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Aztreonam
Aztreonam Shari L. Orlicek, MD Aztreonam is a I~-Iactam antibiotic with a monocyclic ring that is active against gram-negative aerobic bacilli. This drug has no activity against gram-positive or anaerobic organisms. Azbc,onam must be given parenterally and is excreted primarily unchanged by the kidney; therefore, the dosage must be adjusted for patients with renal failure or renal insufficiency. Adverse reactions occur in approximately 7 percent of patients and include local reactions, rash, nausea, vomiting, and diarrhea. As opposed to other I~-Iactams, aztreonam rarely cross-reacts with penicillins or cephalosporins and is weakly immunogenic in humans. Consequently, aztreonam is an excellent agent for usa in patients with gram-negative infections and penicillin or cephalospodn allergy. Because azlxeonam has the same spectrum of activity as aminoglycosides and is not nephrotoxic, the drug is used in patients with gram-negative infections and renal insufficiency.
Copyright9 1999by W.B. Saunders Company
he discover), of bacterially produced [3-1actam antimicrobials was made in 1981 by two independent teams of investigators: Imada et ala and the Squibb Institute. 2 The group from the Squibb Institute used a unique screening procedure to identi~" several monocyclic [3-1actam antibiotics from various soil bacteria, including Gluconobacter,Acetobacter. Pseudomonas, Chromobacterium, Flexibacter, and Agrobactehum.2 They coined the term monobactam derived from monoeyclic, bacterial b" produced, [3-1actam.2 Although monobactams occur naturalb, , the one currently licensed for clinical use is aztreonam, which is completeb, ~'nt hetic.
T
Chemistry The naturally occurring monobactams have relatively poor antimicrobial activity. Structural modifications of these compounds to improve their biologic activity led to the development of aztreonam (Fig 1). In contrast to the bicyclic [3-1actam nucleus present in penicillins and cephalosporins, aztreonam has an aminomonobactamic acid core with a sulfonic acid group at position 1 that activates the [3-1actam carbonyl group.3'~ At position 4, an e~-methyl group provides stability of the ring against hydrolysis by [3-1actamases. An aminothiazolyl oxime group at position 3 imparts activity against gram-negative bacteria. The carbox)4ic acid moiet-/and the methyl groups present on the oxime side chain provide enhanced activity against Pseudomonas species. These structural modifications result in complete loss of activity of aztreonam for gram-positive organisms and anaerobes.4
Mechanism of Action Aztreonam readily passes through the outer membrane of gramnegative organisms and is a bactericidal agent. The drug interferes with bacterial cell wall synthesis by binding preferentialb- to penicillinbinding protein-3, which is the septum peptidoglycan transpeptidase for Enterobacteriaceae, Pseudornonas, and other gram-negative aerobic bacilli)
From the Division oflnfectious Diseases,Department ofPediatrics, Wake Forest University School ofMedicine, Winston-Salem, NC. Address correspondence to Shari L. Orlicek, MD, Department of Pediatrics, Wake Forest University School ofMedicine, Medical CenterBh,d, HS'nston-Salem, NC 2715Z Copyright 9 1999 by W.B. Saunders Cornpany 1045-1870/99/1001-0006510.00/0
As a result of binding, aztreonam causes formation of elongated or filamentous structures that undergo h~is and cell death. 5 Because aztreonam binds poorly to essential penicillin-binding proteins of grampositive and anaerobic bacteria, the drug is inactive against these t2,pes of organisms. The structure of aztreonam is a poor substrate for binding [3-1actamases. Therefore, the drug is not hydrol)xed readily by most plasmid-mediated (TEM-I, TEM-2, and SHV-I) and chromosomally mediated [3-1actamases with the following exceptions: the RichmondSykes %pe IV enzyme (K-l) produced by some strains ofKlebsiella o.Ftoca and cefotaxime-ceftazidime hydrobxing plasmid enzymes, which include TEM-3, TEM-5, TEM-7, and SHV-2. 6~
Spectrum of Activity Susceptibility testing for aztreonam is performed by either disk diffusion or tube dilution studies. Recommended interpretive breakpoints for susceptibili~" testing are -<15 mm for resistance (minimal inhibitor5" concentration [MIC] >32 /xg/mL), 16 to 21 mm for intermediate susceptibility (MIC = 16/~g/mL), and >22 mm for susceptibility (MIC ~8/zg/mL). 6 Aztreonam has a broad spectrum of acti,Aty for gramnegative organisms. Most of the members of the family of Enterobacteriaceae (including Eschaichia coil, Proteus miraNTis, Citrobacterdiversus, KlebsieUa species, and Salmonella species) are highly susceptible with an MICg0 ~<0.5/.Lg/ml.9 However, in a recent study evaluating nosocomial isolates of gram-negative organisms obtained from a tertian" care facility, only 70 percent of Enterobacter species were sensitive, l~ Aztreonam exhibits excellent in ~'itro activity against nonenteric bacteria, such as [3-1actamase-positive and -negative Haemophilus influenzae, Moraxella catarrhalis, Pasteurella multocida. Aeromonas hydrophilia, Plesiomonas shzgelloides, and Noi~seria species. Stenotrophomonas maltophilia, Acinetobacter, Arhromobacter, andAlcaligenes species are usually resistant.6"7"9AJ,t2Aztreonarn is moderately active against Pseudomonas aeruginosa, with approximately 89 percent of isolates reported to be sensitive, but activity against other Pseudomonas species is considerably less.9 A trend for the development of resistance to aztreonam by Pseudomonas species exists.9 Synergistic acti,Aty ~ith aminoglycosides in muhidrug-resistant P aeruginosa strains has been demonstrated. 13 Aztreonam has no actinic" against gram-positive organisms. The drug also lacks activity against gram-negative anaerobes, including Bacteroidesj~agilis and Closthdiurn species. Chlamydia species and Legiondla species uniformly are resistant.
Seminars in Pediatric Infectious Diseases, Vo110, Ab 1 (Januao'), 1999:pp 45-50
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46
Shari L. Orlicek
Table 1. D o s i n g Guidelines for A z t r e o n a m in Adults, Children, and Infants ,
......... ,.o,,o.
"-o
Patient Age
o;____"
CH~ I -c%.
c, l
I
Figure 1.
Structure-activity relationships in t h e a z t r e o n a m molecule. R e p r i n t e d f r o m A m e r i c a n J o u r n a l of Medicine, Vol 78, Sykes RB, B a n n e r DP, A z t r e o n a m : T h e first m o n o b a c t a m , pp 2-10, C o p y r i g h t 1985, with p e r m i s s i o n f r o m E x c e r p t a M e d i c a Inc. 3)
Clinical Pharmacokinetics Aztreonam is not absorbed from the gastrointestinal tract. After a single 0.5-g oral dose, systemic bioavailabifity is less than 1 percent, and peak serum levels are 0.15 /xg/mL for oral solution and 0.14/xg/mL for capsules. 14 Furthermore, fecal flora can synthesize [Mactamases that convert aztreonam into its biologically inactive open ring form, leaving intestinal flora essentially unchanged after oral administration of the drug. 15 Bioavailability of aztreonam approaches nearly 100 percent after intramuscular administration, with peak serum concentrations achieved within 1 hour after the dose. After a single intramuscular dose of 0.25 g, 0.5 g, and 1.0 g, the mean peak serum levels 1 hour later were 12, 22, and 46/xg/mL, respectively, t6 Not only were peak levels high after intramuscular administration, but serum levels were sustained. For instance, after a 0.5-g intramuscular dose of aztreonam, mean serum concentrations were 22/xg/mL at 1 hour, 3.8/xg/mL at 6 hours, 1.7/.*g/mL at 8 hours, and 0.3 /xg/mL at 12 hours. 16 Drug levels 1 hour after an intramuscular dose are the same as those 1 hour after an intravenous dose. The highest serum levels are attained after intravenous administration of aztreonam; mean peak serum levels immediately after a 0.5-, 1.0-, or 2.0-g intravenous dose were 58, 125, or 242/xg/mL, respectively. 16 Multiple-dose studies ofaztreonam show no evidence of drug accumulation with doses up to 1.0 g given every 8 hours either intravenously or intramuscularly. 17 The mean serum half-life of aztreonam is 1.6 hours in normal healthy adults, and the volume of distribution at steady state is 0.21 L/kg, approximating total extracellular water. 17 Protein binding in adults with normal serum albumin levels averages 56 percentJ 7 Aztreonam is distributed to nearly all tissues and body fluids, including gallbladder, fiver, synovial fluid, bone, prostate, heart, and skeletal muscle. Concentrations of aztreonam in some tissues and fluids, including lung, bile, and peritoneal fluid, are nearly equivalent to serum levels. 18 The concentration of aztreonam that penetrates into the cerebrospinal fluid (CSF) is fourfold higher if the meninges are inflamed, as compared with concentrations of drug achieved in the CSF in the presence of uninflamed meninges. 19 After a 2.0-g intravenous dose of aztreonam to persons with meningitis, the mean CSF concentrations 1 and 4 hours postadministration were approximately 2 and 3 /~g/mL, respectively. The main method of elimination is through the kidney. Glomerular filtration and tubular secretion play equally important roles. No active metabolites have been found in the serum or urine. Approximately 68 percent of an administered dose is excreted as unchanged drug in the urine and 1 to 7 percent as the inactive open ring metabofite. 16 Mean urine concentrations after parenteral administration are 10 to 100 times higher than the respective mean serum concentrations. Dosing of aztreonam in adult patients (Table 1) usually is between 1
Adults Serious infection U s u a l dose Children Serious infection U s u a l dose Infants < 1 wk 1-4 wk > 4 wk
Dose
Interval (h)
2g 1g
6 6-12
50 m g / k g / d o s e 30 m g / k g / d o s e
6 6-8
30 m g / k g / d o s e 30 m g / k g / d o s e 30 m g / k g / d o s e
12 8 6-8
and 2 g every 6 to 8 hours, depending on the type and severity of the infection being treated. In adults with normal renal function, the elimination half-life averages 2.0 hours, with a range from 1.3 to 2.2 hours. In adults with renal impairment, the elimination half-fife increases and the serum concentrations are higher, z~ Therefore, in patients with renal dysfunction, the dose of aztreonam should be given at regular intervals, but the dose should be decreased. For anephric patients, 25 percent of the standard dose is recommended; for patients with a creatinine clearance of 30 mL/min, 50 percent of the standard dose is recommended; and for patients with a creatinine clearance of 60 mL/min, 75 percent of the standard dose is recommended, z~ The half-fife of aztreonam is prolonged minimally in adults with hepatic dysfunction, and no dosage adjustment is required. Aztreonam is partially removed by hemodialysis, with approximately 25 to 50 percent removed in a 4-hour session. In peritoneal dialysis, only approximately 10 percent ofa 1.0-g dose is removed in a 6-hour dwell time. 21 The pharmacokinetics of aztreonam in children are similar to those described in adults (Table 2). Mean peak serum concentrations in children 2 to 12 years of age receiving aztreonam doses of 30 mg/kg and 50 mg/kg are 96.9/zg/mL and 214/zg/mL and 6-hour serum levels are 4.9 /xg/mL and 12.8/zg/mL, respectively.22,23 In low-birth-weight infants, peak serum concentrations after a dose of 30 mg/kg are 65/xg/mL to 83 ~g/ml. 24 These lower levels most likely are caused by the increased extracellular fluid volume in the low-birth-weight infants. The elimination half-fife of aztreonam in children 1 month to 12 years of age is equivalent to that in the adult; however, in newborn infants, the elimination half-fife increases to 2.5 hours,24and in low-birthweight infants, it is between 4 and 5.3 hours.25 The serum clearance of aztreonam varies with age. In children older than 2 years, the mean serum clearance is 2.5 mI./min/kg. In younger children and neonates, the serum clearance decreases with age and birth weight from 1.87 mL/min/kg22 to 1.52 mL/min/kg.25 These parameters are consistent with the physiological reduction of renal function seen in low-birthT a b l e 2. P h a r m a c o k i n e t i c P a r a m e t e r s of A z t r e o n a m in A d u l t s and Children
Parameter Dose a d m i n i s t e r e d (intravenously) S e r u m peak c o n c e n t r a t i o n (mean,/xg/mL) U r i n e c o n c e n t r a t i o n (0-3 h, /xg/mL) V o l u m e of distribution (L/kg) E l i m i n a t i o n half-life (h) S e r u m clearance ( m L / min/kg)
Adult
Child
Infant
1.0 g
30 m g / k g
30 m g / k g
125
96.9
118.7
3,000 0.21 1.6
3,727 0.29 1.7
1,414 0.20 1.7
1.7
2.50
1.87
47
Aztreonam weight infants.2~ The volume of distribution increases with decreasing age and is highest in low-birth-weight infants (0.64 to 1.01 L/kg), which corresponds to the high extracellular fluid volume in preterm infants/~ The concentration of aztreonam in the CSF of infants and children with meningitis has been evaluated/2 After a single dose of 30 mg/kg aztreonam intravenously, CSF levels ranged from 2.1 to 20.8 ~g/mL between 1 and 3 hours postinfusion. The mean CSF-to-serum ratio for aztreonam concentration was 17.3 percent. These CSF levels were comparable to those found in adults with inflamed meninges after a 2.0-g dose of intravenous aztreonam.19 Mean urinaq" concentrations of aztreonam in children over age 2 )'ears are equivalent to those found in adults, and levels decrease with age. The peak urinary concentrations for low-birth-~s'eight infants ranged between 246 and 2,141/.~g/mL. In all children and neonates, aztreonam levels in the urine remained above potential therapeutic levels for 18 to 24 hours after infusion ofa 30-mg/kg dose.22 In general, dosing of aztreonam in children (Table l) is 30 mg/kg given every 6 to 8 hours. However, for more serious infections, such as meningitis, dosages up to 50 mg/kg every- 6 hours have been used to ensure adequate levels of drug in the CSF. The dose of aztreonam and interval between dosages should be adjusted for infants (Table 1).
Adverse Reactions Aztreonam is a relatively well-tolerated drug with a safeq" profile similar to those of other [3-1actams. In a study including 3,360 patients who received multiple dosages of aztreonam, 209 (6.2%) patients experienced an adverse drug reaction. 26 The most common side effect reported was a local reaction, including phlebitis and thrombophlebitis, at the injection site (2.6%). Other more common adverse drug reactions included rash (1.8%), nausea or vomiting (0.6%), and diarrhea (0.8%). More serious adverse reactions included CIostridium difficile diarrhea in five patients and culture-negative pseudomembranous colitis in one patient. All six (0.2%) of these patients had other potentially confounding factors for C d/ff/c//e disease. The incidence of abnormal laboratory results associated with aztreonam administration also is low. Studies in children found a mild elevation in liver function tests in approximately 11 percent, with a return to normal levels on discontinuation of the drug. 27 These data are consistent with those in adults. Aztreonam is reported to have no effect on either the prothrombin time or the partial thromboplastin time and does not appear to alter platelet function/8 The incidence of bleeding problems in patients receiving aztreonam is less than 0.1 percent. 26 Because the spectrum of activity of aztreonam mirrors that of the aminoglycosides, comparison of the nephrotoxicity of these drugs is important. In aminoglycoside-controlled trials, the serum creatinine of patients on aztreonam decreased over the course of theral~" and increased slightly in patients who received aminoglycosides.~ In approximately 4,500 patients studied in controlled trials, azotemia related to aztreonam developed in no patients, but azotemia developed in five patients treated with aminoglycoside.27 Therefore, aztreonam is considered a useful alternative for aminoglycosides in patients, particularly when concern of nephrotoxicity is present. Because aztreonam contains a [3-1actam ring, the potential for immunologic cross-reactivity exists in patients allergic to penicillins and cephalosporins. Adkinson et al 3~ identified the side chain of aztreonam to be immunogenic compared with the [3-1actam core, which is immunogenic in the penicillins-cephalosporins, thus explaining the very" low immunologic cross-reactivity between aztreonam and the bi~'clic [3-1acta m s ) ~ Forty--one penicillin-allergic patients with positive reactions for IgE antibody to penicillin did not have cross-reactivi~" to aztreonam. Furthermore, when tested at a later date, reactivity to aztreonam reagents developed in none of these patients) I In addition, aztreonam was given to patients with allergies to penicillin or cephalosporin without sign of allergic reaction. 32 Overall, aztreonam is known to have
negligible cross-reactivi~" with other [3-1actams, including penicillins and cephalosporins, and is a very weak immunogen in humans. These factors render aztreonam a reasonable agent for treatment ofpenicillinand cephalosporin-allergic patients with gram-negative infections. Another important consideration in the evaluation of the safety of aztreonam is the risk ofsuperinfection. Bendush et al26 reported the risk of superinfection during treatment with aztreonam to be 1 to 7 percent, compared with 0 to 6 percent in the control group. During treatment with aztreonam, gram-negative aerobes are reduced in the intestinal flora, but enterococci are overgrown.33 In a group of 45 patients who received aztreonam for gram-negative infections, 8 of 45 (17.8%) patients became infected with or colonized by enterocoecus.34 O f these eight patients, five (11.1%) required further treatment directed against enteroe~cus, and one of the five became bacteremic. Enterococcus is the pathogen most frequently reported to cause superinfection in patients treated with aztreonam; other organisms reported include Staphylococcus aureus. Streptococcus pneumoniae. E coil, and P aerug~nosafl7 In a stud)" of febrile neutropenic patients, the groups treated with empiric antimicrobial regiments, including ~ t r e o n a m , had preservation of anaerobic intestinal flora and a lower frequent" of fungal colonization.'3~ No evidence exists that aztreonam is ototoxic to humans. Extensive animal testing of aztreonam has shown no evidence of mutagenicity or teratogenicity. -r Aztreonam does not compete with bilirubin for binding to human serum albumin and does not displace bilirubin bound to albumin, which is important in considering the use of aztreonam in neonates? 7
Major Clinical Uses Aztreonam has been shown to be an effective agent in the treatment of minor and serious gram-negative infections in adults and children. However, if a gram-positive or anaerobic infection is suspected, other agents should be used in combination with aztreonam to ensure appropriate coverage. Aztreonam has been reported to treat successfully various types of infections, including (but not limited to) urinary tract infections, respirator" tract infections, sepsis, meningitis, bone and joint infections, and pelvic or abdominal infections.
Urinary Tract Infections The efficaQ" of aztreonam for the treatment of complicated and uncomplicated urinal" tract infections has been studied at length in adults and children. Swabb et al :~8have summarized the adult studies. In 681 adult patients with urinal" tract infection caused by susceptible gram-negative bacilli. 56 received a single 1.0-g intramuscular dose of aztreonam for acute uncomplicated c)'stitis and 62.5 patients received multiple parenteral dosages of aztreonam for various t)pes of urinal" tract infections. Microbiological cure was reported in 84 percent of the patients in the single-dose stud)" and in 85 percent of the patients in the multiple-dose stu~'. The most common etiologic agent wasEcoli (44%); other pathogens included Klebsiel/apneumoniae, Enterobacter species, Proteus miraln'lis, and P aeruginosa. Several studies have indicated that aztreonam is effective in treating of urina D" tract infections in children. In a stud)" to evaluate the safety and efficaQ" of aztreonam in gram-negative infections in children, 13 infants and children were treated with 30 mg/kg aztreonam every 6 hours for urinary" tract infections}~9Six of these patients had pyelonephritis. The pathogens isolated were E coli (n = 11) and K pneumoniae (n = 2), and all isolates were sensitive to aztreonam. Clinical and microbiological cures were achieved in all 13 patients. Similar results were reported by Stutman et al40 in a study that used aztreonam to treat 20 infants and children who were diagnosed with pyelonephritis (n = 19) or Q'stitis (n = I). "mSeven of the children had underlying structural anomalies. The most common organism isolated was Ecoli (16 isolates), with one isolate each ofKpneumoniae, Morganella
48
Shari L. Orlicek
morganii, Paeruginosa, and Enterobacter cloacae. All isolates were sensitive to aztreonmn; most of the children were treated with 30 mg/kg aztreonam every 6 hours. Again, clinical and microbiological cures were successful in all patients. One group of investigators evaluated 30 children with "severe" urinary tract infections.41 Underlying urologic abnormalities, including hydronephrosis, vesico-ureteral reflux, and neurogenic bladder, complicated 21 of these cases. Seven patients did not respond to therapy for the current urinary tract infection with other antibiotics, including aminoglycosides and cephalosporins. Etiologic agents were members of the family of Enterobacteriaceae (25 isolates) or P aeruginosa (five isolates). Three of the P aeruginosa isolates were intermediate sensitive to aztreonam, and one of the E cloacae isolates was resistant. The mean dose used for therapy was 47 mg/kg every 12 hours; four patients required dosage adjustment because of renal failure. Overall, 22 of the 30 (73%) patients had a permanent microbiological cure. The majority of urinary tract infections in children are caused by gram-negative bacilli, which are covered by the spectrum of activity of aztreonam. The high concentrations of active drug excreted in the urine and the safety profile, along with the results of clinical trials, render aztreonam a reliable drug for the treatment of complicated and uncomplicated urinary tract infections in infants, children, and adults.
Respiratory Tract Infections For the treatment of acute pulmonary" exacerbations, aztreonam has been studied in children with cystic fibrosis who are chronically colonized with P aeruginosa. In a noncomparative study consisting of 25 children and adolescents with cystic fibrosis and acute pulmonary exacerbations, all patients were treated with 50 mg/kg aztreonam every 6 hours for a minimum of 7 days; no additional gram-negative antimierobial coverage was given.42 O f the 57 isolates of P aeruginosa from pretreatment sputum cultures, 48 were susceptible to aztreonam, 10 were intermediate, and 1 was resistant. After completion of therapy, 11 of the 22 patients who were able to produce sputum were culture negative. Sputum cultures from the remaining l 1 patients grew l 1 aztreonam-susceptible strains o f P aeruginosa, three intermediate, and four resistant. Clinical improvement was scored on the first, seventh, and last day of therapy, and the scores improved significantly with treatment. In a trial comparing the efficacy of aztreonam to tobramycin and azlocillin in cystic fibrosis patients with acute pulmonary exacerbations, 15 patients were selected randomly to each treatment group. 43 The response of patients was assessed on the basis of clinical and pulmonary scores, white blood cell counts, pulmonary function studies, and quantitative bacterial cultures. The responses of all patients were favorable, and at the end of therapy no significant differences in the above-listed parameters between the two groups were noted. Patients in the aztreonam group were treated with 50 mg/kg every 6 hours. Seven of the patients in the aztreonam group previously had been treated with aztreonam. O f these seven, three had P aeruginosa isolates at the end of therapy that were resistant to aztreonana, and four patients, who had not received previous aztreonam therapy, had isolates that were resistant. This result was not significantly different from the increase in resistance that occurred in the control group. Aztreonam also has been used in cystic fibrosis patients with ~3-1actam hypersensitivity. In one report, 15 [$-lactam-allergic cystic fibrosis patients with acute pulmonary exacerbations were treated with aztreonam. ~2 Previous reactions to [Mactams included anaphylactic shock, generalized urticaria, angioneurotic edema, and drug fever reactions. All patients had a negative skin test result to aztreonam a n d P aeruginosa isolates sensitive to aztreonam. Patients were treated for 14 days with 150 mg/kg/d aztreonam and 10 to 20 mg/kg/d tobramycin. Significant improvements in pulmonary function tests were observed in all patients, and no drug reactions occurred.
Results of these studies demonstrate that aztreonam is a safe and effective therapy for acute pulmonary exacerbations in children with cystic fibrosis. Resistance can occur with treatment, but no more so than reported with other antipseudomonal antibiotics. Furthermore, in this group of patients at risk for hypersensitivity to [Mactams caused by repeated exposure, aztreonam can he a safe, effective alternative to bicyclic [Mactams.
Sepsis The use of aztreonam in the treatment of sepsis has been evaluated. One study compared aztreonam in combination with ampicillin to amikacin and ampicillin for the treatment of neonatal bacterial infections.44 A total of 147 neonates in an intensive care unit were enrolled; gram-negative infections developed in 60 patients, and 28 patients were evaluated in the aztreonam group and 32 in the amikacin group. The bacteria isolated included P aeruginosa, K pneumoniae, E cull, and Serratia marcescens. In the aztreonam group, only 2 of 28 patients did not respond to therapy, compared with 9 of 32 patients in the amikacin group. Treatment failures were significantly higher in the amikacin group. Group B streptococcus, E cull, and Listeria monocytogenes are the primary infections seen in neonates. Gram-negative infections, such as those isolated in this study, are more often nosocomially acquired infections. One-third of the patients in this stud?," had nosocomially acquired infections.44 Aztreonam can be used successfully to treat neonatal gram-negative sepsis and does not have the risks of ototoxicity and nephrotoxicity that are associated with aminoglycosides. These risks are of concern in neonates in intensive care settings who are repeatedly exposed to antibiotics.
Meningitis Aztreonan~ has been studied as a potential therapy for gram-negative meningitis. In a large multinational study, 77 patients with cultureconfirmed gram-negative meningitis were treated with aztreonam. 45 Adults received 1 to 2 g, children received 50 mg/kg, and infants received 30 mg/kg; all dosages were given three to four times a day. The predominant organisms were Hinfluenzae (n = 40), Neisseria meningitidis (n = 15), P acruginosa (n = 5), S marcescens (n = 3),Kpneumoniae (n = 3), and Salmonella species (n = 4). Microbiological cure was documented in 71 (92%) patients, and clinical cure was achieved in 66 (86%) patients. Microbiological failures occurred in four patients. Two of these patients were children with Salmonella species who had CSF cultures positive 48 hours into aztreonam therapy. Another infant had Proteus vulgaris intracerebral abscesses, and the fourth patient was an adult with S marcescens meningitis and an intraventricular hemorrhage. Several other studies also have evaluated the efficacy of aztreonam monotherapy for gram-negative meningitis in children.4648The predominant organism in these studies was H inJluenzae Type b (Hib), and microbiological cure was similar to that reported in the previous study. From these studies, aztreonam has proven to be effective therapy for gram-negative meningitis in children and adults. However, with the dechne in Hib disease in children over the past decade, the number of children with gram-negative meningitis has sharply declined. Because the drug is capable of achieving adequate levels in the CSF, aztreonam is an appropriate drug for use in cases of gram-negative meningitis when the organism is known to be susceptible.
Bone and Joint Infections Bone and joint infections caused by gram-negative organisms have responded favorably to therapy with aztreonam. Simons and Lee 49 reported that 17 patients 12 to 70 years of age with either osteomyelitis (n : 11) or septic arthritis (n = 6) were treated successfully with aztreonam. Organisms included P aeruginosa, S mareescens, Enterobacter species, Citrobacterdiversus, a n d P mirabilis. The dosage ofaztreonam was 2 g every 6 to 12 hours, and duration of treatment was 14 to 55 days. All
Aztreonam patients achieved clinical and microbiological cure. In patients with coexisting gram-positive infections, additional appropriate antibiotics were used. The majority of cases of osteomyelitis-septic arthritis in children are caused by S aureus; this should be considered when initiating empiric thera W in children with orthopedic infections. However, for known gram-negative orthopedic infections, aztreonam should be considered an alternative to aminoglycosides for prolonged therapy, as well as an alternative to third-generation cephalosporins in the allergic patient.
Pelvic and Abdominal Infections Aztreonam in combination with clindamycin was compared with gentamicin and clindamycin for use in gynecologic infections, including pelvic inflammato~, disease and endometritis) ~ Fir%" patients were in the aztreonam group, and 38 were in the gentamicin group. The pathogens most commonly isolated were E coli, K pneumoniae, and P mirabilis. Microbiological cure was achieved in 98 percent of the aztreonamclindamycin group, compared with 95 percent in the gentamicinclindamvcin group, Favorable clinical response occurred in 98 and 89 percent, respectively. Aztreonam provides excellent gram-negative coverage in gynecologic infections, but other agents must be added for coverage of gram-positive and anaerobic organisms. For patients with pelvic inflammatory disease, coverage for Chlam)'dia trachomati~ also must be considered because aztreonam has no activity against this organism. The other ~necologic use of aztreonam is for uncomplicated gonococcal cervicitis and urethritis. In a randomized trial that compared a single intramuscular injection of 1 g aztreonam to 2,4 million units intramuscular procaine penicillin plus 1 g oral probenecid, 2% patients with uncomplicated gonococcal cervicitis were enrolled? I O f the 116 patients treated with aztreonam, 101 patients were seen at a 1-week follow-up and had bacteriologic tests of cure. In the aztreonam group, the success rate was 100 percent, compared with 89 percent in the penicillin group. In the group treated with aztreonam, I l of the N gonorr~a isolates were penicillinase-proclucing strains. Aztreonam is a suitable drug for the treatment of uncomplicated gonococcal infections, especially in cephalosporin-allergic patients. As with pelvic infections, aztreonam and clindamycin have been studied for efficacy in intra-abdominal infections) ~Thirty-eight patients were treated with aztreonam and clindarnycin, whereas 42 patients received thera W with imipenem-cilastatin. Therapy was successful in 64 percent of the patients in the aztreonam group and 71 percent of the patients in the imipenem-cilastatin group. The predominant organisms isolated were E coli and Bacteroides fiagilis. Overall, both regimens reasonably were effective in the treatment of intra-abdominal infections. Aztreonam provides excellent coverage for gram-negative aerobic infections. Because the drug is able to achieve good levels in most tissues and body fluids, including CSF, aztreonam is a good agent for a varie~" of infections, ff concern of gram-positive or anaerobic infection exists, aztreonam can be used safely in combination with a variety of antimicrobial drugs. The drug primarily is used as an alternative to aminoglycosides in patients for whom nephrotoxicity is a concern and in place of third-generation cephalosporins in patients who are allergic to [3-1actam.
References 1. Imada A, Kitano K, Kintako K, et al: Sulfazecin and isosulfazecin, novel ~3-1actamantibiotics of bacterial origin. Nature 289:590-591, 198 I 2. Sykes RB, Cimarustiu CM, Bonner DP, et al: Monoc>'clic[~lactam antibiotics produced by bacteria. Nature 291:489-491,1981 3. Sykes RB, Bonner DP: Aztreonam: The first monobactam..AmJ bled 78:2-10, 1985 (suppl A) 4. Neu HC: Structure actix4ty relations of new beta-lactam compounds and in vitro activit2:- against common bacteria. Rev Infect Dis 5:319-336, 1983 (suppl 2)
49
5. Georgopapadakou NH, Smith S.~ Sykes RB: Mode of action of aztreonam. Antimicrob Agents Chemother 21:950, 1982 6. BarD .Mr ThornsberD- C, Jones RN, et al: Aztreonam: Antibacterial actix4%', ~lactamase stability, and interpretive standards and quality control guidelines for disk-diffusion susceptibility tests. Rex Infect Dis 7:$594-$604, 1985 (suppl 4) 7. Neu HC: Aztreonam activity, pharmacology, and clinical uses. Am J Med 88:2S-6,S, 1990 8. Ss'kes liB. Bonner DP, Bush K, et al: Aztreonam (SQ 26,776), a ~'nthetic monobactam specifically active against aerobic gram-negative bacteria. Antimicrob Agents Chemother 21:85-92, 1982 9. Parr:`" biF: Aztreonam susceptibility testing: A retrospective analysis. Am J bled 88:7S-1 IS, 1990 (suppl 3C) 10. Fekete T, Haitham T, Woodwell J, et al: Comparative susceptibilities of Klebsiellaspecies,Enterobacterspecies, andPseudomonasaerug~nosato 11 antimicrobial agents in a tertiary care university hospital. ?~nJ Med 100:20S-25S, 1996 (suppl 6A) 11. Fainstein V, Weaver S, Bode:,-GP: Comparative in vitro stud>"of SQ26,776. Antimicrob Agents Cheroot her 21:294-298, 1982 12. Powell hi, Williams JD: In vitro actix4ties of aztreonam, imipenem, and amoxicillin-clarulanate against ampicillin-resistant Haemophiluz influenzae. Antimicrob.~cdents Chemother 31:1871-1873, 1987 13. Giamarellou H, Zissis NP, Tagari G, et al: In xitro ~'nergistic activities of aminogl>~:osidesand new 13-1actamsagainst multiresistant Pseudomonasaeruginosa..~timicrob Agents Chemother 25:534-536, 1984 14. Swabb E.~ Sugerman AA, Stern hi: Oral bioa~ailability of the monobactam aztreonam (SQ 26,776) in healthy subjects. Antimicrob Agents Chemother 23:548-550, 1983 15. Welling GW. Groen G, Welling-Wester S, et ah Enzymatic inactivation of aztreonam by faecal enz~vne preparations from health:`-~vlunteers. Infection 15:188-191, 1987 16. Swabb EA, Sugerman ..~, Platt TB, et al: Single-dose pharmacokinetics of the monobactam aztreonam (SQ 26,776) in healthy subjects. Antimicrob Agents Chemot her 21:944-949, 1982 17. Sx~zabbF,-~,Sugerman . ~ blckinstry DN: bluhiple-dose pharmacokinetics of the monohactam azthreonam (SQ 26,776) in health>" subjects. Antimicrob .~ents Chemother 23:125-132, 1983 18. Swabb EA: Review of the clinical pharmacology of the monobactam antibiotic azt reonam..~nJ bled 78:11-18, 1985 19. Duma RJ, BerD" AJ, Smith Sbl, et ah Penetration of aztreonam into cerebrospinal fluid of patients ~ t h and without inflamed meninges. Antimicrob Agents Chemother 26:730-733, 1984 20. blihinduJC, Scheld WM, B~lton N'D,et al: Pharmacokinetics of aztreonam in patients x~4th various degrees of renal d>~function. Antimicrob Agents Chemother 24:252-261, 1983 21. GerigJS, Bolton N-D,Swabb EA, et al: Effects of hemodialysis and peritoneal dial>sis on azt reonam pharmacokinetics. Kidney Int 26:308-318, 1984 22. Stutman HR. Marks MI, Swabb F,.k: Single-dose pharmacokinetics of aztreoham in pedit tic patients. Antimicrob ,~gents Chemother 26:196-199, 1984 23. Stotman HR. blarks biI: Pharmacokinteics of two dosages of aztreonam in children. Clin Res 34:25 IA, 1986 (abstr) 24. Likimukul S, McCracken GHJ, Threlkeld N, et al: Pharmacokinetics and plasma bactericidal activity of aztreonam in low-birth-weight infants. Antimicrob Agent s Chemother 31:81-83, 1987 25. Cuzzolin L, Fanos V, Zambreri D, et al: Pbarmacokinetics and renal tolerance of aztreonam in premature infants. Antimicrob Agents Chemother 35:17261728, 1991 26. Bendush CB. Henu' SA, Newman TJ, et al: Aztreonam: World'aide clinical experience ~dth the first monobactam. N~]bled Special Issue: 30-36, 1986 27. Chartrand SA: Safety and toxicity profile of aztreonam. Pediatr Infect DisJ 8:S 120~S123, 1989 28. Tartaglione TA, Duma RJ, Qureshi GD: In vitro and in vivo studies of the effect ofaztreonam on platelet function and coagulation in normal volunteers. Antimicrob Agents Chemother 30:73-77, 1986 29. Newman TJ, Dreslinski GR, Tadros SS: Safe%"profile of aztreonam in clinical trials. Rex Infec Dis 7:$648~$655, 1985 (suppl 4) 31). Adkinson NF. Swabb E.& Sugerman AA: Immunolo~- of the monobactam aztreonam. Antimicrob Agents Chemot her 25:93-97, 1984 31. Saxon A, Swabh E.~ Adkinson NT: Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactams. Am J bled 78:1%26, 1985 (sup# Z~)
50
Shari L. Orlicek
32. Jensen T, Koch C, Piedersen SS, et al: Aztreonam for cystic fibrosis patients with hypersensitivity to other beta-lactams. Lancet 1319-1320, 1987 33. Giuliano M, Jacobus NV, Gorbach SL: Effect of broad-spectrum parenteral antibiotics on composition of intestinal microflora of humans. Antimicrob Agents Chemother 3 h202-206, 1987 34. Chandrasekar PH, Smith BR, LeFrockJL, et al: Enterococcal superinfection and colonization with aztreonam therapy. Antimicrob Agents Chemother 26:280-282, 1984 35. Louie TJ, Chubb H, Bow EJ, et al: Preservation of colonization resistance parameters during empiric therapy with aztreonam in the febrile neutropenic patient. Rev Infect Dis 7:$747-$761, 1985 (suppl 4) 36. Kiem GR, Sibley PL, Hines FA, et al: Parenteral toxicological profile of the monocyclic beta-lactam antibiotic SQ 26,776 in mice, rats and dogs. J Antimicrob Chemother 8:141, 1981 (suppl E) 37. Stutman HR, Parker KM, Marks MI: Potential of moxalactam and other new antimicrobial agents for bilirubin-albumin displacement in neonates. Pediatrics 75:294-298, 1985 38. Swabb EA, Jenkins SA, Muir JG: Summary of worldwide clinical trials of aztreonam in patients with urinary tract infections. Rev Infect Dis 7:$772$777, 1985 (suppl 4) 39. Kline MW, Kaplan SL, Mason EO: Aztreonam therapy of gram-negative infections predominantly of the urinary tract in children. Curr Ther Res 39:625-631, 1986 40. Stutman HR, Chartrand SA, Tolentino T, et al: Aztreonam therapy for serious gram-negative infections in children. A m J Dis Child 140:1147-1151, 1986 41. Rusconi F, Assael BM, Boccazzi A, et al: Aztreonam in the treatment of severe urinary tract infections in pediatric patients. Antimicrob Agents Chemother 30:310-314, 1986
42. Bosso JA, Black PG, Matsen JM: Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis. Pediatr Infect DisJ 6:393-397, 1987 43. BossoJA, Black PG: Controlled trial ofaztreonam vs. tobrarnycin and azlocillin for acute pulmonary exacerbations of cystic fibrosis. Pediatr Infect Dis J 7:171-176, 1988 44. Umana ~ Odio CM, Castro E, et al: Evaluation ofaztreonam and ampicillin vs. amikacin and ampicillin for treatment of neonatal bacterial infections, Pediatr Infect DisJ 9:175-180, 1990 45. Lentnek AL, Williams RR: Aztreonam in the treatment of gram-negative bacterial meningitis. Rev Infect Dis 13:$586-$590, 1991 (suppl 7) 46. Ayroza-GalvaoPA, Milstein-KuschnaroffTM, Mimica IM, et al: Aztreonam in the treatment of bacterial meningitis. Chemotherapy 35:39-44, 1989 (suppl 1) 47. Feris J, Moledina WJ, Rodriguez WJ, et al: Aztreonam in the treatment of gram-negative meningitis and other gTam-negative infections. Chemotherapy 35:38, 1989 (suppl 1) 48. Girgis NI, Abu El Ella AH, Farid A, et al: Parenteral aztreonam in the treatment of Haanophilusinfluenzaetype b meningitis in Egyptian children. ScandJ Infect Dis 20:111-112, 1988 49. Simons WJ, Lee TJ: Aztreonam in the treatment of bone and joint infections caused by gram-negative bacilli. Rev Infect Dis 7:$783-$788, 1985 (suppl 4) 50. Henry SA: Overall clinical experience with aztreonam in the treatment of obstetric-gynecologicinfections. Rev Infect Dis 7:$703-$708, 1985 (soppl 4) 51. Mohanty KC, Deighton R, Strachman RG: Single intramuscular injection of aztreonam in the treatment of uncomplicated gonorrhea in women. Curr Med Res Opin 10:634-637, 1987 52. de Groot HG, Hustinx PA, Lampe AS, et al: Comparison ofimipenem/cilastin with the combination of aztreonam and clindamycin in the treatment of intra-abdominal infections.J Antimicrob Chemother 32:491-500, 1993
Copyright9 1999by W.B. Saunders Company
he discover), of bacterially produced [3-1actam antimicrobials was made in 1981 by two independent teams of investigators: Imada et ala and the Squibb Institute. 2 The group from the Squibb Institute used a unique screening procedure to identi~" several monocyclic [3-1actam antibiotics from various soil bacteria, including Gluconobacter,Acetobacter. Pseudomonas, Chromobacterium, Flexibacter, and Agrobactehum.2 They coined the term monobactam derived from monoeyclic, bacterial b" produced, [3-1actam.2 Although monobactams occur naturalb, , the one currently licensed for clinical use is aztreonam, which is completeb, ~'nt hetic.
T
Chemistry The naturally occurring monobactams have relatively poor antimicrobial activity. Structural modifications of these compounds to improve their biologic activity led to the development of aztreonam (Fig 1). In contrast to the bicyclic [3-1actam nucleus present in penicillins and cephalosporins, aztreonam has an aminomonobactamic acid core with a sulfonic acid group at position 1 that activates the [3-1actam carbonyl group.3'~ At position 4, an e~-methyl group provides stability of the ring against hydrolysis by [3-1actamases. An aminothiazolyl oxime group at position 3 imparts activity against gram-negative bacteria. The carbox)4ic acid moiet-/and the methyl groups present on the oxime side chain provide enhanced activity against Pseudomonas species. These structural modifications result in complete loss of activity of aztreonam for gram-positive organisms and anaerobes.4
Mechanism of Action Aztreonam readily passes through the outer membrane of gramnegative organisms and is a bactericidal agent. The drug interferes with bacterial cell wall synthesis by binding preferentialb- to penicillinbinding protein-3, which is the septum peptidoglycan transpeptidase for Enterobacteriaceae, Pseudornonas, and other gram-negative aerobic bacilli)
From the Division oflnfectious Diseases,Department ofPediatrics, Wake Forest University School ofMedicine, Winston-Salem, NC. Address correspondence to Shari L. Orlicek, MD, Department of Pediatrics, Wake Forest University School ofMedicine, Medical CenterBh,d, HS'nston-Salem, NC 2715Z Copyright 9 1999 by W.B. Saunders Cornpany 1045-1870/99/1001-0006510.00/0
As a result of binding, aztreonam causes formation of elongated or filamentous structures that undergo h~is and cell death. 5 Because aztreonam binds poorly to essential penicillin-binding proteins of grampositive and anaerobic bacteria, the drug is inactive against these t2,pes of organisms. The structure of aztreonam is a poor substrate for binding [3-1actamases. Therefore, the drug is not hydrol)xed readily by most plasmid-mediated (TEM-I, TEM-2, and SHV-I) and chromosomally mediated [3-1actamases with the following exceptions: the RichmondSykes %pe IV enzyme (K-l) produced by some strains ofKlebsiella o.Ftoca and cefotaxime-ceftazidime hydrobxing plasmid enzymes, which include TEM-3, TEM-5, TEM-7, and SHV-2. 6~
Spectrum of Activity Susceptibility testing for aztreonam is performed by either disk diffusion or tube dilution studies. Recommended interpretive breakpoints for susceptibili~" testing are -<15 mm for resistance (minimal inhibitor5" concentration [MIC] >32 /xg/mL), 16 to 21 mm for intermediate susceptibility (MIC = 16/~g/mL), and >22 mm for susceptibility (MIC ~8/zg/mL). 6 Aztreonam has a broad spectrum of acti,Aty for gramnegative organisms. Most of the members of the family of Enterobacteriaceae (including Eschaichia coil, Proteus miraNTis, Citrobacterdiversus, KlebsieUa species, and Salmonella species) are highly susceptible with an MICg0 ~<0.5/.Lg/ml.9 However, in a recent study evaluating nosocomial isolates of gram-negative organisms obtained from a tertian" care facility, only 70 percent of Enterobacter species were sensitive, l~ Aztreonam exhibits excellent in ~'itro activity against nonenteric bacteria, such as [3-1actamase-positive and -negative Haemophilus influenzae, Moraxella catarrhalis, Pasteurella multocida. Aeromonas hydrophilia, Plesiomonas shzgelloides, and Noi~seria species. Stenotrophomonas maltophilia, Acinetobacter, Arhromobacter, andAlcaligenes species are usually resistant.6"7"9AJ,t2Aztreonarn is moderately active against Pseudomonas aeruginosa, with approximately 89 percent of isolates reported to be sensitive, but activity against other Pseudomonas species is considerably less.9 A trend for the development of resistance to aztreonam by Pseudomonas species exists.9 Synergistic acti,Aty ~ith aminoglycosides in muhidrug-resistant P aeruginosa strains has been demonstrated. 13 Aztreonam has no actinic" against gram-positive organisms. The drug also lacks activity against gram-negative anaerobes, including Bacteroidesj~agilis and Closthdiurn species. Chlamydia species and Legiondla species uniformly are resistant.
Seminars in Pediatric Infectious Diseases, Vo110, Ab 1 (Januao'), 1999:pp 45-50
z[5
46
Shari L. Orlicek
Table 1. D o s i n g Guidelines for A z t r e o n a m in Adults, Children, and Infants ,
......... ,.o,,o.
"-o
Patient Age
o;____"
CH~ I -c%.
c, l
I
Figure 1.
Structure-activity relationships in t h e a z t r e o n a m molecule. R e p r i n t e d f r o m A m e r i c a n J o u r n a l of Medicine, Vol 78, Sykes RB, B a n n e r DP, A z t r e o n a m : T h e first m o n o b a c t a m , pp 2-10, C o p y r i g h t 1985, with p e r m i s s i o n f r o m E x c e r p t a M e d i c a Inc. 3)
Clinical Pharmacokinetics Aztreonam is not absorbed from the gastrointestinal tract. After a single 0.5-g oral dose, systemic bioavailabifity is less than 1 percent, and peak serum levels are 0.15 /xg/mL for oral solution and 0.14/xg/mL for capsules. 14 Furthermore, fecal flora can synthesize [Mactamases that convert aztreonam into its biologically inactive open ring form, leaving intestinal flora essentially unchanged after oral administration of the drug. 15 Bioavailability of aztreonam approaches nearly 100 percent after intramuscular administration, with peak serum concentrations achieved within 1 hour after the dose. After a single intramuscular dose of 0.25 g, 0.5 g, and 1.0 g, the mean peak serum levels 1 hour later were 12, 22, and 46/xg/mL, respectively, t6 Not only were peak levels high after intramuscular administration, but serum levels were sustained. For instance, after a 0.5-g intramuscular dose of aztreonam, mean serum concentrations were 22/xg/mL at 1 hour, 3.8/xg/mL at 6 hours, 1.7/.*g/mL at 8 hours, and 0.3 /xg/mL at 12 hours. 16 Drug levels 1 hour after an intramuscular dose are the same as those 1 hour after an intravenous dose. The highest serum levels are attained after intravenous administration of aztreonam; mean peak serum levels immediately after a 0.5-, 1.0-, or 2.0-g intravenous dose were 58, 125, or 242/xg/mL, respectively. 16 Multiple-dose studies ofaztreonam show no evidence of drug accumulation with doses up to 1.0 g given every 8 hours either intravenously or intramuscularly. 17 The mean serum half-life of aztreonam is 1.6 hours in normal healthy adults, and the volume of distribution at steady state is 0.21 L/kg, approximating total extracellular water. 17 Protein binding in adults with normal serum albumin levels averages 56 percentJ 7 Aztreonam is distributed to nearly all tissues and body fluids, including gallbladder, fiver, synovial fluid, bone, prostate, heart, and skeletal muscle. Concentrations of aztreonam in some tissues and fluids, including lung, bile, and peritoneal fluid, are nearly equivalent to serum levels. 18 The concentration of aztreonam that penetrates into the cerebrospinal fluid (CSF) is fourfold higher if the meninges are inflamed, as compared with concentrations of drug achieved in the CSF in the presence of uninflamed meninges. 19 After a 2.0-g intravenous dose of aztreonam to persons with meningitis, the mean CSF concentrations 1 and 4 hours postadministration were approximately 2 and 3 /~g/mL, respectively. The main method of elimination is through the kidney. Glomerular filtration and tubular secretion play equally important roles. No active metabolites have been found in the serum or urine. Approximately 68 percent of an administered dose is excreted as unchanged drug in the urine and 1 to 7 percent as the inactive open ring metabofite. 16 Mean urine concentrations after parenteral administration are 10 to 100 times higher than the respective mean serum concentrations. Dosing of aztreonam in adult patients (Table 1) usually is between 1
Adults Serious infection U s u a l dose Children Serious infection U s u a l dose Infants < 1 wk 1-4 wk > 4 wk
Dose
Interval (h)
2g 1g
6 6-12
50 m g / k g / d o s e 30 m g / k g / d o s e
6 6-8
30 m g / k g / d o s e 30 m g / k g / d o s e 30 m g / k g / d o s e
12 8 6-8
and 2 g every 6 to 8 hours, depending on the type and severity of the infection being treated. In adults with normal renal function, the elimination half-life averages 2.0 hours, with a range from 1.3 to 2.2 hours. In adults with renal impairment, the elimination half-fife increases and the serum concentrations are higher, z~ Therefore, in patients with renal dysfunction, the dose of aztreonam should be given at regular intervals, but the dose should be decreased. For anephric patients, 25 percent of the standard dose is recommended; for patients with a creatinine clearance of 30 mL/min, 50 percent of the standard dose is recommended; and for patients with a creatinine clearance of 60 mL/min, 75 percent of the standard dose is recommended, z~ The half-fife of aztreonam is prolonged minimally in adults with hepatic dysfunction, and no dosage adjustment is required. Aztreonam is partially removed by hemodialysis, with approximately 25 to 50 percent removed in a 4-hour session. In peritoneal dialysis, only approximately 10 percent ofa 1.0-g dose is removed in a 6-hour dwell time. 21 The pharmacokinetics of aztreonam in children are similar to those described in adults (Table 2). Mean peak serum concentrations in children 2 to 12 years of age receiving aztreonam doses of 30 mg/kg and 50 mg/kg are 96.9/zg/mL and 214/zg/mL and 6-hour serum levels are 4.9 /xg/mL and 12.8/zg/mL, respectively.22,23 In low-birth-weight infants, peak serum concentrations after a dose of 30 mg/kg are 65/xg/mL to 83 ~g/ml. 24 These lower levels most likely are caused by the increased extracellular fluid volume in the low-birth-weight infants. The elimination half-fife of aztreonam in children 1 month to 12 years of age is equivalent to that in the adult; however, in newborn infants, the elimination half-fife increases to 2.5 hours,24and in low-birthweight infants, it is between 4 and 5.3 hours.25 The serum clearance of aztreonam varies with age. In children older than 2 years, the mean serum clearance is 2.5 mI./min/kg. In younger children and neonates, the serum clearance decreases with age and birth weight from 1.87 mL/min/kg22 to 1.52 mL/min/kg.25 These parameters are consistent with the physiological reduction of renal function seen in low-birthT a b l e 2. P h a r m a c o k i n e t i c P a r a m e t e r s of A z t r e o n a m in A d u l t s and Children
Parameter Dose a d m i n i s t e r e d (intravenously) S e r u m peak c o n c e n t r a t i o n (mean,/xg/mL) U r i n e c o n c e n t r a t i o n (0-3 h, /xg/mL) V o l u m e of distribution (L/kg) E l i m i n a t i o n half-life (h) S e r u m clearance ( m L / min/kg)
Adult
Child
Infant
1.0 g
30 m g / k g
30 m g / k g
125
96.9
118.7
3,000 0.21 1.6
3,727 0.29 1.7
1,414 0.20 1.7
1.7
2.50
1.87
47
Aztreonam weight infants.2~ The volume of distribution increases with decreasing age and is highest in low-birth-weight infants (0.64 to 1.01 L/kg), which corresponds to the high extracellular fluid volume in preterm infants/~ The concentration of aztreonam in the CSF of infants and children with meningitis has been evaluated/2 After a single dose of 30 mg/kg aztreonam intravenously, CSF levels ranged from 2.1 to 20.8 ~g/mL between 1 and 3 hours postinfusion. The mean CSF-to-serum ratio for aztreonam concentration was 17.3 percent. These CSF levels were comparable to those found in adults with inflamed meninges after a 2.0-g dose of intravenous aztreonam.19 Mean urinaq" concentrations of aztreonam in children over age 2 )'ears are equivalent to those found in adults, and levels decrease with age. The peak urinary concentrations for low-birth-~s'eight infants ranged between 246 and 2,141/.~g/mL. In all children and neonates, aztreonam levels in the urine remained above potential therapeutic levels for 18 to 24 hours after infusion ofa 30-mg/kg dose.22 In general, dosing of aztreonam in children (Table l) is 30 mg/kg given every 6 to 8 hours. However, for more serious infections, such as meningitis, dosages up to 50 mg/kg every- 6 hours have been used to ensure adequate levels of drug in the CSF. The dose of aztreonam and interval between dosages should be adjusted for infants (Table 1).
Adverse Reactions Aztreonam is a relatively well-tolerated drug with a safeq" profile similar to those of other [3-1actams. In a study including 3,360 patients who received multiple dosages of aztreonam, 209 (6.2%) patients experienced an adverse drug reaction. 26 The most common side effect reported was a local reaction, including phlebitis and thrombophlebitis, at the injection site (2.6%). Other more common adverse drug reactions included rash (1.8%), nausea or vomiting (0.6%), and diarrhea (0.8%). More serious adverse reactions included CIostridium difficile diarrhea in five patients and culture-negative pseudomembranous colitis in one patient. All six (0.2%) of these patients had other potentially confounding factors for C d/ff/c//e disease. The incidence of abnormal laboratory results associated with aztreonam administration also is low. Studies in children found a mild elevation in liver function tests in approximately 11 percent, with a return to normal levels on discontinuation of the drug. 27 These data are consistent with those in adults. Aztreonam is reported to have no effect on either the prothrombin time or the partial thromboplastin time and does not appear to alter platelet function/8 The incidence of bleeding problems in patients receiving aztreonam is less than 0.1 percent. 26 Because the spectrum of activity of aztreonam mirrors that of the aminoglycosides, comparison of the nephrotoxicity of these drugs is important. In aminoglycoside-controlled trials, the serum creatinine of patients on aztreonam decreased over the course of theral~" and increased slightly in patients who received aminoglycosides.~ In approximately 4,500 patients studied in controlled trials, azotemia related to aztreonam developed in no patients, but azotemia developed in five patients treated with aminoglycoside.27 Therefore, aztreonam is considered a useful alternative for aminoglycosides in patients, particularly when concern of nephrotoxicity is present. Because aztreonam contains a [3-1actam ring, the potential for immunologic cross-reactivity exists in patients allergic to penicillins and cephalosporins. Adkinson et al 3~ identified the side chain of aztreonam to be immunogenic compared with the [3-1actam core, which is immunogenic in the penicillins-cephalosporins, thus explaining the very" low immunologic cross-reactivity between aztreonam and the bi~'clic [3-1acta m s ) ~ Forty--one penicillin-allergic patients with positive reactions for IgE antibody to penicillin did not have cross-reactivi~" to aztreonam. Furthermore, when tested at a later date, reactivity to aztreonam reagents developed in none of these patients) I In addition, aztreonam was given to patients with allergies to penicillin or cephalosporin without sign of allergic reaction. 32 Overall, aztreonam is known to have
negligible cross-reactivi~" with other [3-1actams, including penicillins and cephalosporins, and is a very weak immunogen in humans. These factors render aztreonam a reasonable agent for treatment ofpenicillinand cephalosporin-allergic patients with gram-negative infections. Another important consideration in the evaluation of the safety of aztreonam is the risk ofsuperinfection. Bendush et al26 reported the risk of superinfection during treatment with aztreonam to be 1 to 7 percent, compared with 0 to 6 percent in the control group. During treatment with aztreonam, gram-negative aerobes are reduced in the intestinal flora, but enterococci are overgrown.33 In a group of 45 patients who received aztreonam for gram-negative infections, 8 of 45 (17.8%) patients became infected with or colonized by enterocoecus.34 O f these eight patients, five (11.1%) required further treatment directed against enteroe~cus, and one of the five became bacteremic. Enterococcus is the pathogen most frequently reported to cause superinfection in patients treated with aztreonam; other organisms reported include Staphylococcus aureus. Streptococcus pneumoniae. E coil, and P aerug~nosafl7 In a stud)" of febrile neutropenic patients, the groups treated with empiric antimicrobial regiments, including ~ t r e o n a m , had preservation of anaerobic intestinal flora and a lower frequent" of fungal colonization.'3~ No evidence exists that aztreonam is ototoxic to humans. Extensive animal testing of aztreonam has shown no evidence of mutagenicity or teratogenicity. -r Aztreonam does not compete with bilirubin for binding to human serum albumin and does not displace bilirubin bound to albumin, which is important in considering the use of aztreonam in neonates? 7
Major Clinical Uses Aztreonam has been shown to be an effective agent in the treatment of minor and serious gram-negative infections in adults and children. However, if a gram-positive or anaerobic infection is suspected, other agents should be used in combination with aztreonam to ensure appropriate coverage. Aztreonam has been reported to treat successfully various types of infections, including (but not limited to) urinary tract infections, respirator" tract infections, sepsis, meningitis, bone and joint infections, and pelvic or abdominal infections.
Urinary Tract Infections The efficaQ" of aztreonam for the treatment of complicated and uncomplicated urinal" tract infections has been studied at length in adults and children. Swabb et al :~8have summarized the adult studies. In 681 adult patients with urinal" tract infection caused by susceptible gram-negative bacilli. 56 received a single 1.0-g intramuscular dose of aztreonam for acute uncomplicated c)'stitis and 62.5 patients received multiple parenteral dosages of aztreonam for various t)pes of urinal" tract infections. Microbiological cure was reported in 84 percent of the patients in the single-dose stud)" and in 85 percent of the patients in the multiple-dose stu~'. The most common etiologic agent wasEcoli (44%); other pathogens included Klebsiel/apneumoniae, Enterobacter species, Proteus miraln'lis, and P aeruginosa. Several studies have indicated that aztreonam is effective in treating of urina D" tract infections in children. In a stud)" to evaluate the safety and efficaQ" of aztreonam in gram-negative infections in children, 13 infants and children were treated with 30 mg/kg aztreonam every 6 hours for urinary" tract infections}~9Six of these patients had pyelonephritis. The pathogens isolated were E coli (n = 11) and K pneumoniae (n = 2), and all isolates were sensitive to aztreonam. Clinical and microbiological cures were achieved in all 13 patients. Similar results were reported by Stutman et al40 in a study that used aztreonam to treat 20 infants and children who were diagnosed with pyelonephritis (n = 19) or Q'stitis (n = I). "mSeven of the children had underlying structural anomalies. The most common organism isolated was Ecoli (16 isolates), with one isolate each ofKpneumoniae, Morganella
48
Shari L. Orlicek
morganii, Paeruginosa, and Enterobacter cloacae. All isolates were sensitive to aztreonmn; most of the children were treated with 30 mg/kg aztreonam every 6 hours. Again, clinical and microbiological cures were successful in all patients. One group of investigators evaluated 30 children with "severe" urinary tract infections.41 Underlying urologic abnormalities, including hydronephrosis, vesico-ureteral reflux, and neurogenic bladder, complicated 21 of these cases. Seven patients did not respond to therapy for the current urinary tract infection with other antibiotics, including aminoglycosides and cephalosporins. Etiologic agents were members of the family of Enterobacteriaceae (25 isolates) or P aeruginosa (five isolates). Three of the P aeruginosa isolates were intermediate sensitive to aztreonam, and one of the E cloacae isolates was resistant. The mean dose used for therapy was 47 mg/kg every 12 hours; four patients required dosage adjustment because of renal failure. Overall, 22 of the 30 (73%) patients had a permanent microbiological cure. The majority of urinary tract infections in children are caused by gram-negative bacilli, which are covered by the spectrum of activity of aztreonam. The high concentrations of active drug excreted in the urine and the safety profile, along with the results of clinical trials, render aztreonam a reliable drug for the treatment of complicated and uncomplicated urinary tract infections in infants, children, and adults.
Respiratory Tract Infections For the treatment of acute pulmonary" exacerbations, aztreonam has been studied in children with cystic fibrosis who are chronically colonized with P aeruginosa. In a noncomparative study consisting of 25 children and adolescents with cystic fibrosis and acute pulmonary exacerbations, all patients were treated with 50 mg/kg aztreonam every 6 hours for a minimum of 7 days; no additional gram-negative antimierobial coverage was given.42 O f the 57 isolates of P aeruginosa from pretreatment sputum cultures, 48 were susceptible to aztreonam, 10 were intermediate, and 1 was resistant. After completion of therapy, 11 of the 22 patients who were able to produce sputum were culture negative. Sputum cultures from the remaining l 1 patients grew l 1 aztreonam-susceptible strains o f P aeruginosa, three intermediate, and four resistant. Clinical improvement was scored on the first, seventh, and last day of therapy, and the scores improved significantly with treatment. In a trial comparing the efficacy of aztreonam to tobramycin and azlocillin in cystic fibrosis patients with acute pulmonary exacerbations, 15 patients were selected randomly to each treatment group. 43 The response of patients was assessed on the basis of clinical and pulmonary scores, white blood cell counts, pulmonary function studies, and quantitative bacterial cultures. The responses of all patients were favorable, and at the end of therapy no significant differences in the above-listed parameters between the two groups were noted. Patients in the aztreonam group were treated with 50 mg/kg every 6 hours. Seven of the patients in the aztreonam group previously had been treated with aztreonam. O f these seven, three had P aeruginosa isolates at the end of therapy that were resistant to aztreonana, and four patients, who had not received previous aztreonam therapy, had isolates that were resistant. This result was not significantly different from the increase in resistance that occurred in the control group. Aztreonam also has been used in cystic fibrosis patients with ~3-1actam hypersensitivity. In one report, 15 [$-lactam-allergic cystic fibrosis patients with acute pulmonary exacerbations were treated with aztreonam. ~2 Previous reactions to [Mactams included anaphylactic shock, generalized urticaria, angioneurotic edema, and drug fever reactions. All patients had a negative skin test result to aztreonam a n d P aeruginosa isolates sensitive to aztreonam. Patients were treated for 14 days with 150 mg/kg/d aztreonam and 10 to 20 mg/kg/d tobramycin. Significant improvements in pulmonary function tests were observed in all patients, and no drug reactions occurred.
Results of these studies demonstrate that aztreonam is a safe and effective therapy for acute pulmonary exacerbations in children with cystic fibrosis. Resistance can occur with treatment, but no more so than reported with other antipseudomonal antibiotics. Furthermore, in this group of patients at risk for hypersensitivity to [Mactams caused by repeated exposure, aztreonam can he a safe, effective alternative to bicyclic [Mactams.
Sepsis The use of aztreonam in the treatment of sepsis has been evaluated. One study compared aztreonam in combination with ampicillin to amikacin and ampicillin for the treatment of neonatal bacterial infections.44 A total of 147 neonates in an intensive care unit were enrolled; gram-negative infections developed in 60 patients, and 28 patients were evaluated in the aztreonam group and 32 in the amikacin group. The bacteria isolated included P aeruginosa, K pneumoniae, E cull, and Serratia marcescens. In the aztreonam group, only 2 of 28 patients did not respond to therapy, compared with 9 of 32 patients in the amikacin group. Treatment failures were significantly higher in the amikacin group. Group B streptococcus, E cull, and Listeria monocytogenes are the primary infections seen in neonates. Gram-negative infections, such as those isolated in this study, are more often nosocomially acquired infections. One-third of the patients in this stud?," had nosocomially acquired infections.44 Aztreonam can be used successfully to treat neonatal gram-negative sepsis and does not have the risks of ototoxicity and nephrotoxicity that are associated with aminoglycosides. These risks are of concern in neonates in intensive care settings who are repeatedly exposed to antibiotics.
Meningitis Aztreonan~ has been studied as a potential therapy for gram-negative meningitis. In a large multinational study, 77 patients with cultureconfirmed gram-negative meningitis were treated with aztreonam. 45 Adults received 1 to 2 g, children received 50 mg/kg, and infants received 30 mg/kg; all dosages were given three to four times a day. The predominant organisms were Hinfluenzae (n = 40), Neisseria meningitidis (n = 15), P acruginosa (n = 5), S marcescens (n = 3),Kpneumoniae (n = 3), and Salmonella species (n = 4). Microbiological cure was documented in 71 (92%) patients, and clinical cure was achieved in 66 (86%) patients. Microbiological failures occurred in four patients. Two of these patients were children with Salmonella species who had CSF cultures positive 48 hours into aztreonam therapy. Another infant had Proteus vulgaris intracerebral abscesses, and the fourth patient was an adult with S marcescens meningitis and an intraventricular hemorrhage. Several other studies also have evaluated the efficacy of aztreonam monotherapy for gram-negative meningitis in children.4648The predominant organism in these studies was H inJluenzae Type b (Hib), and microbiological cure was similar to that reported in the previous study. From these studies, aztreonam has proven to be effective therapy for gram-negative meningitis in children and adults. However, with the dechne in Hib disease in children over the past decade, the number of children with gram-negative meningitis has sharply declined. Because the drug is capable of achieving adequate levels in the CSF, aztreonam is an appropriate drug for use in cases of gram-negative meningitis when the organism is known to be susceptible.
Bone and Joint Infections Bone and joint infections caused by gram-negative organisms have responded favorably to therapy with aztreonam. Simons and Lee 49 reported that 17 patients 12 to 70 years of age with either osteomyelitis (n : 11) or septic arthritis (n = 6) were treated successfully with aztreonam. Organisms included P aeruginosa, S mareescens, Enterobacter species, Citrobacterdiversus, a n d P mirabilis. The dosage ofaztreonam was 2 g every 6 to 12 hours, and duration of treatment was 14 to 55 days. All
Aztreonam patients achieved clinical and microbiological cure. In patients with coexisting gram-positive infections, additional appropriate antibiotics were used. The majority of cases of osteomyelitis-septic arthritis in children are caused by S aureus; this should be considered when initiating empiric thera W in children with orthopedic infections. However, for known gram-negative orthopedic infections, aztreonam should be considered an alternative to aminoglycosides for prolonged therapy, as well as an alternative to third-generation cephalosporins in the allergic patient.
Pelvic and Abdominal Infections Aztreonam in combination with clindamycin was compared with gentamicin and clindamycin for use in gynecologic infections, including pelvic inflammato~, disease and endometritis) ~ Fir%" patients were in the aztreonam group, and 38 were in the gentamicin group. The pathogens most commonly isolated were E coli, K pneumoniae, and P mirabilis. Microbiological cure was achieved in 98 percent of the aztreonamclindamycin group, compared with 95 percent in the gentamicinclindamvcin group, Favorable clinical response occurred in 98 and 89 percent, respectively. Aztreonam provides excellent gram-negative coverage in gynecologic infections, but other agents must be added for coverage of gram-positive and anaerobic organisms. For patients with pelvic inflammatory disease, coverage for Chlam)'dia trachomati~ also must be considered because aztreonam has no activity against this organism. The other ~necologic use of aztreonam is for uncomplicated gonococcal cervicitis and urethritis. In a randomized trial that compared a single intramuscular injection of 1 g aztreonam to 2,4 million units intramuscular procaine penicillin plus 1 g oral probenecid, 2% patients with uncomplicated gonococcal cervicitis were enrolled? I O f the 116 patients treated with aztreonam, 101 patients were seen at a 1-week follow-up and had bacteriologic tests of cure. In the aztreonam group, the success rate was 100 percent, compared with 89 percent in the penicillin group. In the group treated with aztreonam, I l of the N gonorr~a isolates were penicillinase-proclucing strains. Aztreonam is a suitable drug for the treatment of uncomplicated gonococcal infections, especially in cephalosporin-allergic patients. As with pelvic infections, aztreonam and clindamycin have been studied for efficacy in intra-abdominal infections) ~Thirty-eight patients were treated with aztreonam and clindarnycin, whereas 42 patients received thera W with imipenem-cilastatin. Therapy was successful in 64 percent of the patients in the aztreonam group and 71 percent of the patients in the imipenem-cilastatin group. The predominant organisms isolated were E coli and Bacteroides fiagilis. Overall, both regimens reasonably were effective in the treatment of intra-abdominal infections. Aztreonam provides excellent coverage for gram-negative aerobic infections. Because the drug is able to achieve good levels in most tissues and body fluids, including CSF, aztreonam is a good agent for a varie~" of infections, ff concern of gram-positive or anaerobic infection exists, aztreonam can be used safely in combination with a variety of antimicrobial drugs. The drug primarily is used as an alternative to aminoglycosides in patients for whom nephrotoxicity is a concern and in place of third-generation cephalosporins in patients who are allergic to [3-1actam.
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