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Azlocillin

Azlocillin is another ureido-substituted penicillin that has the chemical formula 6D-2-(2-oxoimidazolidine-1-carboxamido-2-phenylacetamido)-penicillanic acid [1]. Azlocillin can also be considered as an a-amino-substituted ampicillin [2]. Azlocillin is an acylampicillin antibiotic with an extended spectrum of activity and greater in vitro potency than the carboxy penicillins. Azlocillin is now not available for clinical use.

Therapeutic use

Being more active than ticarcillin and mezlocillin in vitro against P. aeruginosa, this drug was mainly used for Pseudomonas infections. It was quite effective in serious P. aeruginosa infections, such as septicemia, meningitis, bronchopneumonia, and urinary tract infections [3-6]. Azlocillin plus an aminoglycoside, such as tobramycin, is synergistic in vitro against P. aeruginosa, and in vivo it is satisfactory treatment for infections in neutropenic cancer patients [7-9]. A double b-lactam combination of azlocillin plus ceftazidime was also satisfactory for the treatment of these patients [9].

Cystic fibrosis patients with acute exacerbations of pulmonary infection were treated with either ticarcillin–tobramycin, azlocillin–tobramycin, or azlocillin alone for 10 days. All three regimens had similar beneficial effects on pulmonary function and sputum bacterial concentration. Antibiotic resistance, particularly among strains of P. aeruginosa, developed more frequently in patients treated by azlocillin alone [10]. When azlocillin is used for such patients it should be combined with an aminoglycoside [11-12]. Azlocillin was quite effective for the treatment of P. aeruginosa infections, but was not proven to be clinically superior to carbenicillin or ticarcillin [13]. For the treatment of P. aeruginosa endocarditis, ticarcillin plus an aminoglycoside is preferred [14]. Azlocillin was also not superior to ticarcillin for the treatment of P. aeruginosa infections in irradiated neutropenic mice [15]. Azlocillin is now no longer available for
clinical use.

Dosage and Administration

This drug was given in a dosage of 100–300 mg/kg body weight per day, or occasionally for severe infections 450 mg/kg/day. It was usually administered in four or six divided doses; each dose given i.v. by a rapid injection or as a 15- to 30-minute infusion. In adults, a dosage varying from 1 to 5 g i.v. 6-hourly was used depending on the severity of the infection [3-4, 12]. The usual adult dosage for severe infection was either 4 g every 6 hours or 5 g every 8 hours [16].

Impaired renal function

In patients with severe renal failure, azlocillin dosage should be reduced. The azlocillin serum half-life is normally 43.7 minutes, and this increases to 6.53 hours in patients with end-stage renal failure. Azlocillin clearance is dose dependent. For severe systemic infections in patients with normal renal function, the azlocillin dosage is at least 5 g (80 mg/kg) i.v. every 8 hours. This may also be used in patients with renal failure whose creatinine clearance exceeds 30 ml/min. In more severe renal failure (creatinine clearance 10–30 ml/min), dosage should be reduced to 5 g (80 mg/kg) every 12 hours. In those with a creatinine clearance below 10 ml/min, a loading dose of 5 g (80 mg/kg) can be given, followed by 2.5 g (40 mg/kg) 12-hourly. Azlocillin is removed during hemodialysis, and in patients undergoing long-term hemodialysis 5 g (80 mg/kg) can be given at the end of each dialysis and then 2.5 g (40 mg/kg) 12-hourly between dialyses [17]. During peritoneal dialysis, the removal of azlocillin from the body is slow [18].

Cystic fibrosis

In patients with cystic fibrosis, the renal, and to some extent nonrenal, clearance of azlocillin is much increased, and, similar to piperacillin, much higher azlocillin doses (usually at least doubled) were necessary [19]. This recommendation conflicts with findings by another scientist [20] , who reported that azlocillin elimination did not appear to be altered in cystic fibrosis patients.

Toxicology

Hypersensitivity reactions

One patient treated with azlocillin and tobramycin had a severe hypersensitivity reaction after 18 days of therapy; she developed fever, malaise, rash, eosinophilia, and leukopenia, and recovered rapidly when both antibiotics were ceased [21].

Neurotoxicity

High doses of azlocillin given i.v., similar to ‘‘massive’’ doses of penicillin G or carbenicillin, may have the propensity to cause neurotoxicity [22].

Bleeding disorders

Similar to carbenicillin and ticarcillin, mezlocillin, azlocillin, piperacillin, and apalcillin can cause a disturbance of platelet function [23-24]. Mezlocillin, piperacillin, and apalcillin have a lesser effect on platelet function than carbenicillin and ticarcillin at an equivalent dosage [24-27]. A prolonged bleeding time has been observed in a few patients receiving azlocillin [23], but clinical bleeding has not been reported [28-29].

Neutropenia and thrombocytopenia

As with carbenicillin and ticarcillin and other b-lactam antibiotics, reversible neutropenia can occur during therapy with mezlocillin, azlocillin, and piperacillin [21, 29-30]. This side-effect is more common with these penicillins than with carbenicillin. Thrombocytopenia can also rarely occur [31-33].

Other side-effects

Some patients have developed nausea and diarrhea associated with parenteral use of this drug. Azlocillin and probably also other drugs
of this group induce marked changes in colon microflora [34].

Pharmacokinetic

The pharmacokinetics of azlocillin changes when the dose is increased. With azlocillin doses of 1–2 g, the serum half-life is 0.7–1.1 hours, but with a 5-g dose this is prolonged to 1.2–1.8 hours. At concentrations of 200 mg/ml azlocillin is 30% protein bound. As with other penicillins, concomitant administration of probenecid increases and prolongs the serum levels of azlocillin [19, 35].

Bioavailability  
Protein binding 30%
Metabolism  
Half-life 0.7-1.8 hrs
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion  

Absorption

The drug is not orally available.

Distribution

After a rapid i.v. injection of 1 g azlocillin (15 mg/kg body weight), the peak serum level at 5 minutes is 93 mg/ml, and the drug is  undetectable in the serum at 8 hours. At the end of a 30-minute infusion of 5 g azlocillin (80 mg/kg), the serum level is 409 mg/ml, and it is still 2.6 mg/ml 8 hours after the infusion.

Mezlocillin and piperacillin penetrated poorly into bronchial secretions, while azlocillin may pass into these secretions better than mezlocillin [19]. Mezlocillin, azlocillin, and piperacillin penetrated well into interstitial and wound fluids, but after usual doses only low levels were reached in normal bone [19].

With azlocillin in patients after biliary surgery, a mean peak biliary concentration of 1137 mg/ml occurred 1.0–1.5 hours after a 2-g i.v. dose [19].

In animals, piperacillin penetrates poorly into normal cerebrospinal fluid (CSF). In a patient with P. aeruginosa meningitis treated with azlocillin 5 g 6-hourly i.v., CSF concentrations were 42–125 mg/ml, when serum levels were 137–460 mg/ml [4].

Azlocillin crosses the placenta and attains high concentrations in fetal tissues [38].

Excretion

Mezlocillin, azlocillin, and piperacillin are excreted unchanged in the urine by both glomerular filtration and tubular secretion. Approximately
50–80% of an i.v. dose of these drugs is eliminated via the kidneys in an unchanged form [35, 39-40]. With dose increments, an increasing proportion of all these drugs is recovered unchanged in the urine; for instance, with azlocillin 61% is recovered in the urine after a 1-g dose compared with 69% after a 5-g dose [19]. This is because with higher doses nonrenal mechanisms for drug elimination become saturated. Probenecid decreases renal excretion of these penicillins by partial blockage of renal tubular secretion. High concentrations of the active form of all these drugs are attained in the urine after usual i.m. or i.v. doses.

Significant amounts of mezlocillin, azlocillin, piperacillin, and apalcillin are eliminated via the bile. The percentage of these drugs eliminated via bile may increase in patients with impaired hepatic function; this is probably because there is less biotransformation in the liver [19].

 

Metabolism

 

Mechanism of Action

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, Piperacillin inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that Piperacillin interferes with an autolysin inhibitor.

Antibacterial activity

The antibacterial spectra of ureidopenicillins are similar to those of carbenicillin and ticarcillin, but there are differences between their degree of activity against various bacterial species. All of these antibiotics have lost much of their activity owing to emergence of resistance. To some extent, that problem has been reduced for mezlocillin and piperacillin, which are available in fixed combinations with sulbactam and tazobactam, respectively. The comparative in vitro susceptibility data for these agents against common pathogens are shown in Table 1.

Table 1. In vitro susceptibility of common pathogens to mezlocillin, azlocillin, piperacillin, and apalcillin in comparison with ticarcillin.

Organism

MIC (mg/ml)

Ticarcillin Mezlocillin Azlocillin Piperacillin Apalcillin
Gram-positive          
Staphylococcus aureus, non penicillinase producer 1.25 0.2 0.2 0.78 0.39
Staphylococcus pyogenes 0.5 0.025 <0.1 0.1 0.1
Streptococcus pneumoniae 1.25 0.025 0.1 0.01 0.05
Enterococcus faecalis 125 1 0.5 0.4-1.6 12.5
Clostridium perfringens 0.5 0.07 0.04 0.06-4 1.56
Gram-negative          
Escherichia coli 5 1-2 1-8 0.8 0.39
Enterobacter spp. 5 2-8 12.5-100 1.6 3.1
Klebsiella spp. 500 12.5-100 12.5->100 3.1 6.3
Serratia marcescens 12.5 12.5 12.5 0.8->100 25
Proteus mirabilis 1.25 1.56 1.56 0.2 0.76
Proteus vulgaris 2.5 1.56 12.5 0.78 12.5
Morganella morganii 2.5 1.56 12.5 0.78 3.1
Salmonella typhi 2.5 2 8 0.39 3.1
Neisseria gonorrheae 0.02 0.005 0.005 0.015-0.03 0.1
Haemophilus influenzae 0.25 0.15-0.25 0.06 0.015-0.03 -
Pseudomonas aeruginosa 25 25-50 12.5 6.5 6.3
Prevotella melaninogenica 0.1-4 0.5-4 - - -
Bacteroides fragilis 4-128 1-128 1-128 25 25

The main advantage of this drug is that its activity against P. aeruginosa is somewhat superior to that of carbenicillin, ticarcillin, and mezlocillin. It is also active against many carbenicillin-resistant strains of this organism [1, 41-42]. Azlocillin-resistant P. aeruginosa strains were uncommon; in 24 UK hospitals only 3.9% of strains were resistant
with MICs greater than 32 mg/ml [43]. The superiority of azlocillin over other antipseudomonal penicillins has been disputed. When conventional MIC tests and small inocula are used, azlocillin has lower MICs than the other drugs against P. aeruginosa. When tests for bactericidal activity are performed, using large inocula, the activity of azlocillin, mezlocillin, and piperacillin may appear inferior to that of carbenicillin and ticarcillin. These drugs, unlike carbenicillin and ticarcillin, are susceptible to chromosomally mediated pseudomonal b-lactamases, so that they are inactivated in dense bacterial populations during overnight incubation [44-46]. It is possible to produce in vitro strains of P. aeruginosa that, as a result of enzyme induction or spontaneous chromosomal mutation, produce increased amounts of b-lactamase. If high inocula are used for testing, sensitivities of these strains to azlocillin and piperacillin are reduced at least 10-fold, whereas those for carbenicillin and ticarcillin are reduced by only 2- to 5-fold [47]. Estimates of the comparative activity of antipseudomonal b-lactam antibiotics (including newer cephalosporins) varied with the in vitro test used. With P. aeruginosa, standard MIC tests may underestimate resistance to azlocillin, other ureido-penicillins, and cephalosporins [48]. The clinical relevance of these in vitro observations is unclear, as piperacillin, in particular, appears highly effective. Compared with mezlocillin, azlocillin had the same activity against Bacteroides fragilis, but it is somewhat less active against most other Gram-negative bacilli [3, 48]. Azlocillin is as active as mezlocillin against H. influenzae, N. meningitidis, N. gonorrhoeae, and Gram-positive bacteria [49-50] Its activity against Enterococcus faecalis is similar to that of ampicillin [51]. Aeromonas spp. are usually azlocillin sensitive [52].
 

Other pharmacological effects

 


 

Medicinal Chemistry

CAS number:  37091-66-0 EINECS: 253-348-2

Molecular Formula:  C20H23N5O6S

Average mass: 461.491486 Da

Monoisotopic mass:  461.136902 Da

Systematic name: (2S,5R,6R)-3,3-dimethyl-7-oxo-6-{[(2R)-2-{[(2-oxoimidazolidin-1-yl)carbonyl]amino}-2-phenylacetyl]amino}-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)[C@@H](C3=CC=CC=C3)NC(=O)N4CCNC4=O)C(=O)O)C

Std. InChI: 1S/C20H23N5O6S/c1-20(2)13(17(28)29)25-15(27)12(16(25)32-20)22-14(26)11(10-6-4-3-5-7-10)23-19(31)24-9-8-21-18(24)30/h3-7,11-13,16H,8-9H2,1-2H3,(H,21,30)(H,22,26)(H,23,31)(H,28,29)/t11-,12-,13+,16-/m1/s1

ACD/LogP: -0.34±0.66 # of Rule of 5 Violations: 1
ACD/LogD (pH 5.5): -3.32 ACD/LogD (pH 7.4): -4.06
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 11 #H bond donors: 4
#Freely Rotating Bonds: 5 Polar Surface Area: 173.45 Ĺ2
Index of Refraction: 1.697 Molar Refractivity: 114.2±0.4 cm3
Molar Volume: 296.6±5.0 cm3 Polarizability: 45.3±0.5 10-24cm3
Surface Tension: 83.6±5.0 dyne/cm Density: 1.6±0.1 g/cm3
Flash Point: °C Enthalpy of Vaporization: kJ/mol
Boiling Point: °C at 760 mmHg Vapour Pressure: mmHg at 25°C

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

logP:

pKa:
 

Stability:

 


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