Aztreonam: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Aztreonam belongs to the class of beta-lactam antibiotics known as monobactams. Unlike penicillins and cephalosporins the monobactams have only the beta-lactam ring, with the thiazolidine ring (characteristic of penicillins) and the dihydrothiazide ring (characteristic of cephalosporins) missing. In monobactams, a sulphonate group is present. In nature, monobactams are synthesized by bacteria.

Aztreonam (3-aminothiazole-oxime, 4a-methyl 1-monobactamic acid) is a synthetic member of this group, developed at the Squibb Institute for Medical Research. The antibacterial spectrum of this drug is not as wide as that of the third-generation cephalosporins and it somewhat resembles that of the aminoglycosides, in that no clinically useful activity is present against Gram-positive or anaerobic organisms (Sykes et al., 1981; Sykes and Bonner, 1985). The molecular weight of aztreonam is 435.4 g/mol. The chemical structure of aztreonam is shown in Figure 35.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Only Gram-negative aerobic bacteria are sensitive to aztreonam. The drug is quite active against the Enterobacteriaceae such as Escherichia coli, Proteus mirabilis, other Proteus spp., Klebsiella, Enterobacter, Serratia, Providencia, Citrobacter, Salmonella, Shigella, Edwardsiella, Yersinia spp., and Morganella morganii, providing that they do not produce extended-spectrum beta-lactamases (ESBLs) or KPC-type beta-lactamases or hyperproduce AmpC beta-lactamases (Sykes et al., 1981; Jacobus et al., 1982; Barry et al., 1985; Tunkel and Scheld, 1990; Nijssen et al., 2004; Paterson and Bonomo, 2005; Sader et al., 2005; Deshpande et al., 2006; Rhomberg and Jones, 2007). Neisseria gonorrhoeae and Haemophilus influenzae, including beta-lactamase producers, are also quite sensitive (Barry et al., 1985).

b. Emerging resistance and cross-resistance

Aztreonam is stable to narrow-spectrum, plasmid-mediated enzymes of Gram-negative bacteria such as TEM-1 and SHV-1 (Sykes and Bonner, 1985). Many newer b-lactamases, especially ESBLs and carbapenemases (class A, C or D; serine b-lactamases), have been reported to cause resistance to aztreonam (Paterson and Bonomo, 2005; Bonomo and Szabo, 2006; Queenan and Bush, 2007). This includes the TEM, SHV, and CTX-M type ESBLs. Klebsiella oxytoca produces a chromosomally encoded beta-lactamase called K1. Mutational hyperproduction of this enzyme leads to a very characteristic antibiotic resistance profile, with resistance to aztreonam being one of its features (Livermore, 1995). Mutational hyperproduction of the chromosomally encoded AmpC beta-lactamase of Enterobacter cloacae, Serratia marcescens, Citrobacter freundii, and other related bacteria also leads to aztreonam resistance.

MECHANISM OF DRUG ACTION

The intrinsic activity of monobactams against bacteria is determined by their binding to particular penicillin-binding proteins (PBPs), and this in turn is determined by the nature of the substituents on their beta-lactam nucleus (Georgopapadakou et al., 1983). Aztreonam, similar to the cephalosporins, specifically affects septum formation in E. coli (and most likely other aerobic Gram-negative bacteria) and it produces filamentous forms of bacteria (Georgopapadakou et al., 1982). This appears to be due to the high affinity of aztreonam for PBP3 of Gram-negative bacteria, and this may be sufficient to cause cell death. The drug is bactericidal (Shah et al., 1981).

MODE OF DRUG ADMINISTRATION AND DOSAGE

The drug is usually administered by the parenteral route. However, inhaled aztreonam lysine therapy for the treatment of patients with cystic fibrosis is currently under active clinical study (Gibson et al., 2006; McCoy et al., 2008; Retsch-Bogart et al., 2008).

a. Adults

For moderately severe infections, doses of 1–2 g every 8–12 hours given i.v. may be sufficient (Clergeot et al., 1989). For seriously ill patients, such as those with severe sepsis or meningitis, doses of 2 g 8- or 6-hourly have been used i.v. (De Maria et al., 1989; Farid et al., 1990; Lentnek and Williams, 1991; Gotuzzo et al., 1994).

b. Newborn infants and children

For moderately severe infections, a dosage of 30 mg/kg, given i.v. every 6–8 hours is sufficient. For severe infections, a dosage of 50 mg/kg, administered 6- or 8-hourly, is recommended (Stutman et al., 1984; Girgis et al., 1988; Stutman, 1991).

c. Altered dosages

Impaired renal function

Patients with renal failure require dosage modification. Renal clearance of the drug correlates closely with the creatinine clearance, which can be estimated from the patient’s serum creatinine, age, and sex. Mihindu et al. (1983) studied noninfected volunteers with various degrees of renal failure, and found that the elimination half-life of aztreonam increased from about 2 hours in normal subjects to 6 hours in anephric patients.

Impaired hepatic function

Patients with primary biliary cirrhosis and alcoholic cirrhosis have prolonged elimination half-lives (2.2 and 3.2 hours, respectively) compared with normal subjects (1.9 hours). Renal and nonrenal clearances were reduced in patients with alcoholic cirrhosis. If longterm therapy with high doses is given, some dosage reduction may be warranted in these patients (MacLeod et al., 1984; El Touny et al., 1992).

The elderly

In elderly patients the ability to eliminate aztreonam is reduced (Creasey et al., 1985; Meyers et al., 1993). Dosage should be adjusted in accordance with renal function in elderly subjects.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Aztreonam is poorly absorbed after oral administration, peak serum levels of only 0.1–0.2 mg/ml being achieved 2 hours after 0.5 oral doses (Swabb et al., 1983b). The systemic bioavailability of intraperitoneally administered aztreonam is approximately 60–70% (Swabb, 1985).

The mean half-life is about 2 hours in healthy adults (Mihindu et al., 1983). The half-life in low-birth weight neonates in the first week of life is 5.7 hours. However, full-term newborns and children have a similar drug elimination profile and the half-life is 1.7–2.6 hours (Stutman et al., 1984).

The serum protein binding is 56% and declines slightly as renal insufficiency increases (Swabb, 1985).

b. Drug distribution

When i.m. doses of 1.0 and 2.0 g were given to normal volunteers, serum levels at 1 hour were 22.0 and 46.0 and at 4 hours 8.9 and 18.4 mg/ml, respectively (Swabb, 1985). Normal subjects given 3-minute i.v. infusions of 0.5, 1.0, and 2.0 g of aztreonam had mean peak serum levels of 58, 125, and 242 mg/ml, respectively, 5 minutes after the infusion; 1 hour after infusion these levels had fallen to 11.8, 23.3, and 48.6 mg/ml, respectively (Swabb et al., 1981).

c. Clinically important pharmacokinetic and pharmacodynamic features

Similar to other b-lactams, time above MIC (TWMIC) is generally thought as the most important pharmacokinetic/pharmacodynamic parameter that correlates with the therapeutic efficacy of aztreonam (Craig, 1998; Turnidge, 1998). However, these data are often based on studies in animal models, and clinical pharmacodynamic data in humans remain limited.

d. Excretion

The main method of elimination of aztreonam is via the kidneys, and about 68% of an administered dose is excreted unchanged in the urine (Swabb et al., 1982). Approximately equal amounts of serum aztreonam unbound to protein are cleared by renal tubular secretion and glomerular filtration. Probenecid reduced renal tubular secretion by about 50%, but it only slightly increased the steady-state serum concentration and elimination half-life of aztreonam (Swabb, 1985).

Inactivation in the body

Aztreonam is not extensively metabolized. Its major metabolite in humans (designated SQ26,992) results from hydrolytic opening of the beta-lactam ring. The site of its formation is unknown. It is eliminated at a much slower rate than the parent compound (Swabb et al., 1983c) and appears to be devoid of any significant antimicrobial activity (Kripalani et al., 1984).

e. Drug interactions

Few interactions occur between aztreonam and other drugs. Coadministration of metronidazole parenteral solutions and the injectable aztreonam may lead to the development of pink color in their intravenous admixtures (Thakur et al., 1991). Nitrite ions may be produced in metronidazole solutions at the time of preparation or during storage by the effects of temperature and light. Under acidic pH conditions, the aminothiazole moiety of aztreonam can be diazotized by the nitrite ion contributed by metronidazole solutions.

TOXICITY

a. Hypersensitivity reactions

Aztreonam is a monocyclic beta-lactam antibiotic. Studies in humans as well as animals have demonstrated only a low level of immunologic cross-reactivity between aztreonam and IgG antibodies to penicillin G and cephalothin (Adkinson et al., 1984; Adkinson et al., 1985). Crossreactivity with penicillins and cephalosporins seems to be rare. When skin tests were performed on 41 penicillin-allergic subjects with positive reactions for IgE antibody to penicillin, there was no crossreactivity with aztreonam reagents (Saxon et al., 1984).

b. Other side-effects

The safety profile of aztreonam in clinical trials has been analyzed (Newman et al., 1985). Of 2388 patients who received multiple doses, 163 (6.8%) experienced 172 adverse effects. The most common were local reactions at the injection site, rash, diarrhea, nausea and/or vomiting, and slight elevations of serum aspartate aminotransferase and alanine transaminase levels.

c. Risks in pregnancy and fetal toxicity

Aztreonam is a Food and Drug Administration’s Pregnancy category B drug and an Australian Drug Evaluation Committee category B1 agent. The manufacturer of the drug states that studies in pregnant rats and rabbits revealed no evidence of embryo- or fetotoxicity or teratogenicity. However, it also states that there are no adequate and well-controlled studies in pregnant women, and aztreonam should be used during pregnancy only if clearly needed.

CLINICAL USES OF THE DRUG

Aztreonam has been used for the treatment of a variety of infections caused by aerobic Gram-negative bacteria including Pseudomonas. There are descriptions about aztreonam in practice guidelines for various infections, for example community-acquired pneumonia in adults, bacterial meningitis, and skin and soft-tissue infections (Brown et al., 1990; Mermel et al., 2001; Solomkin et al., 2003; Lipsky et al., 2004; Tunkel et al., 2004; Stevens et al., 2005; Mandell et al., 2007). In particular, aztreonam is potentially useful in the treatment for the patients with penicillin or other b-lactam allergy because crossreactivity with penicillin or other b-lactams is rare

a. Urinary tract infections

Greenberg et al. (1984) reported that aztreonam cured 45 of 67 patients with pyelonephritis; however, seven patients developed enterococcal bladder superinfections. Relapse occurred in ten patients 4 weeks after ceasing therapy; two of these were young women without obvious predisposing factors.

b. Skin and skin structure infection

Aztreonam has been studied in skin and skin structure infections, but only in combination with agents active against staphylococci. In this situation, the activity of the antistaphylococcal agent is more relevant to overall effectiveness than the activity of aztreonam. For example, Ellis-Grosse et al. (2005) conducted a randomized study in 1116 patients comparing vancomycin plus aztreonam treatment with tigecycline monotherapy for skin and skin structure infection.

c. Inhaled aztreonam lysine therapy for cystic fibrosis patients

Recently, trials of inhaled aztreonam therapy for cystic fibrosis (CF) patients have been reported (Gibson et al., 2006; McCoy et al., 2008; Retsch-Bogart et al., 2008). For this inhalation therapy, a lysine salt formulation of aztreonam was developed because intravenous aztreonam formulation contains arginine, which has been shown to cause airway inflammation after chronic inhalation therapy in patients with CF.

d. Other respiratory tract infections

Boucher (2000) has summarized studies in which aztreonam has been used in the treatment of nosocomial pneumonia. Overall, the track record of aztreonam in combination with appropriate antibiotics providing coverage against Gram-positive bacteria has been quite favorable. For example, Nolen et al. (1985) found aztreonam to be effective in all but one of 35 patients with lower respiratory tract infections caused by Gram-negative bacilli. Raad et al. (2001) has more recently found equivalent outcomes in patients with nosocomial pneumonia randomized to receive either piperacillin–tazobactam or the combination of clindamycin plus aztreonam.

e. Bloodstream infection with Gram-negative organisms

All but two of 20 patients with Gram-negative aerobic rod septicemia treated with 2 g of aztreonam i.v. 6-hourly were cured (Greenberg et al., 1984). Scully and Neu (1985) treated 87 patients with aztreonam, most of whom had severe infections caused by aerobic Gram-negative rods. Eleven had bacteremia and ten of these were cured, including four due to P. aeruginosa. Aztreonam alone is at least as effective as one of the aminoglycosides for the treatment of proven aerobic Gram-negative organism septicemias; aminoglycosides have the disadvantage of nephrotoxicity, but aztreonam therapy often leads to superinfections, mainly by E. faecalis (Gudiol et al., 1986; Pierard et al., 1986; Smith et al., 1988; De Maria et al., 1989).

f. Initial therapy for neutropenic patients with fever

A pilot study of aztreonam plus cefazolin has been performed in patients with neutropenic fever (Dominguez et al., 2000). In this small study of cycling strategies in neutropenic patients, outcomes were similar in patients treated with aztreonam–cefazolin and those treated with vancomycin–ceftazidime, imipenem, or ciprofloxacin–clindamycin.

g. Bacterial meningitis

Aztreonam is quite effective for the treatment of H. influenzae meningitis (Girgis et al., 1988), but for this infection cefotaxime or cefriaxone is preferred. In animals, aztreonam was as effective as imipenem, ceftazidime, and mezlocillin for the treatment of E. coli meningitis (McCracken et al., 1985).

h. Severe neonatal sepsis

An ampicillin–aztreonam combination proved to be about as effective as ampicillin plus amikacin in one study (Lebel and McCracken, 1988; Stutman, 1991). However, ampicillin–aztreonam is rarely used in clinical practice.

i. Prosthetic joint infection

Aztreonam has been studied in cement spacers used in two-stage revision of total hip replacements (Hsieh et al., 2006). An articulating polymethylmethacrylate (PMMA) spacer was loaded with vancomycin and aztreonam and evaluated in 46 patients.

j. Osteomyelitis

In an experimental rabbit model of osteomyelitis due to P. aeruginosa, aztreonam given for 4 weeks failed to eradicate the organism (Norden and Budinsky, 1988). Seven patients, in three of whom recent treatment with aminoglycosides had failed despite sensitivity of the organisms involved, were treated for 6 weeks with 1–2 g of aztreonam i.m. or i.v. every 8 hours.

k. Bacterial gastroenteritis

Despite its poor absorption after oral administration, oral aztreonam has been trialed. A dose of 100 mg was administered three times daily for 5 days in patients with bacterial diarrhea.

l. Typhoid fever and other Salmonella infections

Aztreonam is effective in the treatment of systemic Salmonella infections in experimental animals (Bonina et al., 1990). Farid et al. (1990) cured four typhoid fever patients with aztreonam. In a randomized trial in children, aztreonam appeared about as effective as chloramphenicol for typhoid (Tanaka-Kido et al., 1990).

m. Selective reduction of bowel flora

The poor oral absorption of aztreonam (o1%) and its good activity against aerobic Gram-negative bacteria, but not anaerobes, suggests that it may be useful for selective reduction of bowel flora. However, selection of ESBL producers, enterococci, or Candida is a concern. In ten volunteers, elimination of Gram-negative aerobes was achieved by using either 300 or 1500 mg daily doses of oral aztreonam after an average of 4.4 and 3.0 days, respectively.

n. Malignant otitis externa

Giamarellou et al. (1984) used aztreonam in a patient with malignant otitis externa in whom several courses of aminoglycosides had previously been unsuccessful. The patient received 6 g daily for 6 weeks and when assessed at ten months he was considered to be cured (Giamarellou et al., 1984).

o. Otitis media

A small, prospective, randomized trial of ceftazidime versus aztreonam has been performed in 30 children with chronic suppurative otitis media without cholesteatoma (Somekh and Cordova, 2000). All patients had a pure culture of P. aeruginosa. Complete disappearance of discharge occurred in 84.6% of ceftazidime-treated patients and 67% of aztreonam-treated patients. This difference was not statistically significant.

p. Gonorrhoea

A single i.m. injection of 1 g aztreonam is satisfactory therapy for uncomplicated urethral gonorrhoea in men and is probably effective for endocervical and rectal infection as well (Gottlieb and Mills, 1985). This regimen also cures gonorrhoea in males and females caused by beta-lactamase-producing strains (Miller et al., 1983; Evans et al., 1986; Mohanty et al., 1988; Bonomo and Szabo, 2006).

q. Perioperative prophylaxis

Aztreonam–metronidazole proved to be unsatisfactory prophylaxis in elective colorectal surgery, as sepsis due to Gram-positive organisms, particularly S. aureus, occurred (Morris et al., 1990). However, clindamycin plus aztreonam was effective for this purpose, and the results obtained were similar to those with clindamycin–gentamicin (Rodolico et al., 1991).

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