AZTREONAM

BURKE A. CUNHA, M.D.

From the Infectious Disease Division, Winthrop-University Hospital, Mineola, and the School of Medicine, State University of New York, Stony Brook, New York

ABSTRACT-Axtreonam is the first monobactam and is unique among fl-hu- tam antibiotics for its spectrum of activity that is exclusively active agai:$::t gram-negative aerobic bacteria. Broad clinical experience with this agent supl- ports its use in the treatment of adults with severe or complicated urologic infections. Axtreonam may be safely used in patients with penicillin allergy. With a spectrum of activity that is comparable to the aminoglycosides bz t without the potential for ototoxicity or nephrotoxicity, axtreonam represent,s a rational choice of therapy for treatment of systemic urinary tract infections due to susceptible organisms.

Urinary tract infections are a significant source of morbidity and mortality in the hospitalized patient. Approximately 500,000 urinary tract infections occur annually in acute-care hospi- tals in the United States,’ and nosocomial uro- sepsis is responsible for over 3,500 deaths each year.2 The urinary tract is the site of origin for approximately 40 percent of gram-negative ba- cillary bacteremias that develop in patients.3

Traditional therapy of serious urinary tract infections with or without urologic complica- tions consists of parenteral antibiotics. Aminoglycosides are frequently used in this set- ting because they achieve high concentrations in blood, renal tissue, and urine. In addition, the aminoglycosides are bactericidal and are ac- tive against many aerobic gram-negative uro- pathogens, including the Enterobacteriaceae and Pseudomonas aeruginosa. The potential for toxicity remains a significant disadvantage to aminoglycoside therapy, and therapeutic serum concentration monitoring elevates the cost of therapy and complicates patient management. Economic analysis of aminoglycoside therapy has shown that the development of aminoglyco- side-induced renal toxicity increases the cost per patient per course of therapy by $2,500. Even in patients in whom nephrotoxicity does not de- velop as a consequence of aminoglycoside therapy, renal function tests, serum drug con- centration monitoring, and consultations add an additional $620 to the hospital bi11.4

UROLOGY i MARCH 1993 i VOLUME 41, NUMBER 3

Aztreonam has a spectrum of antimicrcbial activity that consists exclusively of aerobic gram-negative pathogens. Thus, the in vitro ac- tivity of aztreonam resembles that of the aminoglycosides. 5 High concentrations are achieved in the urine and renal tissues, and aztreonam is a remarkably safe ant:ibiotic. :Em- piric therapy with aztreonam for infectio:ns, such as pneumonia or intra-abdominal. infec- tion, requires administration with1 other anti- biotics that have activity against anaerobes and gram-positive aerobes. However, when the Gram stain of the urine is not suggestive of a gram-positive infection, aztreonam is an appro- priate empiric choice for monotherapy of urinary tract infections caused by susceptible gram-negative aerobic pathogens.

Historical Background

The discovery of a new class of naturally oc- curring compounds with antimicrobial activity was reported independently in the early 1980s by two separate teams of investigatorse17 These agents were named monobactams because they were derived from monocyclic P-lactams pro- duced by bacteria. 8 Structural modifications, which were necessary to improve the relatively poor in vitro activity of the natural monobac- tams, resulted in the development of aztreonam (Fig. 1). The sulfonic acid group at position 1 activates the @-lactam ring. The a-methoxy

249

FIGURE 1. Chemical configuration and structure- activity relationships of aztreonam (reproduced from Ma&en PO, et al.,51 with permission).

group at position 4 increases antibacterial activ- ity and also provides stability to P-lactamases. The aminothiazole oxime group at position 3 is responsible for activity against gram-negative aerobes. Increased activity against Pseudomo- nas is attributed to the presence of a carboxyl group at this position.e-ll

Antimicrobial Activity

Aztreonam is a bactericidal antibiotic with a mechanism of action that is similar to the peni- cillins and cephalosporins. Aztreonam inhibits the bacterial cell-wall synthesis of gram-nega- tive bacteria by binding preferentially to peni- cillin-binding protein (PBP)-3. Aztreonam does not bind the PBP found in gram-positive or anaerobic bacteria, which accounts for the nar- row spectrum of activity of this agent. After binding to PBP-3, aztreonam causes elongation or filamentation, holes in the cell wall, cell ly- sis, and cell death.i2 Aztreonam is highly stable to the P-lactamases produced by gram-negative and gram-positive organisms. 13,14

Aztreonam possesses in vitro activity against gram-negative aerobic uropathogens, including

most Enterobacteriaceae and many Pseudomo- nas species (Table I). Established susceptibility breakpoints for aztreonam with agar or broth dilution techniques are 18 PglmL (suscepti- ble), 16 pg/mL (intermediate), and 132 pg/mL (resistant). Inhibition zones using the Kirby- Bauer disk diffusion technique (with a disk con- taining 30 pg of aztreonam) are 222 mm (sus- ceptible), 16 to 22 mm (moderate), and 515 mm (resistant). l5 Aztreonam demonstrates minimum bactericidal concentrations (MBC) that are equal to, or twofold or fourfold greater than, the minimum inhibitory concentrations (MIC) for susceptible strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and P aeruginosa. 16-l’

The inhibitory concentrations for most En- terobacteriaceae are well below achievable concentrations of aztreonam in the urine, renal parenchyma, and prostate.lE21 When tested in vitro against clinical isolates from patients with complicated or nosocomial urinary tract infec- tionsle or a variety of other infections,1eT22-24 most strains of Enterobacteriaceae are inhibited by concentrations of aztreonam that are less than or equal to 1.6 PglmL. Higher concentra- tions are needed for inhibition of Enterobacter species and I? aeruginosa. The activity of aztreonam against gram-negative aerobes is therefore similar to that of the third-generation cephalosporins. However, aztreonam possesses no activity against gram-positive organisms or anaerobic organisms. Thus, the microbiologic activity of aztreonam is unique among /3-lactam agents and is similar to the anti-aerobic, gram- negative spectrum of aminoglycosides.

TABLE I. In vitro activity of axtreonam and third-generation cephalosporins * Oganism MIGo (pglmL)

(No. of Strains) Aztreonam Cefotaxime Ceftazidime Cefoperazone

E. coli (79) 0.2 0.2 0.4 >lOO K. pneumoniae (68) 0.3 0.3 1.1 >lOO E. cloacae (29) 12.5 25.0 12.5 100 E. (13) aerogenes 33.3 42.9 >lOO >lOO S. marcescens (113) 1.6 8.4 1.5 > 100 F! mirabilis (25) <O.l <O.l 0.1 2.4 P. vulgaris (11) <O.l 5.5 <O.l 5.8 P. rettgeri (6) <O.l 0.2 2.3 10.7 l? morganii (19) 0.6 1.6 3.1 6.3 F! stuartii (15) <O.l 3.0 4.7 > 100 C. freundii (25) ::: 0.4 2.0 4.7 N. gonorrhoeae (20) <O.l <O.l 0.2 l? aeruginosa (61) 12.0 NA 3.0 6.0

KEY: NA = not applicable. *Adapted from Sykes RB, et al. ,24 with permission.

250 UROLOGY / MARCH 1993 I VOLUME 41, NUMBER 3

TABLE II. Pharmacokinetic parameters of aztreonam in healthy volunteers

Parameter Mean Value

Peak serum cont. (IV) 0.5 g 38.7 pg/mL

lg 99.5 pg/mL

2g 242 PglmL Peak serum cont. (IM)

0.5 g 18.2 PglmL

lg 36.1 pg/mL Time to peak serum cont. (IM)

0.5 g lh

lg lh Elimination half-life (IV) 1.7 h Volume of distribution (IV)

(steady state) 0.21 L/kg Clearance (IV)

Plasma 89 mL/min Renal 66 mL/min

Protein binding (IV) 56% 24-hour urinary recovery (IV) 600%74%

KEY: IV = intravenous; IM = intramuscular.

Because of its fl-lactam structure, hydrolysis by fl-lactamases is the most important means of bacterial resistance to aztreonam.25 Aztreonam is stable to hydrolysis by most plasmid-me- diated fl-lactamases from E. coli and F! aeru- ginosa and chromosomally mediated enzymes from C. freundii, E. cloacae, E. coli, M. morganii, Providencia species, Serratia species, and I? aeruginosa. Some fl-lactamases, particu- larly Kl and SHV-5 from Klebsiella species and the PSE-2 from I?. aeruginosa are able to hydro- lyze aztreonam, resulting in microbial resist- ance to these strains. 17,26*27 Unlike some other p- lactam antibiotics (e.g., cefoxitin), aztreonam has not been shown to induce the production of chromosomally mediated fl-lactamases in E. cloacae and M . morganii.28

Pharmacokinetics

Absorption and distribution Less than 1 percent of an administered dose

of aztreonam is absorbed following oral ad- ministration.2e Thus, aztreonam is given exclu- sively via parenteral administration. Aztreonam is rapidly absorbed following intra- muscular administration. Peak serum concen- trations of 18.2 pg/mL and 36.1 pg/mL are at- tained within one hour of single intramuscular doses of 0.5 g and 1 g, respectively. Peak serum concentrations were 38.7 PglmL, 99.5 pg/mL, and 242 PglmL following three-minute intrave- nous infusions of 0.5 g, 1 g,30 and 2 g,31 respec- tively (Table II). Mean serum concentrations

c

UROLOGY / MARCH 1993 / VOLUME 41, NUMBER 3

FIGURE 2. Mean urinary concentrations of aztreonam (pg/mL) after intravenous and intramus- cular administration in healthy volunteers.31

twelve hours after a l-g dose were 0.65 PglmL (intramuscular administrations) and 0.51 pgl mL (intravenous administration) .31

Therapeutic doses of 0.5 g and 1 g result in high and sustained urinary concentrations of aztreonam (Fig. 2). Urine concentrations are ten-fold to one hundred-fold greater than con- current serum concentrations. Peak urine con- centrations after a l-g intravenous dose are 3,000 pg/mL; urinary concentrations twelve hours after the dose are 11 pg/mLa31 In general, urine concentrations of aztreonam greatly ex- ceed the MICso values for most gram-negative uropathogens for at least twelve hours after the dose.

The pharmacokinetic properties of aztreonam can be characterized by a two-com- partment, open, linear model. The mean elimination half-life is 1.7 hours and the vol- ume of distribution at steady state is 0.21 L/kg, which approximates total extracellular fluid volume.30 In healthy volunteers, approximately 56 percent of an administered dose of aztreonam is bound to plasma proteins (Table II). 3o These parameters are similar to many penicillins and cephalosporins. 32*33

Aztreonam distributes to various body fluids, including peritoneal fluid,= blister fluid 35 cer- ebrospinal fluid,3e aqueous humour, bronchial secretions,38 bile, and breast milk.3e The con- centrations of aztreonam also have been measured in human prostate tissue18,21 and in renal tissue from postnephrectomy patients (Table III).2o Prostate tissue was obtained from men undergoing transurethral resection follow- ing single l-g intravenous doses of aztreonam. m21 The mean aztreonam concen- trations in prostate tissue between fifty and one hundred eighty minutes after the dose were

251

TABLE III. Aztreonam concentrations in serum, renal tissue, and prostate1ae1

Diagnosis (N) Serum Cont.

(pg/mL) -Tissue Conc~~;a~ns (cg/g)- Cortex Papilla

Renal tissue Severe renal disease

Transplant rejection (1) Transplant rejection (1) Transplant rejection (1) Transplant rejection (1) Chronic glomerulonephritis (1)

Chronic glomerulonephritis (1)

Polycystic (1)

Chronic pyelonephritis (1)

Prostate tissue Benign hypertrophy (8) Benign hypertrophy (10)

52 27 43 50

162 70 108 16 101 R 51

90 L 36 156 R 62 141 L 61 68 R 4.6 62 L 5.7

111 R 83 86 L 66

31 7.8 38 6

31 34 49 57 62 103 32 25 62 63 46 51 74 60 60 77 . .

ii . .

. .

ii 73

7.P’ and 6 pg/g tissue.21 The mean prostate: serum concentration ratio was 0.25 and ex- ceeded the MIC values for most Enterobacte- riaceae that cause chronic prostatitis.‘* The postnephrectomy findings from 8 patients with severe renal disease demonstrate that intrarenal aztreonam concentrations (i.e., 16 pglg to 103 pg/g) are somewhat lower than simultaneous serum concentrations (i.e., 43 PglmL to 162 PgI mL), but are higher than the MIC& values of susceptible gram-negative uropathogens.20

Metabolism and excretion

Time (h)

Aztreonam is excreted unchanged in the urine by both glomerular filtration and tubular secretion.40,41 The renal clearance of aztreonam is 66 mllmin, and 60 percent to 74 percent of an administered dose is excreted in the urine af- ter twenty-four hours (Table II).3o,35 A minor proportion of the dose (1% ) is excreted un- changed in the feces. A microbiologically inac- tive metabolite accounts for an additional 7 percent of urinary and 3 percent of fecal excre- tion.42 The elimination half-life of 1.7 hours in healthy subjects is prolonged to 2.2 hours in pa- tients with biliary cirrhosis and 3.2 hours in al- coholics.43

FIGURE 3. Urinary concentrations (mean f SD) and cumulative urinary excretion (% of dose in- jected) in 9 elderly patients after a single l-g intrave- nous dose of axtreonam (reproduced from Naber KG, et al.,‘O with permission).

and thermal injury. 48 Because of minimal me- tabolism and predominant urinary elimination, the pharmacokinetic properties of aztreonam are most affected by renal impairment.40

Pharmacokinetics in special populations The pharmacokinetic properties of

aztreonam have been described in normal vol- unteers,31,35 healthy elderly volunteers,10 pa- tients with renal failure,44,45 hematologic ma- lignancies, 48 alcoholic cirrhosis 43 infections,34x47 9

Pharmacokinetics in the elderly. The elimination half-life of aztreonam in elderly in- dividuals is prolonged from 1.7 to 2.7 hours.lg However, approximately 70 percent of an ad- ministered dose is excreted in the urine in twelve hours9 (Fig. 3) and serum concentra- tions associated with equivalent doses are not higher in elderly versus younger patients.4g Dos- age adjustments based solely on advanced age are, therefore, not necessary.

Pharmacokinetics in renal dysfunction. The elimination half-life of aztreonam increases to six hours and the renal clearance decreases to

252 UROLOGY / MARCH1993 / VOLUME41,NUMBER3

29 mL/min in anephric patients. There is no change in the volume of distribution, but the hypoproteinemic state that is associated with renal failure reduces protein binding to 36 per- cent. Thus, serum concentrations of free and pharmacologically active antibiotic (i.e., that portion of the dose that is not bound to plasma proteins) are somewhat increased.45

Pharmacokinetics in renal dialysis. A four- hour hemodialysis session in 6 anephric patients increased mean aztreonam plasma clearance from 24 mL/min to 40 mL/min and decreased elimination half-life from 7.9 to 2.7 hours. He- modialysis removed approximately 40 percent of the administered dose of aztreonam.44 Thus, half of the aztreonam dose should be given at the conclusion of hemodialysis. Chronic ambu- latory peritoneal dialysis increased aztreonam plasma clearance by less than 10 percent when the dose was administered intravenously. Dialy- sate concentrations of 105 pg/mL were achieved six hours following an intraperitoneal dose of 1 g; measurable drug concentrations persisted for forty-eight hours after the dose despite 8 dialysate exchanges,44 which suggests that the intraperitoneal route of administration may be of use in these patients.

Clinical Use in Urology

Clinical experience with aztreonam is exten- sive, and urinary tract infections represent the most frequent types of infection that are treated with this agent. 50-52 Pooled data from studies conducted around the world reveal clinical re- sponse rates to aztreonam monotherapy for urinary tract infections in excess of 80 per- cent. 51-53

Aztreonam is effective in the treatment of complicated, uncomplicated, and recurrent urinary tract infections, including pyelone- phritis, cystitis, prostatitis, epididymitis, and other types of unspecified urinary tract infec- tions.51,53 As with other antibiotics, therapeutic response depends to a large extent on the pres- ence of complicating factors, such as urologic abnormalities, obstruction, and foreign bodies. Microbiologic cures have been attained in infec- tions caused by I? aeruginosa and Pseudomonas species and various Enterobacteriaceae, includ- ing E. coli and Klebsiella, Enterobacter, Serra- tia, Proteus, Citrobacter, Providencia, Acineto- batter, and Morganella species. 53

Controlled studies have compared aztreonam with second- and third-generation cephalospo-

rins and the aminoglycosides in the treatment of urinary tract infections. The clinical and micro- biologic efficacy of aztreonam is comparable to standard therapy with these agents. Cefaman- dole (1 g three times daily) was compared to aztreonam (0.5 or 1 g twice or thrice daily) in 159 patients with nosocomial urinary tract in- fection.54 After five to nine days of therapy, pathogens were eradicated from the urine of 87.5 percent of patients treated with aztreonam three times daily. This response was slightly greater than that attained in the aztreonam twice-daily (82.7 %) or cefamandole (78.3 %) groups. Relapse, reinfection, and superinfec- tion in patients treated with aztreonam were most commonly caused by Enterobacteriaceae ( i.e., E. coli, Klebsiella species, and Citrobac- ter species). I? aeruginosa was the most com- mon cause of treatment failure among patients treated with cefamandole.

Aztreonam also has been shown to be as ef- fective as cefotaxime19 and cefuroxime55 in hos- pitalized patients with complicated urinary tract infections. In one series, aztreonam (1 g twice daily) was compared with cefotaxime (1 g twice daily) in the treatment of 39 adult uro- logic patients with complicated and/or nosoco- mial urinary tract infections.lg The initial in- fecting pathogens were eradicated in all patients in the aztreonam group and in 19 of 20 cefotaxime patients; complete cures were at- tained in approximately one third of patients in both groups. However, one to two days after completing therapy, 16 percent of aztreonam patients and 10 percent of cefotaxime patients had significant bacteriuria. At follow-up one to four weeks later, superinfections (3 for aztreonam; 1 for cefotaxime), relapses (7 for aztreonam; 6 for cefotaxime), and reinfections (3 for aztreonam; 5 for cefotaxime) had oc- curred in both treatment groups. Enterococci were associated with reinfection, particularly in postoperative patients. In another series, aztreonam (1 g three times daily) produced comparable clinical (89 % versus 87 % ) and mi- crobiologic cures (70 % versus 73 % ) as cefurox- ime (1.5 g three times daily) .55

Aztreonam has been compared with aminoglycoside therapy and is as effective as gentamicin, 56,57 tobramycin,5s,59 or amikacin58 in patients with urinary tract infections. Sattler and colleagues 57 demonstrated that aztreonam was as effective and may be less toxic than gen- tamicin in 52 hospitalized patients with serious urinary tract infections. Most patients achieved

UROLOGY / MARCH 1993 / VOLUME 41, NUMBER 3 253

unequivocal clinical cures (66 % aztreonam; 53 % gentamicin), cures with relapse (17 % aztreonam; 6 % gentamicin), or cures with reinfection (17 % aztreonam; 24 % gentamicin) . (Cure rates between treatment groups were not significantly different.) Side effects that were associated with aztreonam therapy were lim- ited to injection-site phlebitis (1 patient), bad taste (1)) Candida vaginitis (1)) and asympto- matic hepatic function test abnormalities (7), but 4 patients in the gentamicin group expe- rienced significantly elevated serum creatinine concentrations (p = 0.009). Enterococcal su- perinfection was more common in the aztreonam group. In vitro susceptibility studies revealed that isolates of I? aeruginosa, E. coli, and S. marcescens that were resistant or moder- ately susceptible to gentamicin were sensitive to aztreonam.

Prostatitis Aztreonam penetrates into prostate tissue1*s21

and has been shown to be effective in the treat- ment of prostatitis, including infections caused by multidrug-resistant bacteria.53,80 In an open study of 16 patients with prostatitis, aztreonam therapy resulted in favorable clinical responses (100% of 16 patients) and microbiologic cures (81%) .53 Larger, comparative studies are needed before the place of aztreonam in the treatment of prostatitis is determined.

Multidrug-resistant pathogens Aztreonam has been evaluated in the treat-

ment of urinary tract infections caused by or- ganisms that are resistant to multiple anti- biotics.53,s0 In one study, 135 patients with urinary tract infections that were complicated by multidrug-resistance and obstruction, geni- tourinary tract malignancy, neurogenic disease, renal calculi, or chronic pyelonephritis were treated with aztreonam.eO To be eligible for this study, the pathogen had to demonstrate resist- ance on disk diffusion to ampicillin and first- and second-generation cephalosporins, with or without resistance to the aminoglycosides. The study regimens consisted of aztreonam 1 g three times a day (40 patients) or 0.5 g twice daily (95 patients). The most common pathogen in the two dosage groups was F! aeruginosa. E. coli, Serratia, Morganella, and Providencia species were also very commonly isolated. Clinical cures were attained in 98 percent and 96 per- cent of patients in the 1 g three-times-daily and the 0.5 g twice-daily groups, respectively.e0

P aeruginosa infection is common in patients with complicated urinary tract infections, espe- cially in those who have received multiple courses of antibiotics. In the series by COX,~O un- qualified cure (i.e., without relapse or superin- fection) of urinary tract infections caused by multi-drug resistant Pseudomonas occurred in 96 percent of 55 patients, When data from open and controlled clinical studies involving 681 patients with urinary tract infections were pooled, aztreonam therapy resulted in clinical and microbiologic cure rates of 98 percent and 76 percent, respectively, in 112 patients infected with F! aeruginosa. 53 Pseudomonal superinfec- tions occur more often in patients treated with cefamandole or aminoglycosides than during aztreonam therapy. In contrast, aztreonam is more commonly associated with staphylococcal and enterococcal superinfections. 51+31

Dosage of axtreonam in urologic infections Aztreonam may be administered intramuscu-

larly or intravenously in doses of 0.5 or 1 g every eight or twelve hours for most urinary tract infections in the adult population. Serious infections (e.g., pyelonephritis with bactere- mia) or those caused by less susceptible or- ganisms (e.g., I? aeruginosa) may require more aggressive treatment with intravenous doses of up to 2 g every six to eight hours. Patients with hepatic dysfunction do not require dosage ad- justment; however, dosage adjustments are needed in patients with renal impairment.

Aztreonam clearance correlates directly with adjusted creatinine clearance. This observa- tion, together with the pharmacokinetic changes associated with renal dysfunction, form the basis for dosage adjustment in patients with systemic disease. Patients with normal re- nal function (e.g., creatinine clearances of 100 mL/min) would receive 0.5 g or 1 g every eight or twelve hours for urinary tract infections. Higher and/or more frequent doses are appro- priate for severe or systemic infections (i.e., 1 g or 2 g every 6 or 8 hours). The maintenance dose of aztreonam for patients with moderate renal impairment (e.g., creatinine clearances of approximately 30 mL/min) should be halved af- ter the administration of an initial loading dose of 1 g or 2 g.e2 Anephric or hemodialysis pa- tients should receive an initial loading dose of 0.5 g or 1 g followed by maintenance doses ad- ministered after dialysis that are 25 percent of the loading dose. Old age alone is not cause for dosage adjustment. However, renal function as

254 UROLOGY / MARCH 1993 / VOLUME 41, NUMBER 3

TABLE IV. Adverse effects of axtreonam therapy*

Adverse Effect Incidence ( % )

Dermatologic (1.8 % ) Rash 1.3 Rash with eosinophilia 0.2 Pruritus 0.2 Purpura 0.1

Gastrointestinal (2.2%) Diarrhea 1.0 Nausea/vomiting 0.6 Taste alteration 0.2 Clostridium difficile colitis 0.3 Jaundice/hepatitis 0.1

Thrombophlebitis 1.9 Central nervous system (0.5 %)

Headache 0.2 Dizziness 0.1 Other 0.2

Miscellaneous Drug fever 0.07 Hypersensitivity 0.04 Bleeding 0.09 Other 0.4

*Adapted from Chartrand SA,B3 with permission.

determined by creatinine clearance is a primary determinant of dosage adjustment in elderly patients, l8 and higher doses may be needed in patients with severe burn injury.48

Safety of axtreonam

The adverse-effect profile of aztreonam in the general adult, elderly, and pediatric popula- tions49,63,64 and in patients with urinary tract in- fectionP has been extensively reviewed. Ad- verse reactions occur in 7 percent of patients and are serious enough to require discontinua- tion of therapy in 2 percent of patients.e4 A re- view of pooled findings from published studies and data from the manufacturer in over 4,500 adults83 reveals a low incidence of adverse ef- fects (Table IV). Rash, which occurred in less than 2 percent of patients, was the most com- monly reported adverse effect. Diarrhea was reported by 1 percent of patients. Individual central nervous system effects occurred in fewer than 0.5 percent of patients, and none had seizures that were related to aztreonam therapy. Aztreonam does not contain the N- methylthiotetrazole group and does not alter the anaerobic bowel flora; therefore bleeding diatheses do not occur during therapy.

The spectrum of laboratory abnormalities as- sociated with aztreonam therapy is similar to therapy with cefamandole and the aminoglyco- sides. A notable exception is the relatively greater incidence of elevated serum creatinine

concentrations that are associated with aminoglycoside therapy as compared with aztreonam. The findings of comparative studies of aztreonam and aminoglycosides in patients with urinary tract infections or lower respira- tory tract infections were evaluated for marked deviations in serum creatinine concentrations. Marked deviations in serum creatinine concen- trations were defined as an increase of 20.5 mg/dL in patients with baseline values of < 3.0 mg/dL or an increase of 2 1.0 mg/dL when baseline values were 2 3.0 mg/dL. Aminogly- coside therapy was associated with markedly el- evated serum creatinine in 9 percent of 121 pa- tients, in 5 of whom azotemia also developed. In contrast, 4 percent of 275 aztreonam-treated patients exhibited elevated serum creatinine concentrations and none became azotemic.e4 The lack of renal toxicity associated with aztreonam was confirmed in a study of 11 pa- tients with urinary tract infections. Evaluation of renal function tests and concentrations of urinary enzymes before, during, and after a five-day course of therapy revealed no clinically significant adverse effects on renal function.e5

When the dose is adjusted according to creatinine clearance, aztreonam can be safely administered to patients with renal insuffi- ciency,ea including the elderly.49 Sion and col- leagues 66 treated 39 patients (25 with chronic and 14 with acute renal failure) with a variety of gram-negative infections (22 urinary tract in- fections) with aztreonam. Adverse effects were limited to transient elevations in serum tran- saminases (4 patients) and intramuscular injec- tion-site reactions (5 patients). Renal function improved in this population as demonstrated by mean reductions in serum creatinine concentra- tions from 3.79 f 2.84 mg/dL (baseline) to 3.30 f 2.52 mg/dL (end of therapy; ~~0.003).

Clinically significant changes in laboratory test values during aztreonam therapy are un- common. Aztreonam therapy was associated with three-fold increases in hepatic trans- aminases in 27 of 2,388 patients from a pooled database. Elevated liver enzymes resolved spontaneously in 21 of the 27 patients and were not judged to be related to aztreonam therapy in 5 others. Adverse clinical effects or abnormal laboratory test findings resulted in premature discontinuation of aztreonam therapy in 2 per- cent of 2,388 patients because of rash or other dermatologic reaction (nearly half of patients), abnormal liver function tests (10 patients), or other reactions. In comparative studies, the

UROLOGY / MARCH 1993 / VOLUME 41, NUMBER 3 25s

discontinuation of aztreonam therapy because of adverse effects or laboratory test abnormali- ties occurred at the same rate as in cefamandole or aminoglycoside therapy (1.7 percent versus 1.5 percent, respectively). 64

The possibility of cross-reactions in patients who are allergic to penicillins or cephalosporins is of potential concern with the use of agents possessing a /3-lactam ring structure (e.g., aztreonam). However, the findings from re- views of clinical experience in the general popu- lation8~51~67-0e and studies designed to assess its immunogenic potential in penicillin-allergic in- dividuals70-74 indicate that aztreonam therapy presents minimal risk of hypersensitivity reac- tions. Fewer than 1 percent of persons with documented allergy to penicillins and cephalo- sporins exhibited possible hypersensitivity reac- tions to aztreonam. 7o-72,74 Antibodies produced in rabbits in response to penicillin G, including immunoglobulin E (IgE) antibodies to major and minor determinants, and cephalothin were not cross-reactive with aztreonam, which sug- gests that aztreonam may be safely adminis- tered to patients who are allergic to penicillin and the cephalosporins . ‘On

Summary Extensive clinical experience supports the use

of aztreonam in the treatment of serious urinary tract infections. This monobactam pos- sesses a spectrum of activity similar to the aminoglycosides yet without their toxic effects. Usual therapeutic doses of 0.5 or 1 g achieve concentrations in the blood, renal parenchyma, prostate tissue, and urine that exceed the mini- mum inhibitory concentrations of most gram- negative uropathogens. Intravenous doses of 2 g administered every eight hours are needed for infections caused by I? aeruginosa.

Comparative clinical studies of adults with serious and/or complicated aerobic, gram-neg- ative urinary tract infections have demon- strated that monotherapy with aztreonam is as effective as cephalosporins and aminoglyco- sides. Aztreonam is remarkably well tolerated. The most commonly reported adverse reactions are rash and diarrhea, which are mild, fully re- versible, and have generally not been severe enough to require discontinuation of therapy. Aztreonam does not cause renal toxicity and may be administered to patients with penicillin allergy.

Thus, aztreonam represents rational therapy for patients with complicated/severe urinary

TABLE V. Urologic uses of aztreonam

Urologic Empiric Combination Infection Monotherapy Therapy

Acute cystitis (gram- negative bacilli in compromised hosts) + NA

Acute prostatitis Young patient + NA Elderly patient + Add ampicillin if

enterococci present Acute epididymitis

Young patient + Add doxycycline for Chlamydia

Elderly patient +* NA Acute pyelonephritis + NA Urosepsis

Postinstrumentation + * Add ampicillin if enterococci present

Nonleukopenic compromised host (diabetic, lupus, immunosuppressive therapy) +* NA

Abnormal anatomy/ obstetric + Add ampicillin if

enterococci present

KEY: NA = not applicable. ‘P aeruginosa is a common pathogen in these settings. Specific

therapy should be guided by susceptibility testing. If P aeruginosa resistance to aztreonam is a problem, initial empiric therapy with amikacin would be preferable.

tract infections. Aztreonam may be used as a single agent when Gram stain of the urine indi- cates the presence of a gram-negative pathogen. However, when gram-positive organisms (e.g., enterococci) are present, an antibiotic that cov- ers these organisms should be used instead or added to the therapeutic regimen (Table V).

Infectious Disease Division Winthrop-University Hospital

Mineola, New York 11501

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