and facultative gram-negative bacilli, such as the Enterobacteriaceae, including Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Proteus, Salmonella, and Shigella spp. It also has significant activity against P. aemginosa, being more active than
most third-generation cephalosporins although slightly less active than imipenem and ceftazidime. The mechanism of action of aztreonam is similar to that of beta-lactam agents in its inhibition of synthesis of the bacterial cell wall. It does not induce bacterial chromosomal beta-lactamases, and most beta-lactamases produced by gram-negative rods will not inactivate this drug [4]. Initially susceptible bacteria can, however, develop resistance secondary to membraneprotein changes that inhibit antibiotic penetration, and such resistant bacteria are often cross-resistant with the third-generation cephalosporins. Aztreonam is also similar to other beta-lactams in its toxicity profile, but it differs in that it has little if any crossimmunogenicity with the other beta-lactam agents
3G22S
March 23, 1990
The American Journal of Medicine
and has not been found to cause coagulation abnormalities such as those produced by carboxypenicillins and the methylthiotetrazide cephalosporins. It is neither nephrotoxic nor ototoxic [5,6]. The decision to use aztreonam is based on its proved efficacy against gram-negative bacilli and its spectrum of activity, which is similar to that of the aminoglycosides. Aztreonam can be considered as alternative therapy for any gram-negative infection for which an aminoglycoside might have been used. Since aztreonam is often synergistic and never antagonistic with aminoglycosides against gram-negative bacilli, it also can be used in combination with an aminoglycoside, rather than as a substitute, to broaden the spectrum against gram-negative bacilli and possibly obtain synergy. Aztreonam also can be used with other betalactams to extend the spectrum of activity, but such combinations may not yield synergy [4]. Single-Drug Empiric Therapy with Aztreonam
Aztreonam can be justified for single-agent empiric therapy only in the treatment of hospital- or community-acquired urinary tract infections, especially if the infection is serious enough to require intravenous or intramuscular therapy 17-91. Biliary tract sepsis is another relatively common infection that is primarily due to gram-negative bacilli; gram-positive bacteria and anaerobes are relatively infrequent causes unless there has been longstanding obstruction. However logical the use of aztreonam in biliary tract disease, there are not sufficient studies to strongly support its solitary empiric use in these infections [lo]. Additionally, enterococcal bacteremia can occasionally complicate biliary tract sepsis. Aztreonam in Empiric Combination Therapy
Aztreonam has proved effective in combination with different antibiotics for treatment of a wide range of clinical syndromes. Used alone, it has been found to be equal to aminoglycosides in the treatment of serious urinary tract infections [81, and used in combination with gram-positive agents, it has been as effective as aminoglycoside combinations in the empiric treatment of lower respiratory tract infection [ll-131, skin and soft tissue infection [141, and gynecologic and intraabdominal infection [15-171. Gram-negative bacteremia, including that due to P. aeruginosa, also has been successfully treated with aztreonam [4,18-201. In addition, this agent has been combined with clindamycin to treat lower respiratory tract, intra-abdominal, and gynecologic infection, and it has been combined with vancomycin for treatment of sepsis in granulocytopenic cancer patients [21,221. Host Factors Indicative of Aztreonam as Treatment of Choice
In patients who are strongly penicillin allergic, aztreonam may be considered the drug of choice in empiric therapy for gram-negative sepsis, since such allergy contraindicates the use of cephalosporins, carbapenems, and penicillins, and aztreonam is less toxic than aminoglycosides. Other host characteristics also strongly suggest the use of aztreonam. These include advanced age, underlying central nervous system defects, gastrointestinal bleeding, and high risk of neph-
Volume 88 (suppl 3C)
SYMPOSIUM
rotoxicity from aminoglycosides, as in liver- and renaltransplant patients. Aztreonam might also be useful for treatment of patients receiving beta-lactam therapy for a known or suspected infection who nevertheless continue to have fever and in whom the possibility of beta-la&am fever is suspected. For these patients, there is a theoretic benefit to switching to aztreonam, which is not immunologically cross-reactive with other beta-la&am antibiotics. Although not prospectively proved, this approach has been used by the author with apparent success and allows lysis of fever within a few days while continuing to provide relatively safe beta-la&am therapy. Comparison of Aztreonam with Other Beta-Lactams
The potential benefit of aztreonam over other relatively nontoxic drugs, such as the third-generation cephalosporins and carbapenems, has yet to be determined. Imipenem, however, despite its broad-spectrum activity against gram-positive and anaerobic bacteria and its excellent gram-negative coverage, becomes less desirable as empiric therapy in the presence of advanced age and prior neurologic disease or azotemia. Similarly, except for ceftazidime, the thirdgeneration cephalosporins do not exert adequate activity against P. aeruginosa compared with aztreonam. Nevertheless, there is no proved superiority of aztreonam compared with ceftazidime, except in penicillin-allergic patients, for whom aztreonam would be the better choice. A decision between these two agents might be made on the basis of acquisition cost of the drugs. Despite its inclusion in the familiar betalactam class of drugs, aztreonam is currently underutilized in many situations due to a lack of familiarity with the drug by the practicing physician.
COMMENTS There is little question that aztreonam is a safe and effective drug to use for the treatment of suspected gram-negative sepsis in most clinical situations. Unless the source of the infection is the urinary tract, however, aztreonam must always be combined with a second agent such as an aminoglycoside or an agent with gram-positive activity.
ON AZTREONAM I LEVIN
REFERENCES 1. Finland M: Empiric therapy for bacterial infections: the historical perspective. Rev infect Dis 1983; 5 (suppl): SZ-S8.~ 2. Donowitz GR, Mandell GL: Empiric therapy for pneumonia. Rev Infect Dis 1983; 5 (suppl): s40-s54. 3. Briceland LL, Nightingale CH, Quintiliani R, eta/: Antibiotic streamlining from combrnation therapy to monotherapy utilizing an interdisciplinary approach. Arch Intern Med 1988; 148: 2019-2022. 4. Scully BE, Neu HC: Use of aztreonam in the treatment of serrous infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa. Am J Med 1985; 78: 251-261. 5. Adkinson NF Jr, Saxon A, Spence MR, et a/; Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985: 7 ~SUDDI4): S613-S621. 6. Saxon A, Beall GN, Rohr AS, et a/; Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107: 204-215. 7. Childs SJ: Aztreonam in the treatment of urinary tract Infection. Am J Med 1985; 78 (suppl 2A): 44-46. 8. Sattler FS, Moyer JE, Schramm M, et at Aztreonam compared with gentamicin for treatment of serious urinary tract infections. Lancet 1984; I: 1315-1318. 9. Cox CE: Aztreonam therapy for complicated urinary tract infections caused by multidrug-resistant bacteria. Rev Infect Dis 1985; 7 (suppl 4): S767-S777. 10. Condon RE. Friedhoff LT. Edmiston CE. ef al: Aztreonam concentration in abdominal tissues and bile. Antimicrob’Agents Chemother 1986; 29: 1101-1103. 11. Schentag JJ, Vari Al, Winslade NE, et at Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia. Am J Med 1985; 78 (suppl 2A): 34-41. 12. Nolen TM, Phillips HL, Hall HJ: Comparison of aztreonam and tobramycrn in the treatment of lower respiratory tract infections caused by gram-negative bacilli. Rev Infect Dis 1985; 7 (suppl 4): S666-S668. 13. Greenberg RN, Reilly PM, Luppen KL, et at Aztreonam therapy for gram-negative oneumonia. Am J Med 1985: 78 lsu~ol 2AI: 31-33. i4. Simons WJ, Lee TJ: Treatment’of’gram-negative infections with aztreonam. Am J Med 1985; 78 (suppl 2A): 27-30. 15. Birolini D, Moraes MF, deSouza OS: Aztreonam plus clindamycin vs. tobramycin plus clindamycin for the treatment of intraabdominal infections. Rev Infect Dis 1985; 7 (suppl 41: S724-S761. lb. Henry SA: Overall clinical experience with aztreonam In the treatment of obstetricgynecologic infections. Rev Infect Dis 1985; 7 (suppl 4): S703-S708. 17. Pastorek JG II, Cole C, Aldridge KE, et al: Aztreonam plus ckndamycin as therapy for pelvic infections in women. Am J Med 1985: 78 ISUDDI2AI: 47-50. 18. LeFrock JL, Smith BR, Chandrasekar P, et al: Efficacy and safety of aztreonam in the treatment of serious gram-negative bacterial infections. Arch Int Med 1987; 147: 325328. 19. Cone LA, Woodard DR: Aztreonam therapy for serious gram-negative bacillary infections. Rev Infect Dis 1985: 7 lsuo~l 41: S794-S802. 20. McKellar PP: Clinical evaluation of aztreonam therapy for serious infections due to gram-negative bacteria. Rev Infect Dis 1985; 7 (suppl 4): S803-5809. 21. Jones P, Rolston K, Fainstein V, et at Aztreonam plus vancomycin (plus amikacin) vs. moxalactam plus ticarcillin for the empiric treatment of febrile eprsodes in neutropenic cancer patients. Rev Infect Dis 1985; 7 (suppl 4): S741-S746. 22. Lagast H, Kiastersky J, Kains JP, et at Empiric antimicrobial therapy with aztreonam or ceftazidime in gram-negative septicemia. Am J Med 1986; 80 (suppl 5C): 7984.
March 23, 1990
The American Journal of Medicine
Volume 88 (suppl 3C)
3G23S