SYMPOSIUM ON ANTIMICROBIAL AGENTS-Part III

The Monobactams

NELSON S. BREWER, M.D.,* WALTER C. HELLINGER, M.D.,* Division of Infectious Diseasesand Internal Medicine

The monobactam antibiotics are synthetic compounds, although monocyclic 13-lactam compounds havebeen found in nature in various soil bacteria. Although additional orally and parenterally adminis­tered monobactams are under investigation, the first marketed monobactam was aztreonam. Thisagent has an antimicrobial spectrum similar to that of gentamicin and tobramycin, aminoglycosideantibiotics. Aztreonam, however, is not nephrotoxic, is weakly immunogenic, and has not beenassociated with disorders of coagulation. Aztreonam may be administered intramuscularly or intrave­nously; absorption after oral administration is poor. The primary route of elimination is the urine.The serum half-life of the drug in patients with normal renal function is 1.5 to 2.1 hours; therecommended dosing interval in patients with normal renal function is every 8 hours. Dosageadjustment is necessary in patients with renal impairment. The strictly gram-negative aerobicspectrum of aztreonam limits its use as a single empiric agent. Approved indications for its use includeinfections of the urinary tract or lower respiratory tract, intra-abdominal and gynecologic infections,septicemia, and cutaneous infections caused by susceptible organisms. Concurrent initial therapy withother antimicrobial agents is recommended before the causative organism (or organisms) has beendetermined in patients who are seriously ill and at risk for gram-positive or anaerobic infections.

Monocyclic l3-lactam compounds with weak antibacterialactivity have been found in various soil bacteria such asAcinetobacter, Chromobacterium, Flexibacter, and Glu­conobacter. I Aztreonarn, the first marketed monobactam, isa synthetic compound of major clinical importance becauseof its toxicity profile. Similar to certain aminoglycosides(gentamicin and tobramycin), it has a gram-negative, aerobicantibacterial spectrum. Aztreonam, however, is not nephro­toxic, is weakly immunogenic, andhas not been associatedwith abnormalities in coagulation. Although it is currently

*Mayo Clinic Jacksonville, Jacksonville, Florida.

Individual reprints of this article are not available. The entireSymposium on Antimicrobial Agents will be available for purchaseas a bound booklet from the Proceedings Circulation Office at alater date.

expensive, it may be an important antibacterial agent inspecific situations. Carumonam, another parenterally ad­ministered monobactam, is currently under investigation.i"Tigemonam is an orally administered investigational mono­bactam. This agent seems to have impressive activityagainst most Enterobacteriaceae but considerably less activ­ity against nonfermenter pathogens."

STRUCTURE AND ACTIVITYIn contrast to the bicyclic l3-lactams such as the cepha­losporins and penicillins, aztreonam has a sulfonic acidgroup on the nitrogen at the N-l position; this sulfonic acidgroup activates the l3-lactamring and thus assists acetylationof transpeptidases that manufacture bacterial cell walls."When aztreonam binds these transpeptidases or penicillin­binding proteins, it, like other l3-lactam antibiotics, inhibits

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the synthesis of bacterial cell walls, and cell lysis or theformation of elongated, filamentous cells ensues. 10 The druglacks affinity for the penicillin-binding proteins of gram­positive bacteria and also anaerobic organisms; thus, theantibacterial spectrum is limited to aerobic gram-negativebacilli. The 2-aminothiazolyl side chain of aztreonam con­tributes to the activity against gram-negative bacteria, and animinopropyl carbonyl group on the side chain enhances theactivity and provides ~-lactamase stability against Pseudo­monas aeruginosa,'

STABILITY OF ~-LACTAMASES

Aztreonam is not hydrolyzed by the most common plasmid­mediated TEM-l, TEM-2, and SHV-l and the chromo­somally mediatedHlactamases. Furthermore, it is not hy­drolyzed by staphylococcal f-lactamase and by most ~-lac­

tamases produced by Bacteroides species. 12-14 Aztreonam isdestroyed by cefotaxime- or ceftazidime-hydrolyzing, plas­mid-mediated 13-lactamases, such as TEM-3, TEM-5, TEM­7, and SHV-2. The drug does not induce production of~­

lactamases in Pseudomonas, Citrobacter, Enterobacter, orSerratia species!" and generally is a weak inducer of chro­mosomally mediated l3-lactamases. ' 5

ANTIBACTERIAL SPECTRUMIn general, effective antimicrobial activity can be demon­strated against most Enterobacteriaceae. Most Entero­bacteriaceae are inhibited at concentrations of less than 1 llg/ml; 12-14 however, C. freundii, E. aerogenes, and E. cloacaeare sometimes resistant to aztreonam, as they are to cefotax­ime and ceftazidirne.P'? Enterobacteriaceae are killed atconcentrations of 2 to 4 times the minimal inhibitory concen­tration." Minimal inhibitory concentrations to P. aerugi­nosa range from 4 to 50 ug/ml; aztreonam reportedly kills P.aeruginosa at 4 to 16 times the minimal inhibitory concen­tration.P All Neisseria meningitidis and N. gonorrhoeaeorganisms are inhibited at 0.03 to 0.06 ug/ml, includingpenicillinase-producing N. gonorrhoeae/" ~-Lactamaseandnon-l3-lactamase strains of Haemophilus influenzae are in­hibited by 0.03 to 0.25 ug/ml of aztreonam.'?

In a study of clinical isolates at the Mayo Clinic, with useof 8 ug/ml as the lowest tested concentration, susceptibilitydata were collected from January through December 1989(Table 1). These data confirm limited activity against strainsof Acinetobacter, Alcaligenes, Flavobacterium, P.fluorescens, and Xanthomonas maltophilia. Synergy may bedemonstrated with aminoglycosides in vitro in 30 to 60% ofgram-negative organisms tested; however, the drug has notbeen shown to produce synergy with other ~-lactam

agents.":" Although aztreonam is bactericidal at concentra­tions near or at 2 to 4 times the minimal inhibitory concentra­tion, some strains of P. aeruginosa and Enterobacter species

MONOBACTAMS 1153

Table I.-Mayo Clinic Susceptibility Data: Percentage ofStrains of Various Organisms Inhibited by Aztreonam*

Minimal inhibitoryNo. of concentration

Organism strains 8llg/ml 161lg/ml

Achromobacter sp 4 Not inhibited at anylevel tested

Acinetobacter calcoaceticusvar anitratus III 9 27

A. calcoaceticus var lwoffi 78 67 78Aeromonas sp 13 100Alcaligenes sp 20 5 20Citrobacter amalonaticus 12 92C. diversus 80 100Ci freundii 248 85 90Edwardsiella tarda I 100Enterobacter aerogenes 340 84 89E. agglomerans 35 97 100E. cloacae 522 80 83Escherichia coli 4,016 99 100Flavobacterium sp 15 13Haemophilus aphrophilus 2 100Hafnia alvei 12 92Kingella denitrificans 26 100Klebsiella sp 6 100K. oxytoca 322 96 97K. ozaenae 3 100K. pneumoniae 1,047 99 99Moraxella sp 30 97Morganella morganii 164 96 99Pasteurella multocida 18 100Pleisomonas shigelloides 1 100Proteus mirabilis 534 99 99P. vulgaris 47 100Providencia rettgeri 16 100P. stuartii 14 100Pseudomonas aeruginosa 1,323 78 88P. cepacia 17 71 82P. fluorescens or putida 45 9 22P. stutzeri 7 71 100Salmonella sp non-typhi 39 100Serratia liquefaciens 13 100S. marcescens 246 97 98Shigella sonnei 2 100Xanthomonas maltophilia 242 9 10Yersinia enterocolitica 10 100

*Data collected from January through December 1989.

may be tolerant.v-" Antagonism between aztreonam andother 13-lactam drugs has also been demonstrated. For ex­ample, cefoxitin antagonizes the activity of aztreonamagainst Enterobacter species; this antagonism probably re­lates to the cefoxitin-induced production of 13-lactamase.2 I.22

PHARMACOLOGIC AND DOSING FEATURESAztreonam may be administered intramuscularly or intrave­nously; absorption after oral administration is poor. After

1154 MONOBACTAMS

intravenous infusion of O.5-g, l-g, and 2-g doses in healthysubjects, mean peak serum concentrations of 65.5 ug/ml,I64llg/ml, and 255 ug/ml, respectively, have been recorded;8-hour concentrations average 1 to 2 ug/ml and 2.5 to 4 Ilg/ml after l-g and 2-g doses, respectively." Urinary excretionof unchanged drug is the primary route of elimination. Inadults with normal renal function, urinary concentrationsreach 250 to 330 ug/ml and 710 to 720 ug/ml 4 to 6 hoursafter intravenous administration of single 0.5-g and I-gdoses, respectively. The serum half-life in patients withnormal renal function is 1.5 to 2.1 hours." Protein bindinghas been measured at 56 to 71%.26 In biliary T-tube studies,Martinez and associates'? found less than 1% of the totaldose in the bile.

In patients with renal impairment, the dose of aztreonammust be adjusted. The serum half-life of aztreonam inanephric patients is 6 to 8 hours." The serum half-lifeduring hemodialysis may decrease to 2.7 hours; approxi­mately 38% of an administered dose may be cleared duringan average hemodialysis. Thus, administration of a smallsupplementary dose may be necessary after dialysis. Thedrug is cleared much more slowly by peritoneal dialysis."

The recommended dosing regimen is 1 g every 8 hours inpatients with normal renal function. In seriously ill patients,especially those with P. aeruginosa infection, a dosage of 2 gevery 6 to 8 hours has been suggested. Urinary infectionscaused by gram-negative bacteria may be treated by intra­muscular administration of 500 mg once or twice daily.Organisms with a minimal inhibitory concentration of 8 Ilg/ml or less are considered susceptible, whereas those with aminimal inhibitory concentration of 32 ug/ml or more areresistant.

In patients with uninflamed meninges, a 2-g dose ofaztreonam produced concentrations of 0.5 ug/ml and 1 Ilg/ml in the cerebrospinal fluid at I and 4 hours, respectively.Mean levels increased to 2 ug/ml and 3.2 ug/ml, respec­tively, when the meninges were inflamed.P-"

The manufacturer had provided data on the concentrationof aztreonam at various extravascular sites (Table 2). Thesedata, however, have not included accumulated concentra­tions of the drug in the various solid organs or secretionsafter a multiple-dose regimen.

INDICATIONS AND CLINICAL USEThe strictly gram-negative aerobic spectrum of aztreonamlimits its use as a single empiric agent, similar to the ami­noglycosides. Many studies have shown efficacy of aztreo­nam when used as a single agent in infections ofthe urinarytract caused by Enterobacteriaceae, P. aeruginosa, and Prov­idencia;33.36 some of these organisms were resistant to theaminopenicillins, first- and second-generation cepha­losporins, aminoglycosides, or some combination of these

Mayo CliD Proc, November 1991, Vol 66

drugs. Dosages that have ranged from 0.5 g every 12 hoursto I g every 8 hours have yielded comparable effectiveness.

Aztreonam in combination with other agents has provedefficacious in numerous pelvic and peritoneal infections. Inone study, the combination of clindamycin and aztreonamwas effective in acute pelvic inflammatory disease." Otherreports have also described therapeutic effectiveness withthis combination of drugs in pelvic infections in women."Aztreonam in combination with other agents has been effec­tive in spontaneous bacterial peritonitis in patients with cir­rhosis." Peritonitis associated with continuous ambulatoryperitoneal dialysis has been effectively treated with the com­bination of vancomycin and aztreonam." The aztreonam­clindamycin combination has efficacy similar to that ofclindamycin-aminoglycoside regimens in the treatment ofintra-abdominal infections.v-F

Aztreonam has been effective in the treatment of gram­negative osteomyelitis.v-" Successful therapy for osteo­myelitis, however, depends on surgical and other variables,and long-term follow-up is necessary for evaluation. Gram­negative septicemia from various sources has been success­fully treated in patients with and without neutropenia.rv'v"Aztreonam in combination with vancomycin was shown tobe as effective as the combination of vancomycin, aztreo­nam, and amikacin or moxalactam and ticarcillin in febrilepatients with neutropenia."

The combination of aztreonam and clindamycin has beenshown to be as effective as the combination of tobramycinand clindamycin in gram-negative pneumonia." With use ofaztreonam, cure rates of 70 to 100% have been reported ingram-negative pneumonia.P'" Aztreonam has been shownto be equivalent or superior to tobramycin in therapy fornosocomial pneumonia.v-"

The Food and Drug Administration has approved aztreo­nam for treatment of infections of the urinary tract, lowerrespiratory tract, and skin and skin structures, intra-abdomi­nal and gynecologic infections, and septicemia caused bysusceptible gram-negative microorganisms. Concurrent ini­tial therapy with other antimicrobial agents is recommendedbefore the causative organism (or organisms) has been deter­mined in patients who are seriously ill and at risk for gram­positive or anaerobic infections. The only listed contraindi­cation is a known allergy to the drug.

SAFETY AND REPORTED TOXICITYThe overall adverse rate of reactions to aztreonam among2,700 patients was 6.8%.51 Local reactions at sites of injec­tion were most common, followed by rash, diarrhea, nausea,and vomiting. No single reaction occurred in more than2.5% of patients in clinical trials. Nephrotoxicity was re­ported only rarely. Clinical bleeding did not occur, andplatelet abnormalities were infrequently noted. Pseudo-

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Table 2.-Extravascular Concentrations of Aztreonam AfterParenteral Administration* of a Single Dose

MeanDose Hours after No. of concentration

Fluid or tissue (g) injection patients (ug/rnl or Ilg/g)

FluidsBile 1 2 10 39Blister fluid I 1 6 20Bronchial secretion 2 4 7 5Cerebrospinal fluid

(inflamed meninges) 2 0.9-4.3 16 3Pericardial fluid 2 1 6 33Pleural fluid 2 1.1-3.0 3 51Synovial fluid 2 0.8-1.9 11 83

TissuesAtrial appendage 2 0.9-1.6 12 22Endometrium 2 0.7-1.9 4 9Fallopian tube 2 0.7-1.9 8 12Fat 2 1.3-2.0 10 5Femur 2 1.0-2.1 15 16Gallbladder 2 0.8-1.3 4 23Kidney 2 2.4-5.6 5 67Large intestine 2 0.8-1.9 9 12Liver 2 0.9-2.0 6 47Lung 2 1.2-2.1 6 22Myometrium 2 0.7-1.9 9 11Ovary 2 0.7-1.9 7 13Prostate 1 0.8-3.0 8 8Skeletal muscle 2 0.3-0.7 6 16Skin 2 0.0-1.0 8 25Sternum 2 1 6 6

*Route of administration was intravenous except for prostate measurement.From Azactam package insert. Issued June 1991.32 By permission of E. R. Squibb& Sons, Inc.

membranous enterocolitis occurred in only 3 of 2,388 pa­tients who received the drug and had appropriate follow-up.Adverse laboratory changes reported during clinical trialsincluded increased levels of aspartate aminotransferase,alanine aminotransferase, and alkaline phosphatase, butsigns or symptoms of hepatobiliary dysfunction were evi­dent in less than I%. Increases in prothrombin time andpartial thromboplastin time, eosinophilia, positive results ofCoombs' test, and some instances of increased creatinineconcentration were noted.

Aztreonam is relatively weakly immunogenic. In 1984,Saxon and colleagues'? investigated the penicillin andaztreonam cross-reactivity in 41 patients who were allergicto penicillin. The skin tests for aztreonam were negative in37 of these 41 patients and in all 40 control subjects who hadnegative skin tests for penicillin. In the four patients withequivocal results on skin tests for aztreonam, retesting pro­duced negative results. Therefore, no reproducible evidenceof cross-reactivity was detected in that study. In 1987,Saxon and associates'" described 26 patients with positive

skin tests for penicillin who safely received I-g doses ofaztreonam without a reaction, as measured by IgE antibodytiters. They further emphasized that the site of antibodyrecognition of aztreonam is different from that of the bicy­clic 13-lactams; immunologic recognition of aztreonam,when it occurs, is due to antibodies specific for the side chainof aztreonam rather than the nucleus, as shown with penicil­lin and cephalosporins.

Immediate hypersensitivity in temporal relationship toadministration of aztreonam has been reported in two pa­tients with a history of penicillin hypersensitivity.54 Otherinvestigators have reported immediate hypersensitivity reac­tions to aztreonam as well. 55 The package insert from themanufacturer of aztreonam states that the incidence of hy­persensitivity reactions, including anaphylaxis, associatedwith use of aztreonam alone is less than 1%.32

CONCLUSIONAztreonam, the first available monobactam, is an importantnew antibiotic agent. Other monobactam agents are cur-

1156 MONOBACTAMS

rently being investigated. The demonstrated efficacy andfavorable toxicity profile of aztreonam provide an alterna­tive to the aminoglycosides, especially in elderly patients.More widespread use would be promoted if the drug wereless expensive. Nevertheless, on the basis of a more globalperspective, if the acquisition cost of aztreonam was com­pared with the total costs of the aminoglycosides, includingmonitoring of renal function and serum levels as well as theadded cost of therapy for aminoglycoside-induced renalimpairment (which occurs in an estimated 7.3% of amino­glycoside-treated patients)," the net drug costs may becomparable.

REFERENCESI. Sykes RB, Bonner DP: Aztreonam: the first monobactam.

Am J Med 78 (SuppI2A):2-1O, 19852. Shimazaki C, Inaba T, Murakami S, Oku N, Itoh K, Ura Y,

Nakagawa M, Fujita N: Effect of combination therapy withcarumonam and clindamycin on severe infections in patientswith hematologic malignancies. Jpn J Antibiot 43:1402­1406,1990

3. Kakizaki H, Ishii N, Murakami S, Suzuki K, Takamizawa A,Hirano J, Mitobe K, Saito M, Hirano K, Imamura A,et al: Clinical evaluation of the combination of carumonamand fosfomycin in the treatment of complicated urinary tractinfection. Hinyokika Kiyo 36:731-735,1990

4. Jacoby GA, Carreras I: Activities of ~-Iactam antibioticsagainst Escherichia coli strains producing extended-spectrum~-Iactamases. Antimicrob Agents Chemother 34:858-862,1990

5. Whitby M, Hempenstall J, Gilpin C, Weir L, Nimmo G:Penetration of monobactam antibiotics (aztreonam, caru­monam) into human prostatic tissue. Chemotherapy 35:7-11,1989

6. Patel IH, Soni PP, Portmann R, Suter K, Banken L, Wei­dekamm E: Multiple intravenous dose pharmacokineticstudy of carumonam in healthy subjects. J Antimicrob Che­mother 23:107-111,1989

7. Shah PM, Ganger-Farshid G, Mulert R, Stille W: Bacteri­cidal activity of tigernonam, alone and in combination withgentamicin. J Chemother 1 (SuppI2):45-48, 1989

8. Schito GC, Debbia E, Bandelloni R, Paglia P, Pesce A: Anti­bacterial activity in vitro of tigemonam, a new oral monobac­tam. J Chemother 1 (Suppl 2):41-44, 1989

9. Sykes RB, Bonner DP: Discovery and development of themonobactams. Rev Infect Dis 7 (SuppI4):S579-S593, 1985

10. Gutmann L, Vincent S, Billot-Klein D, Acar JF, Mrena E,Williamson R: Involvement of penicillin-binding protein 2with other penicillin-binding proteins in lysis of Escherichiacoli by some ~-lactam antibiotics alone and in synergisticlytic effect of amdinocillin (mecillinam). Antimicrob AgentsChemother 30:906-912,1986

II. Bonner DP, Sykes RB: Structure activity relationshipsamong the monobactams. J Antimicrob Chemother 14:313­327, 1984

12. Neu HC, Labthavikul P: In vitro activity and ~-lactamase

stability of a monobactam, SQ 26,917, compared with thoseof aztreonam and other agents. Antimicrob Agents Che­mother 24:227-232, 1983

Mayo CliD Proc, November 1991, Vol 66

13. Phillips I, King A, Shannon K, Warren C: SQ 26,776: in­vitro antibacterial activity and susceptibility to ~-Iactamases.

J Antimicrob Chemother 8 (Suppl E): 103-110, 198114. Sykes RB, Bonner DP, Bush K, Georgopapadakou NH:

Azthreonam (SQ 26,776), a synthetic monobactam specifi­cally active against aerobic gram-negative bacteria. Antimi­crob Agents Chemother 21:85~92, 1982

15. Bush K, Sykes RB: Interaction of new ~-Iactams with ~­

lactamases and ~-Iactamase-producing gram-negative rods.In New /3-LactamAntibiotics; A Review From Chemistry toClinical Efficacy of the New Cephalosporins. Edited by HCNeu. Philadelphia, Francis Clark Wood Institute for theHistory of Medicine, College of Physicians of Philadelphia,1982, pp 47-64

16. Acar JF, Kitzis MD, Goldstein FW; In-vitro activity of SQ26,776 against multiple-resistant enterobacteria-prelimi­nary results. J Antimicrob Chemother 8 (Suppl E):97-101,1981

17. Barry AL, Thornsberry C, Jones RN, Gavan TL: Aztreonam:antibacterial activity, ~-Iactamase stability, and interpretivestandards and quality control guidelines for disk-diffusionsusceptibility tests. Rev Infect Dis 7 (Suppl 4):S594-S604,1985

18. Fainstein V, Weaver S, Bodey GP: Comparative in vitrostudy of SQ26,776. Antimicrob Agents Chemother 21:294­298, 1982

19. Livermore DM, Williams JD: In-vitro activity of the mono­bactam, SQ 26,776, against gram-negative bacteria and itsstability to their /3-lactamases. J Antimicrob Chemother 8(Suppl E):29-37, 1981

20. Strandberg DA, Jorgensen JH, Drutz DJ: Activity of aztreo­nam and new beta-Iactam antibiotics against penicillinase­producing Neisseria gonorrhoeae. Curr Ther Res Clin Exp34:955-959, 1983

21. Sturman HR, Welch DF, Scribner RK, Marks MI: In vitroantimicrobial activity of aztreonam alone and in combinationagainst bacterial isolates from pediatric patients. AntimicrobAgents Chemother 25:212-215,1984

22. Buesing MA, Jorgensen JH; In vitro activity of aztreonam incombination with newer ~-Iactams and amikacin againstmultiply resistant gram-negative bacilli. Antirnicrob AgentsChemother 25:283-285, 1984

23. Aronoff SC, Klinger JD: In vitro activities of aztreonam,piperacillin, and ticarcillin combined with amikacin againstarnikacin-resistant Pseudomonas aeruginosa and P. cepaciaisolates from. children with cystic fibrosis. AntimicrobAgents Chemother 25:279-280, 1984

24. Van Laethem Y, Husson M, Klastersky J: Serum bactericidalactivity of aztreonam, cefoperazone, and amikacin, alone orin combination, against Escherichia coli, Klebsiella pneumo­niae, Serratia marcescens, and Pseudomonas aeruginosa.Antimicrob Agents Chemother 26;224-227, 1984

25. Scully BE, Swabb EA, Neu HC: Pharmacology of aztreonamafter intravenous infusion. Antimicrob Agents Chemother24:18-22,1983

26. Swabb EA, Singhvi SM, Leitz MA, Frantz M, SugermanAA: Metabolism and pharmacokinetics of aztreonam inhealthy subjects. Antimicrob Agents Chemother 24;394­400,1983

27. Martinez OV, Levi JU, Devlin RG: Biliary excretion ofaztreonam in patients with biliary tract disease. AntimicrobAgents Chemother 25:358-361, 1984

Mayo Clin Proc, November 1991,Vol66

28. Mihindu JCL, ScheId WM, Bolton ND, Spyker DA, SwabbEA, Bolton WK: Pharmacokinetics of aztreonam in patientswith various degrees of renal dysfunction. AntimicrobAgents Chemother 24:252-261, 1983

29. Gerig JS, Bolton ND, Swabb EA, ScheId WM, Bolton WK:Effect of hemodialysis and peritoneal dialysis on aztreonampharmacokinetics. Kidney Int 26:308-318, 1984

30. Duma RJ, Berry AJ, Smith SM, BaggettJW, Swabb EA, PlattTB: Penetration of aztreonam into cerebrospinal fluid ofpatients with and without inflamed meninges. AntimicrobAgents Chemother 26:730-733,1984

31. Modai J, Vittecoq D, Decazes JM, Wolff M, Meulemans A:Penetration of aztreonam into cerebrospinal fluid of patientswith bacterial meningitis. Antimicrob Agents Chemother29:281-283,1986

32. Azactam package insert. Princeton, New Jersey, E. R. Squibb& Sons, Inc., issued June 1991

33. Giamarellou H, Galanakis N, Douzinas E, Petrikkos G, Mes­sidi ME, Papoulias G, Daikos GK: Evaluation of aztreonamin difficult-to-treat infections with prolonged posttreatmentfollow-up. Antimicrob Agents Chemother 26:245-249, 1984

34. Greenberg RN, Reilly PM, Luppen KL, McMillian R, Bollin­ger M, Wolk SM, Darji TB, Noorani AA: Treatment ofserious gram-negative infections with aztreonam. J InfectDis 150:623-630, 1984

35. Childs S1: Aztreonam in the treatment of urinary tract infec­tion. Am J Med 78 (SuppI2A):44-46, 1985

36. Cox CE: Aztreonam therapy for complicated urinary tractinfections caused by multidrug-resistant bacteria. Rev InfectDis 7 (SuppI4):S767-S771, 1985

37. Dodson MG, Faro S, Gentry LO: Treatment of acute pelvicinflammatory disease with aztreonarn, a new monocyclic {3­lactam antibiotic, and clindamycin. Obstet Gynecol 67:657­662, 1986

38. Pastorek JG II, Cole C, Aldridge KE, Crapanzano JC:Aztreonam plus clindamycin as therapy for pelvic infectionsin women. Am J Med 78 (SuppI2A):47-50, 1985

39. Ariza J, Gudiol F, Dolz C, Xiol J, Linares J, Bosch J, PallaresR: Evaluation of aztreonam in the treatment of spontaneousbacterial peritonitis in patients with cirrhosis. Hepatology6:906-910, 1986

40. Brown J, Altmann P, Cunningham J, Shaw E, Marsh F:Pharmacokinetics of once daily intra-peritoneal aztreonamand vancomycin in the treatment of CAPD peritonitis. JAntimicrob Chemother 25:141-147, 1990

41. Berne TV, Yellin AE, Appleman MD, Gill MA, Chenella FC,Heseltine PNR: Surgically treated gangrenous or perforatedappendicitis: a comparison of aztreonam and clindamycinversus gentamicin and clindamycin. Ann Surg 205: 133-137,1987

42. Birolini D, Moraes MF, de Souza OS: Aztreonam plusclindamycin vs. tobramycin plus clindamycin for the treat-

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ment of intraabdominal infections. Rev Infect Dis 7 (Suppl4):S724-S728, 1985

43. Simons WJ, Lee TJ: Aztreonam in the treatment of bone andjoint infections caused by gram-negative bacilli. Rev InfectDis 7 (Suppl 4):S783-S788, 1985

44. Pribyl C, Salzer R, Beskin J, Haddad RJ, Pollock B, BevilleR, Holmes B, Mogabgab Wl: Aztreonam in the treatment ofserious orthopedic infections. Am J Med 78 (Suppl 2A):51­56, 1985

45. Pierard D, Boelaert J, Van Landuyt HW, Naessens A, Huygh­ens L, Lauwers S: Aztreonam treatment of gram-negativesepticemia. Antimicrob Agents Chemother 29:359-361,1986

46. Scully BE, Henry SA: Clinical experience with aztreonam inthe treatment of gram-negative bacteremia. Rev Infect Dis 7(SuppI4):S789-S793, 1985

47. Jones PG, Rolston KVI, Fainstein V, Elting L, Walters RS,Bodey GP: Aztreonam therapy in neutropenic patients withcancer. Am J Med 81:243-248, 1986

48. Rodriguez JR, Ramirez-Ronda CH, Nevarez M: Efficacy andsafety of aztreonam-clindamycin versus tobramycin­clindamycin in the treatment of lower respiratory tract infec­tions caused by aerobic gram-negative bacilli. AntimicrobAgents Chemother 27:246-251, 1985

49. Schentag JJ, Vari AJ, Winslade NE, Swanson OJ, Smith IL,Simons GW, Vigano A: Treatment with aztreonam or tobra­mycin in critical care patients with nosocomial gram-negativepneumonia. Am J Med 78 (Suppl 2A):34-41, 1985

50. Nolen TM, Phillips HL, Hall HJ: Comparison of aztreonamand tobramycin in the treatment of lower respiratory tractinfections caused by gram-negative bacilli. Rev Infect Dis 7(Supp14):S666-S668, 1985

51. Newman TJ, Dreslinski GR, Tadros SS: Safety profile ofaztreonam in clinical trials. Rev Infect Dis 7 (SuppI4):S648­S655, 1985

52. Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF Jr:Lack of cross-reactivity between aztreonam, a monobactamantibiotic, and penicillin in penicillin-allergic subjects. JInfect Dis 149:16-22,1984

53. Saxon A, Beall GN, Rohr AS, Adelman DC: Immediatehypersensitivity reactions to beta-Iactam antibiotics. AnnIntern Med 107:204-215, 1987

54. Soto Alvarez J, Sacristan Del Castillo JA, Sampedro Garcia I,Alsar Ortiz MJ: Immediate hypersensitivity to aztreonam(letter to the editor). Lancet 335: 1094, 1990

55. Hantson P, de Coninck B, Hom JL, Mahieu P: Immediatehypersensitivity to aztreonam and imipenem. BMJ 302:294­295, 1991

56. Eisenberg JM, Koffer H, Glick HA, Connell ML, Loss LE,Talbot GH, Shusterman NH, Strom BL: What is the cost ofnephrotoxicity associated with arninoglycosides? Urology31 (June Suppl):45-56, 1988