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-hutam antibiotics for its spectrum of activity that is exclusively active agai:$::t gram-negative aerobic bacteria. Broad clinical experience with this agent suplports 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 hospitals in the United States, and nosocomial urosepsis 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 bacillary bacteremias that develop in patients.3 Traditional therapy of serious urinary tract infections with or without urologic complications consists of parenteral antibiotics. Aminoglycosides are frequently used in this setting because they achieve high concentrations in blood, renal tissue, and urine. In addition, the aminoglycosides are bactericidal and are active against many aerobic gram-negative uropathogens, 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 aminoglycoside-induced renal toxicity increases the cost per patient per course of therapy by $2,500. Even in patients in whom nephrotoxicity does not develop as a consequence of aminoglycoside therapy, renal function tests, serum drug concentration monitoring, and consultations add an additional $620 to the hospital bi11.4 Aztreonam has a spectrum of antimicrcbial activity that consists exclusively of aerobic gram-negative pathogens. Thus, the in vitro activity 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. :Empiric therapy with aztreonam for infectio:ns, such as pneumonia or intra-abdominal. infection, requires administration with1 other antibiotics 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 appropriate 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 occurring 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 produced by bacteria. 8 Structural modifications, which were necessary to improve the relatively poor in vitro activity of the natural monobactams, resulted in the development of aztreonam (Fig. 1). The sulfonic acid group at position 1 activates the @-lactam ring. The a-methoxy

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FIGURE1. Chemical activity relationships from Ma&en PO, et

configuration and structureof aztreonam (reproduced al.,51 with permission).

group at position 4 increases antibacterial activity 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 Pseudomonas 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 penicillins and cephalosporins. Aztreonam inhibits the bacterial cell-wall synthesis of gram-negative bacteria by binding preferentially to penicillin-binding protein (PBP)-3. Aztreonam does not bind the PBP found in gram-positive or anaerobic bacteria, which accounts for the narrow spectrum of activity of this agent. After binding to PBP-3, aztreonam causes elongation or filamentation, holes in the cell wall, cell lysis, 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
TABLE I. Oganism

most Enterobacteriaceae and many Pseudomonas species (Table I). Established susceptibility breakpoints for aztreonam with agar or broth dilution techniques are 18 PglmL (susceptible), 16 pg/mL (intermediate), and 132 pg/mL (resistant). Inhibition zones using the KirbyBauer disk diffusion technique (with a disk containing 30 pg of aztreonam) are 222 mm (susceptible), 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 Enterobacteriaceae 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 infectionsle 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 concentrations 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, gramnegative spectrum of aminoglycosides.
and third-generation cephalosporins *
Cefoperazone >lOO >lOO 100 >lOO > 100 2.4 5.8 10.7 6.3 > 100 4.7 0.2 6.0

In vitro activity of axtreonam

Aztreonam 0.2 0.3 12.5 33.3 1.6 <O.l <O.l <O.l 0.6 <O.l ::: 12.0

(No. of Strains)
E. coli (79) K. pneumoniae (68) E. cloacae (29) E. aerogenes (13) S. marcescens (113) F! mirabilis (25) P. vulgaris (11) P. rettgeri (6) l? morganii (19) F! stuartii (15) C. freundii (25) N. gonorrhoeae (20) l? aeruginosa (61)

Cefotaxime 0.2 0.3 25.0 42.9 8.4 <O.l 5.5 0.2 1.6 3.0 0.4 <O.l NA

MIGo (pglmL) Ceftazidime 0.4 1.1 12.5 >lOO 1.5 0.1 <O.l 2.3 3.1 4.7 2.0 <O.l 3.0

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

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TABLE

II. Pharmacokinetic parameters aztreonam in healthy volunteers

Parameter cont. (IV)

of

Mean Value 38.7 pg/mL 99.5 pg/mL 242 PglmL

Peak serum 0.5 g lg 2g Peak serum 0.5 g

cont.

(IM) 18.2 PglmL 36.1 pg/mL (IM) lh lh 1.7 h 0.21 L/kg 89 mL/min 66 mL/min 56% 600%74% FIGURE 2. Mean urinary concentrations of aztreonam (pg/mL) after intravenous and intramuscular administration in healthy volunteers.31

lg Time to peak serum cont. 0.5 g

lg Elimination half-life (IV) Volume of distribution (IV) (steady state) Clearance (IV) Plasma Renal Protein binding (IV) 24-hour urinary recovery (IV)
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-mediated fl-lactamases from E. coli and F! aeruginosa and chromosomally mediated enzymes from C. freundii, E. cloacae, E. coli, M. morganii, Providencia species, Serratia species, and I? aeruginosa. Some fl-lactamases, particularly Kl and SHV-5 from Klebsiella species and the PSE-2 from I?. aeruginosa are able to hydrolyze aztreonam, resulting in microbial resistance to these strains. 17,26*27 Unlike some other plactam 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 administration.2e Thus, aztreonam is given exclusively via parenteral administration. Aztreonam is rapidly absorbed following intramuscular administration. Peak serum concentrations of 18.2 pg/mL and 36.1 pg/mL are attained 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 intravenous infusions of 0.5 g, 1 g,30 and 2 g,31 respectively (Table II). Mean serum concentrations c
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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 concurrent serum concentrations. Peak urine concentrations 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 exceed 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-compartment, open, linear model. The mean elimination half-life is 1.7 hours and the volume 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 cerebrospinal fluid,3e aqueous humour, bronchial secretions,38 bile, and breast milk.3e The concentrations 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 following single l-g intravenous doses of aztreonam. m21 The mean aztreonam concentrations in prostate tissue between fifty and one hundred eighty minutes after the dose were

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TABLE III. Diagnosis (N) Renal tissue Severe renal disease Transplant rejection (1) Transplant rejection (1) Transplant rejection (1) Transplant rejection (1) Chronic glomerulonephritis Chronic glomerulonephritis Polycystic (1) Chronic pyelonephritis (1)

Aztreonam concentrations in serum, renal tissue, and prostate1ae1

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

(1) (1)

52 43 162 108 101 90 156 141 68 62 111 86

R L R L R L R L

27 50 70 16 51 36 62 61 4.6 5.7 83 66

31 49 62 32 62 46 74 60 . . ii . .

34 57 103 25 63 51 60 77 . . ii 73

Prostate tissue Benign hypertrophy Benign hypertrophy

(8) (10)

31 38

7.8 6

7.P and 6 pg/g tissue.21 The mean prostate: serum concentration ratio was 0.25 and exceeded the MIC values for most Enterobacteriaceae 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 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 after twenty-four hours (Table II).3o,35 A minor proportion of the dose (1% ) is excreted unchanged in the feces. A microbiologically inactive metabolite accounts for an additional 7 percent of urinary and 3 percent of fecal excretion.42 The elimination half-life of 1.7 hours in healthy subjects is prolonged to 2.2 hours in patients with biliary cirrhosis and 3.2 hours in alcoholics.43 Pharmacokinetics in special populations The pharmacokinetic properties of aztreonam have been described in normal volunteers,31,35 healthy elderly volunteers,10 patients with renal failure,44,45 hematologic ma43 lignancies, 48 alcoholic cirrhosis 9 infections,34x47

Time (h)

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

and thermal injury. 48 Because of minimal metabolism and predominant urinary elimination, the pharmacokinetic properties of aztreonam are most affected by renal impairment.40 Pharmacokinetics in the elderly. The elimination half-life of aztreonam in elderly individuals is prolonged from 1.7 to 2.7 hours.lg However, approximately 70 percent of an administered dose is excreted in the urine in twelve hours9 (Fig. 3) and serum concentrations associated with equivalent doses are not higher in elderly versus younger patients.4g Dosage 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

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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 percent. 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 fourhour 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. Hemodialysis 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 ambulatory peritoneal dialysis increased aztreonam plasma clearance by less than 10 percent when the dose was administered intravenously. Dialysate 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 extensive, and urinary tract infections represent the most frequent types of infection that are treated with this agent. 50-52Pooled data from studies conducted around the world reveal clinical response rates to aztreonam monotherapy for urinary tract infections in excess of 80 percent. 51-53 Aztreonam is effective in the treatment of complicated, uncomplicated, and recurrent urinary tract infections, including pyelonephritis, cystitis, prostatitis, epididymitis, and other types of unspecified urinary tract infections.51,53 As with other antibiotics, therapeutic response depends to a large extent on the presence of complicating factors, such as urologic abnormalities, obstruction, and foreign bodies. Microbiologic cures have been attained in infections caused by I? aeruginosa and Pseudomonas species and various Enterobacteriaceae, including E. coli and Klebsiella, Enterobacter, Serratia, Proteus, Citrobacter, Providencia, Acinetobatter, 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 microbiologic efficacy of aztreonam is comparable to standard therapy with these agents. Cefamandole (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 infection.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 superinfection in patients treated with aztreonam were most commonly caused by Enterobacteriaceae (i.e., E. coli, Klebsiella species, and Citrobacter species). I? aeruginosa was the most common cause of treatment failure among patients treated with cefamandole. Aztreonam also has been shown to be as effective as cefotaxime19 and cefuroxime55 in hospitalized 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 urologic patients with complicated and/or nosocomial urinary tract infections.lg The initial infecting pathogens were eradicated in all patients in the aztreonam group and in 19 of 20 cefotaxime patients; complete cures were attained 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 occurred 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 microbiologic cures (70 % versus 73 % ) as cefuroxime (1.5 g three times daily) .55 Aztreonam has been compared with aminoglycoside therapy and is as effective as gentamicin, 56,57tobramycin,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 gentamicin in 52 hospitalized patients with serious urinary tract infections. Most patients achieved

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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 limited to injection-site phlebitis (1 patient), bad taste (1)) Candida vaginitis (1)) and asymptomatic hepatic function test abnormalities (7), but 4 patients in the gentamicin group experienced significantly elevated serum creatinine concentrations (p = 0.009). Enterococcal superinfection 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 moderately susceptible to gentamicin were sensitive to aztreonam. Prostatitis Aztreonam penetrates into prostate tissue1*s21 and has been shown to be effective in the treatment 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

P aeruginosa infection is common in patients with complicated urinary tract infections, especially in those who have received multiple courses of antibiotics. In the series by COX,~O unqualified cure (i.e., without relapse or superinfection) 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 superinfections 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 intramuscularly 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 bacteremia) or those caused by less susceptible organisms (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 adjustment; however, dosage adjustments are needed in patients with renal impairment. Aztreonam clearance correlates directly with adjusted creatinine clearance. This observation, together with the pharmacokinetic changes associated with renal dysfunction, form the basis for dosage adjustment in patients with systemic disease. Patients with normal renal 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 appropriate 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 after the administration of an initial loading dose of 1 g or 2 g.e2 Anephric or hemodialysis patients should receive an initial loading dose of 0.5 g or 1 g followed by maintenance doses administered after dialysis that are 25 percent of the loading dose. Old age alone is not cause for dosage adjustment. However, renal function as

Aztreonam has been evaluated in the treatment of urinary tract infections caused by organisms that are resistant to multiple antibiotics.53,s0 In one study, 135 patients with urinary tract infections that were complicated by multidrug-resistance and obstruction, genitourinary 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 resistance on disk diffusion to ampicillin and firstand 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 percent of patients in the 1 g three-times-daily and the 0.5 g twice-daily groups, respectively.e0

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TABLE IV.

Adverse effects of axtreonam therapy*

Effect Incidence 1.3 0.2 0.2 0.1 1.0 0.6 0.2 0.3 0.1 1.9 0.2 0.1 0.2 0.07 0.04 0.09 0.4

Adverse

( %)

Dermatologic (1.8 % ) Rash Rash with eosinophilia Pruritus Purpura Gastrointestinal (2.2%) Diarrhea Nausea/vomiting Taste alteration Clostridium difficile colitis Jaundice/hepatitis Thrombophlebitis Central nervous system (0.5 %) Headache Dizziness Other Miscellaneous Drug fever Hypersensitivity Bleeding Other
*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 populations49,63,64 and in patients with urinary tract infectionP has been extensively reviewed. Adverse reactions occur in 7 percent of patients and are serious enough to require discontinuation of therapy in 2 percent of patients.e4 A review of pooled findings from published studies and data from the manufacturer in over 4,500 adults83 reveals a low incidence of adverse effects (Table IV). Rash, which occurred in less than 2 percent of patients, was the most commonly 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 Nmethylthiotetrazole group and does not alter the anaerobic bowel flora; therefore bleeding diatheses do not occur during therapy. The spectrum of laboratory abnormalities associated with aztreonam therapy is similar to therapy with cefamandole and the aminoglycosides. 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 respiratory tract infections were evaluated for marked deviations in serum creatinine concentrations. Marked deviations in serum creatinine concentrations 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. Aminoglycoside therapy was associated with markedly elevated serum creatinine in 9 percent of 121 patients, 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 patients 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 insufficiency,ea including the elderly.49 Sion and colleagues 66 treated 39 patients (25 with chronic and 14 with acute renal failure) with a variety of gram-negative infections (22 urinary tract infections) with aztreonam. Adverse effects were limited to transient elevations in serum transaminases (4 patients) and intramuscular injection-site reactions (5 patients). Renal function improved in this population as demonstrated by mean reductions in serum creatinine concentrations 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 uncommon. Aztreonam therapy was associated with three-fold increases in hepatic transaminases 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 percent 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

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discontinuation of aztreonam therapy because of adverse effects or laboratory test abnormalities 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 reviews of clinical experience in the general population8~51~67-0e and studies designed to assess its immunogenic potential in penicillin-allergic individuals70-74 indicate that aztreonam therapy presents minimal risk of hypersensitivity reactions. Fewer than 1 percent of persons with documented allergy to penicillins and cephalosporins exhibited possible hypersensitivity reactions 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 suggests that aztreonam may be safely administered to patients who are allergic to penicillin On and the cephalosporins . Summary Extensive clinical experience supports the use of aztreonam in the treatment of serious urinary tract infections. This monobactam possesses 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 minimum inhibitory concentrations of most gramnegative 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-negative urinary tract infections have demonstrated that monotherapy with aztreonam is as effective as cephalosporins and aminoglycosides. Aztreonam is remarkably well tolerated. The most commonly reported adverse reactions are rash and diarrhea, which are mild, fully reversible, 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 Infection

Urologic uses of aztreonam Empiric Monotherapy Combination Therapy

Acute cystitis (gramnegative bacilli in compromised hosts) Acute prostatitis Young patient Elderly patient Acute epididymitis Young patient Elderly patient Acute pyelonephritis Urosepsis Postinstrumentation

+ + +

NA NA Add ampicillin if enterococci present Add doxycycline for Chlamydia NA NA

+ +* +

+ * 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. aeruginosa is a common pathogen in these settings. Specific P 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 indicates the presence of a gram-negative pathogen. However, when gram-positive organisms (e.g., enterococci) are present, an antibiotic that covers these organisms should be used instead or added to the therapeutic regimen (Table V).
Infectious Disease Division Winthrop-University Hospital Mineola, New York 11501 References
1. Platt R: Diagnosis and empiric therapy of urinary tract infection in the seriously ill patient, Rev Infect Dis (Suppl 1) 5: S65 (1983). 2. Bryan CS, and Reynolds KL: Hospital-acquired bacteremic urinary tract infection: epidemiology and outcome, J Urol 132: 494 (1984). 3. Bryan CS, Reynolds KL, and Brenner ER: Analysis of 1,186 episodes of gram-negative bacteremia in nonuniversity hospitals: the effects of antimicrobial therapy, Rev Infect Dis 5: 629 (1983). 4. Eisenberg JM, et al: What is the cost of nephrotoxicity associated with aminoglycosides? Ann Intern Med 107: 900 (1987). 5. Cunha BA: Aminoglycosides in urology, Urology 36: 1 (1990). 6. Imada A, et al: Sulfazecin and isosulfazecin, novel @-lactam antibiotics of bacterial origin, Nature 289: 590 (1981). 7. Sykes RB, et aE: Monocyclic S-lactam antibiotics produced

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