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Successful use of aztreonam in a patient who failed oral penicillin desensitization
ccessful use of aztreonam in iled oral penicillin desensitization ichard C. Loria, MD, Nancy Finnerty, St. Louis. MO.
alien
MD, and H. James Wedner,
A 69-year-old woman with Pseudomonasaeruginosasepsis developed wheezing during tke course of an oral penicillin desensitization. Despite treatment of the bronchospasm and readministration of the same dose of pkenoxymetkyl penicillin, wheezing recurred requiring stopping the desensitization procedure. Aztreonam, a monobactam antibiotic with activity against aerobic gram-negative bacilli, was adminsitered along with an aminoglycoside. The patient tolerated a full course of aztreonam with no adverse reactions. This case report supports previous in vitro and in vivo studies, suggesting that aztreonam does not crossreact with penicillin-specijc antibodies and that it may be well tolerated in P-lactam-allergic individuals (J ALLEUCYCLINIMMUNOL 1989;83:735-7.)
In the appropriate medical setting, penicillin desensitization generally provides an effective and safe means of introducing effective antimicrobial therapy in the P-lactam-allergic individual. Although most adverse reactions that occur during this procedure can be readily reversed with appropriate medications, the procedure is generally reserved for those patients in whom the use of a p-lactam is absolutely necessary. More specifically, Sullivan et al.’ proposed five criteria for desensitization to penicillin. Among these criteria is that no alternative non-P-lactam antibiotic be available. The monobactam class of antibiotics, in particular aztreonam, have a spectrum of activity limited to the aerobic gram-negative bacilli.2, 3 In such infections, aztreonam appears to be synergistic when it is administered in conjunction with an aminoglycoside.4. 5 In addition, several in vitro and in vivo studies have indicated that aztreonam does not cross-react with plactam-specific antibodies and may be well tolerated by &lactam-allergic individuals.6-” The patient we describe experienced bronchospasm during a penicillin desensitization but tolerated a full course of aztreonam without any adverse reactions. This case highlights the potential clinical use of az-
From the WashingtonUniversity School of Medicine, Department of Medicine, Division of Allergy and Immunology, St. Louis, MO. Received for publication June 21, 1988. Accepted for publication Sept. 13, 1988. Reprint requests:H. JamesWedner, MD, WashingtonU. School of Medicine, Departmentof Medicine, 600 S. Euclid, St. Louis, MO 43110.
treonam in the highly penicillin-allergic patient and suggests that the use of aztreonam may be considered before submitting a patient to a penicillin desensitization . CASE REPORT A 69-year-old white woman was admitted to the Burn
Unit at BarnesHospital with full and partial thickness burns over 31% of her body. Multiple debridementsand skin grafts were performed. One month into the hospitalization,
she
developedsepticemia. Becauseof a poorly defined history of penicillin allergy, she was empirically treated with gen-
tamicin and vancomycin. Multiple blood cultures subsequently grew out Pseudomonas aeruginosa sensitive to ticarcillin and gentamicin. Consultation from the Allergy Service was requested. Although perioperative use of a cephalosporin(Ancef; SmithKline Corp., Philadelphia, Pa.) 10 days earlier was uneventful, we believed that this did not preclude the possibility of an allergic reaction to ticarciliin, a semisynthetic penicillin derivative. In addition, the patient was receiving hydroxyzine (Vistaril; Pfizer Laboratories, New York, N.Y.), a known I-I, blocking agent, tluis preventing us from performing penicillin skin testing. An oral penicillin desensitization procedure, according to the method as described by Sullivan et al. ,’ was then attempted. The patient tolerated doses of 0.0625, 0.125, and 0.25 mg (100, 200, and 400 units) of phenoxymethyl penicillin. Shortly after receiving 0.5 mg (SO0 units) of phenoxymethyl penicillin, inspiratory and expiratory wheezing was noted. The patient was treated with nebulized metaproterenol (Alupent; Boehringer Ingelheim, Kidgetield, Conn.) and intravenous diphenhydramine (Benadryl; Parke-Davis, Morris Plains, N.J.), 50 mg. Wheezing cleared with this treatment. In an attempt to complete the procedure safely, another 0.5 mg of phenoxymethyl penicillin was administered. Within 5 minutes, the patient again experienced dif-
736
Loria et ai.
AZTREONAM FIG. 1. General aztreonam.
J. ALLERGY
CAHzl
structure
of pencillins,
ceftazidime,
and
fuse wheezing. The penicillin desensitization was aborted at this time, and the patient was treated for the bronchospasm. On reviewing any viable alternative antipseudomonal agents,the monobactam,aztreonamwas believed to be the most appropriateagent. Becauseof uncertainty about cross-reactivity between the p-lactams and the monobactams in highly penicillin-allergic patients, a rapid provocative dose challenge with aztreonam was attempted. The patient tolerated several intravenous doses of aztreonam, ranging from 40 mg to 800 mg with no adversereactions. Furthermore, she tolerated a complete 12-day course of aztreonamand gentamicin with no adversereaction, despite having clearly experienced an immediate-type hypersensitivity reaction to phenoxymethyl penicillin. She improved clinically and was subsequently discharged from the hospital. Further in vivo or in vitro studies of p-lactam sensitivity were refused by the patient.
The monobactams are bacterially produced monocyclic p-lactam antibiotics.” These compounds interfere with bacterial cell wall biosynthesis because of their interaction with various penicillin-binding proteins of bacteria.‘* In addition to its ability to interfere with bacterial cell-wall synthesis, aztreonam is highly resistant to hydrolytic inactivation caused by plasmid-mediated or chromosomally mediated plactamases. “. I3 Although clinical trials of aztreonam have dem.onstrated it to be effective in infections of urine, lung, skin, blood, bones, joints, pelvis, and abdomen, it has a very narrow antimicrobial spectrum 14,I5 limited to aerobic gram-negative organ-
CLiN.
;MiVUNOL. APRIL 1989
isms.‘, 3, I’, I3 Several studies3-‘, I4 have confirmed the use of aztreonam in infections with P. aeruginosa. Although aztreonam is active when it is used alone against P. aeruginosa, there is clear evidence of synergism when it is used in conjunction with an aminoglycoside. It is relatively inactive against grampositive and anaerobic bacteria. “. I3 Unlike the bicyclic nuclear structure. characteristic of the penicillins and cephalosporins, aztreonam possesses a monocyclic p-lactam nucleus’ (Fig. 1) and a side chain identical to that of the third generation cephalosporin, ceftazidime.8 The usefulness of aztreonam in the P-lactam-allergic individual is based on in vitro and in vivo data that suggest that aztreonam does not cross-react with antibodies directed toward penicillins or cephalosporins. In vitro assays demonstrated that aztreonam displays minimal, if any, immunologic cross-reactivity with other plactams.6, 7 In addition, free aztreonam was as effective as various conjugated analogs of aztreonam in reacting with antibodies raised against conjugated aztreonam, suggesting that antibodies to aztreonam are side chain rather than nucleus specifL6, ’ Additional confirmation that the immune response was directed against the side chain of aztreonam was provided by Adkinson et al.” in experiments demonstrative complete inhibition of a rabbit antiaz~eonyl-bovine thyroglobin antibody binding by ceftazidime. Saxon et a1.7,’ evaluated in vivo cross-reactivity between IgE antibodies to penicillin and aztreonam. Of 41 patients with documented immediate-type skin tests to various penicillin determinants, none demonstrated reproducible reactivity to aztreQnam or aztreonam-protein conjugates. Aztreonam appears to be a poor immunogen in humanP Although IgG antibodies that cross-react with aztreonam have been described in healthy subjects, after 1 week of treatment with full doses of aztreonam, only one subject developed an increase in aztreonam cross-reactive IgG titer. This IgG was side chain specific and did not cross-react with any of the penicillin or cephalosporin conjugates tested. No aztreonam-specific IgE antibody was detected in any of these subjects. The case we have described represents a therapeutic success with aztreonam in a highly penicillin-al~~r~~~ patient with a serious gram-negative infection who could not be desensitized by the oral route. Many more patients will need to be treated successfully with aztreonam before a complete assessment of the use of this drug in P-lactam-sensitive patients can be made. However, the previous studies demonstrating lack of cross-reactivity and the present case report suggest that aztreonam may be the drug of choice in highly
VOLUME NUMBER
Aztreonam use in peniciliin
83 4
P-lactam-allergic individuals with aerobic gramnegative infections. Particular caution should be taken in the patient with a history of an allergic reaction to ceftazidime, as this cephalosporin contains the same side chain as does aztreonam.’ REFERENCES 1. Sullivan TJ, Yecies LD, Shatz GS, Parker CW, Wedner HJ. Desensitization of patients allergic to penicillin using orally administered p-lactam antibiotics. AM J OBSTET GYNECOL 1982;69:215. 2. Principi N. New trends in paediatric antibiotic therapy. Drugs Exp Clin Res 1987;13:589. 3. Sykes RB, Bonner DP. Discovery and development of the monobactams. Rev Infect Dis 1985;7:S579. 4. Lemer SA, Dudek EJ, Boisvert WE, Bemdt KD. Effect of highly potent antipseudomonal beta-lactam agents alone and in combination with aminoglycosides against Pseudomonas aeruginosa. Rev Infect Dis 1984;6:S678. 5. Greenberg RN, Bollinger M, Compton J. Synergistic activity of amikacin with aztreonam against Pseudomonas aeruginosa and other gram-negative organisms. Clin Ther 1986;8;354. 6. Adkinson NF Jr, Swabb EA, Sugerman AA. Immunology of the monobactam aztreonam. Antimicrob Agents Chemother I984;25:93.
al~~~~~
737
7. Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic cross-reactivity of aztreonam with other betalactam antibiotics. Am J Med 1985;78:i9. 8. Saxon A, Hassner A, Swabb EA, Wheeier EC,Adkinson NF Jr. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J Infect Dis 1984;149:16. 9. Adkinson NF Jr, Saxon A, Spence MR, Swabb EA. Crossallergenicity and immunogenicity of aztreonam. Rev infect Dis 1985;7:S613. 10. Adkinson NF Jr, Swabb EA, Sugerman AA. Immunology of the monobactam aztreonam. Antimicrob Agents Chemother 1984;25:933. 11. Saxon A, Beall GN, Rolu AS, Adelman DC, Immediate bypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204. 12. Sykes RB, Bonner DP. Aztreonam: the first monobactam. Am J Med 1985;78:2. 13. Childs SJ, Bodey GP. Aztreonam. Pharmacotherapy 1986; 6:138. 14. Hopefl AW. Aztreonam-an overview. Drug Intel! Clin PhaTm 1985;19:171. 15. Mohanty KC, Deighton R, Strachan RG. Single intramuscular injection of aztreonam in the treatment of uncomplicated gonorrhea in women. Curr Med Res Opin 1987;10:634.
AVAILABLE NOW! The PROCEEDINGS OF THE INTERNATIONAL CONGRESS OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY can be purchased from the Publisher. This collection of “state-of-the-art” presentations from the XII Congress held October 2025, 1985, in Washington, D.C., brings together the current advances in basic and applied aspects of allergy and allergic diseases. It includes 528 pages covering such topics as IgE, roles of the different cell types and their products, clinical problems, asthma, rhinitis, and reactions to foods and drugs and occupational agents, collected and reviewed by Editor Charles E. Reed, MD (USA) and Associate Editors Joseph Bellanti, MD (USA), Robert J. Davies, MD (UK), Sidney Friedlaender, MD (USA), Albert Oehling, MD (Spain), and Raymond G. Slavin, MD (USA). To purchase, call or write: The C.V. Mosby Company, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or telephone FREE l-800-32.5-4177, Journal Fulfillment, ext. 531 (in Missouri call collect at 314-872-8370, Journal Fulfillment, ext. 531). Prepayment required. Make checks payable to The C.V. Mosby Company. (All payments must be in US funds drawn on a US bank.) Price: $36.50 in the US, $40.50 in Canada, and $41.50 international (surface shipping charges included).
alien
MD, and H. James Wedner,
A 69-year-old woman with Pseudomonasaeruginosasepsis developed wheezing during tke course of an oral penicillin desensitization. Despite treatment of the bronchospasm and readministration of the same dose of pkenoxymetkyl penicillin, wheezing recurred requiring stopping the desensitization procedure. Aztreonam, a monobactam antibiotic with activity against aerobic gram-negative bacilli, was adminsitered along with an aminoglycoside. The patient tolerated a full course of aztreonam with no adverse reactions. This case report supports previous in vitro and in vivo studies, suggesting that aztreonam does not crossreact with penicillin-specijc antibodies and that it may be well tolerated in P-lactam-allergic individuals (J ALLEUCYCLINIMMUNOL 1989;83:735-7.)
In the appropriate medical setting, penicillin desensitization generally provides an effective and safe means of introducing effective antimicrobial therapy in the P-lactam-allergic individual. Although most adverse reactions that occur during this procedure can be readily reversed with appropriate medications, the procedure is generally reserved for those patients in whom the use of a p-lactam is absolutely necessary. More specifically, Sullivan et al.’ proposed five criteria for desensitization to penicillin. Among these criteria is that no alternative non-P-lactam antibiotic be available. The monobactam class of antibiotics, in particular aztreonam, have a spectrum of activity limited to the aerobic gram-negative bacilli.2, 3 In such infections, aztreonam appears to be synergistic when it is administered in conjunction with an aminoglycoside.4. 5 In addition, several in vitro and in vivo studies have indicated that aztreonam does not cross-react with plactam-specific antibodies and may be well tolerated by &lactam-allergic individuals.6-” The patient we describe experienced bronchospasm during a penicillin desensitization but tolerated a full course of aztreonam without any adverse reactions. This case highlights the potential clinical use of az-
From the WashingtonUniversity School of Medicine, Department of Medicine, Division of Allergy and Immunology, St. Louis, MO. Received for publication June 21, 1988. Accepted for publication Sept. 13, 1988. Reprint requests:H. JamesWedner, MD, WashingtonU. School of Medicine, Departmentof Medicine, 600 S. Euclid, St. Louis, MO 43110.
treonam in the highly penicillin-allergic patient and suggests that the use of aztreonam may be considered before submitting a patient to a penicillin desensitization . CASE REPORT A 69-year-old white woman was admitted to the Burn
Unit at BarnesHospital with full and partial thickness burns over 31% of her body. Multiple debridementsand skin grafts were performed. One month into the hospitalization,
she
developedsepticemia. Becauseof a poorly defined history of penicillin allergy, she was empirically treated with gen-
tamicin and vancomycin. Multiple blood cultures subsequently grew out Pseudomonas aeruginosa sensitive to ticarcillin and gentamicin. Consultation from the Allergy Service was requested. Although perioperative use of a cephalosporin(Ancef; SmithKline Corp., Philadelphia, Pa.) 10 days earlier was uneventful, we believed that this did not preclude the possibility of an allergic reaction to ticarciliin, a semisynthetic penicillin derivative. In addition, the patient was receiving hydroxyzine (Vistaril; Pfizer Laboratories, New York, N.Y.), a known I-I, blocking agent, tluis preventing us from performing penicillin skin testing. An oral penicillin desensitization procedure, according to the method as described by Sullivan et al. ,’ was then attempted. The patient tolerated doses of 0.0625, 0.125, and 0.25 mg (100, 200, and 400 units) of phenoxymethyl penicillin. Shortly after receiving 0.5 mg (SO0 units) of phenoxymethyl penicillin, inspiratory and expiratory wheezing was noted. The patient was treated with nebulized metaproterenol (Alupent; Boehringer Ingelheim, Kidgetield, Conn.) and intravenous diphenhydramine (Benadryl; Parke-Davis, Morris Plains, N.J.), 50 mg. Wheezing cleared with this treatment. In an attempt to complete the procedure safely, another 0.5 mg of phenoxymethyl penicillin was administered. Within 5 minutes, the patient again experienced dif-
736
Loria et ai.
AZTREONAM FIG. 1. General aztreonam.
J. ALLERGY
CAHzl
structure
of pencillins,
ceftazidime,
and
fuse wheezing. The penicillin desensitization was aborted at this time, and the patient was treated for the bronchospasm. On reviewing any viable alternative antipseudomonal agents,the monobactam,aztreonamwas believed to be the most appropriateagent. Becauseof uncertainty about cross-reactivity between the p-lactams and the monobactams in highly penicillin-allergic patients, a rapid provocative dose challenge with aztreonam was attempted. The patient tolerated several intravenous doses of aztreonam, ranging from 40 mg to 800 mg with no adversereactions. Furthermore, she tolerated a complete 12-day course of aztreonamand gentamicin with no adversereaction, despite having clearly experienced an immediate-type hypersensitivity reaction to phenoxymethyl penicillin. She improved clinically and was subsequently discharged from the hospital. Further in vivo or in vitro studies of p-lactam sensitivity were refused by the patient.
The monobactams are bacterially produced monocyclic p-lactam antibiotics.” These compounds interfere with bacterial cell wall biosynthesis because of their interaction with various penicillin-binding proteins of bacteria.‘* In addition to its ability to interfere with bacterial cell-wall synthesis, aztreonam is highly resistant to hydrolytic inactivation caused by plasmid-mediated or chromosomally mediated plactamases. “. I3 Although clinical trials of aztreonam have dem.onstrated it to be effective in infections of urine, lung, skin, blood, bones, joints, pelvis, and abdomen, it has a very narrow antimicrobial spectrum 14,I5 limited to aerobic gram-negative organ-
CLiN.
;MiVUNOL. APRIL 1989
isms.‘, 3, I’, I3 Several studies3-‘, I4 have confirmed the use of aztreonam in infections with P. aeruginosa. Although aztreonam is active when it is used alone against P. aeruginosa, there is clear evidence of synergism when it is used in conjunction with an aminoglycoside. It is relatively inactive against grampositive and anaerobic bacteria. “. I3 Unlike the bicyclic nuclear structure. characteristic of the penicillins and cephalosporins, aztreonam possesses a monocyclic p-lactam nucleus’ (Fig. 1) and a side chain identical to that of the third generation cephalosporin, ceftazidime.8 The usefulness of aztreonam in the P-lactam-allergic individual is based on in vitro and in vivo data that suggest that aztreonam does not cross-react with antibodies directed toward penicillins or cephalosporins. In vitro assays demonstrated that aztreonam displays minimal, if any, immunologic cross-reactivity with other plactams.6, 7 In addition, free aztreonam was as effective as various conjugated analogs of aztreonam in reacting with antibodies raised against conjugated aztreonam, suggesting that antibodies to aztreonam are side chain rather than nucleus specifL6, ’ Additional confirmation that the immune response was directed against the side chain of aztreonam was provided by Adkinson et al.” in experiments demonstrative complete inhibition of a rabbit antiaz~eonyl-bovine thyroglobin antibody binding by ceftazidime. Saxon et a1.7,’ evaluated in vivo cross-reactivity between IgE antibodies to penicillin and aztreonam. Of 41 patients with documented immediate-type skin tests to various penicillin determinants, none demonstrated reproducible reactivity to aztreQnam or aztreonam-protein conjugates. Aztreonam appears to be a poor immunogen in humanP Although IgG antibodies that cross-react with aztreonam have been described in healthy subjects, after 1 week of treatment with full doses of aztreonam, only one subject developed an increase in aztreonam cross-reactive IgG titer. This IgG was side chain specific and did not cross-react with any of the penicillin or cephalosporin conjugates tested. No aztreonam-specific IgE antibody was detected in any of these subjects. The case we have described represents a therapeutic success with aztreonam in a highly penicillin-al~~r~~~ patient with a serious gram-negative infection who could not be desensitized by the oral route. Many more patients will need to be treated successfully with aztreonam before a complete assessment of the use of this drug in P-lactam-sensitive patients can be made. However, the previous studies demonstrating lack of cross-reactivity and the present case report suggest that aztreonam may be the drug of choice in highly
VOLUME NUMBER
Aztreonam use in peniciliin
83 4
P-lactam-allergic individuals with aerobic gramnegative infections. Particular caution should be taken in the patient with a history of an allergic reaction to ceftazidime, as this cephalosporin contains the same side chain as does aztreonam.’ REFERENCES 1. Sullivan TJ, Yecies LD, Shatz GS, Parker CW, Wedner HJ. Desensitization of patients allergic to penicillin using orally administered p-lactam antibiotics. AM J OBSTET GYNECOL 1982;69:215. 2. Principi N. New trends in paediatric antibiotic therapy. Drugs Exp Clin Res 1987;13:589. 3. Sykes RB, Bonner DP. Discovery and development of the monobactams. Rev Infect Dis 1985;7:S579. 4. Lemer SA, Dudek EJ, Boisvert WE, Bemdt KD. Effect of highly potent antipseudomonal beta-lactam agents alone and in combination with aminoglycosides against Pseudomonas aeruginosa. Rev Infect Dis 1984;6:S678. 5. Greenberg RN, Bollinger M, Compton J. Synergistic activity of amikacin with aztreonam against Pseudomonas aeruginosa and other gram-negative organisms. Clin Ther 1986;8;354. 6. Adkinson NF Jr, Swabb EA, Sugerman AA. Immunology of the monobactam aztreonam. Antimicrob Agents Chemother I984;25:93.
al~~~~~
737
7. Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic cross-reactivity of aztreonam with other betalactam antibiotics. Am J Med 1985;78:i9. 8. Saxon A, Hassner A, Swabb EA, Wheeier EC,Adkinson NF Jr. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J Infect Dis 1984;149:16. 9. Adkinson NF Jr, Saxon A, Spence MR, Swabb EA. Crossallergenicity and immunogenicity of aztreonam. Rev infect Dis 1985;7:S613. 10. Adkinson NF Jr, Swabb EA, Sugerman AA. Immunology of the monobactam aztreonam. Antimicrob Agents Chemother 1984;25:933. 11. Saxon A, Beall GN, Rolu AS, Adelman DC, Immediate bypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204. 12. Sykes RB, Bonner DP. Aztreonam: the first monobactam. Am J Med 1985;78:2. 13. Childs SJ, Bodey GP. Aztreonam. Pharmacotherapy 1986; 6:138. 14. Hopefl AW. Aztreonam-an overview. Drug Intel! Clin PhaTm 1985;19:171. 15. Mohanty KC, Deighton R, Strachan RG. Single intramuscular injection of aztreonam in the treatment of uncomplicated gonorrhea in women. Curr Med Res Opin 1987;10:634.
AVAILABLE NOW! The PROCEEDINGS OF THE INTERNATIONAL CONGRESS OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY can be purchased from the Publisher. This collection of “state-of-the-art” presentations from the XII Congress held October 2025, 1985, in Washington, D.C., brings together the current advances in basic and applied aspects of allergy and allergic diseases. It includes 528 pages covering such topics as IgE, roles of the different cell types and their products, clinical problems, asthma, rhinitis, and reactions to foods and drugs and occupational agents, collected and reviewed by Editor Charles E. Reed, MD (USA) and Associate Editors Joseph Bellanti, MD (USA), Robert J. Davies, MD (UK), Sidney Friedlaender, MD (USA), Albert Oehling, MD (Spain), and Raymond G. Slavin, MD (USA). To purchase, call or write: The C.V. Mosby Company, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or telephone FREE l-800-32.5-4177, Journal Fulfillment, ext. 531 (in Missouri call collect at 314-872-8370, Journal Fulfillment, ext. 531). Prepayment required. Make checks payable to The C.V. Mosby Company. (All payments must be in US funds drawn on a US bank.) Price: $36.50 in the US, $40.50 in Canada, and $41.50 international (surface shipping charges included).