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Oxacillin

Chemically this is 3-methyl-5-phenyl-4-isoxazolyl penicillin. It was synthesized in 1961 and has been extensively used in North America. It is available as an oral solution of 120 mg/5 ml. It usually comes in an injectable formulation of 1 and 2 g. A 10 g injectable formulation is also marketed.

Therapeutic use

Oxacillin is used primarily for the treatment of penicillin resistant methicillin-susceptible staphylococcal infections of all grades of severity.

Mild to moderate S. aureus infections

Cellulitis is often managed with an i.v. isoxazolyl penicillin initially. This is often combined with penicillin G to treat S. pyogenes, but it makes no difference to the outcome [1], confirming that isoxazolyl penicillins alone can effectively cover S. aureus and S. pyogenes in this
setting.

For moderately severe complicated skin and skin structure infections, oxacillin i.v. followed by dicloxacillin orally has been shown to be effective [2].

Severe S. aureus infections

Results similar with those obtained with methicillin or nafcillin have been obtained with oxacillin administered in large doses parenterally (6–18 g daily for adults) for the treatment of severe staphylococcal infections, including severe pneumonia, meningitis, and endocarditis [3-7]. Some clinical studies have suggested that the oxacillin–rifampicin combination may be slightly superior to oxacillin therapy alone for patients severely ill with S. aureus sepsis [8-9].

S. aureus endocarditis

High doses of an intravenous isoxazolyl penicillin are standard treatment for acute bacterial endocarditis caused by penicillin-resistant S. aureus. Therapy is frequently combined with gentamicin, extrapolating from a study of nafcillin plus gentamicin [10]. The addition of gentamicin is often associated with increased nephrotoxicity [11]. Despite the availability of good medical treatment, many patients with S. aureus endocarditis still need emergency valve replacement during the acute phase of their illness [12].

Shorter courses of antistaphylococcal penicillins have been tried for right-sided endocarditis. 

Bone and joint infections

Isoxazolyl penicillins play a major role in the inpatient and outpatient treatment of acute bone and joint infections. They are considered standard therapy in acute osteomyelitis in children, and are the drugs of choice if S. aureus is proven. It is not clear that they are superior to other agents [13]. They are effective as prolonged outpatient treatment of chronic osteomyelitis [14-18].  Isoxazolyl penicillins are sometimes employed for surgical prophylaxis in situations predisposed to postoperative S. aureus or S. epidermidis infections.

Staphylococcal toxic shock

The clinical entity of the toxic shock syndrome results from a toxin or toxins elaborated by S. aureus, the infection commonly being in the
vagina. Bacteremia is absent in most cases [19-20]. A penicillinase-resistant antibiotic, should be given parenterally to these patients, in addition to general supportive measures to combat shock. In some cases toxic shock syndrome has been associated with S. aureus septicemia and endocarditis [21-22]. A variant of the toxic shock syndrome has been described in patients with AIDS.

Isoxazolyl penicillins are suitable for the treatment of hospital-acquired coagulase-negative staphylococcal infections only if the strain involved is methicillin sensitive.

Dosage and Administration

Parenteral administration

Oxacillin, cloxacillin, dicloxacillin, and flucloxacillin can be administered intramuscularly (i.m.) or intravenously (i.v.). The usual adult parenteral dose is 1 g every 4–6 hours. This is often doubled or even further increased for severe infections. Oxacillin in a dosage of up to 18 g daily i.v. has been used to treat seriously ill patients [3]. Comparable i.v. doses for children are 100–300 mg/kg/day.

Newborn infants and children

The usual pediatric doses are 25–50 mg/kg 6-hourly. Children weighing more that 40 kg should be given adult doses. Conventional doses for isoxazolyl penicillins in neonates have been in the range of 25–50 mg/kg every 8–12 hours.

Impaired renal function

Compared with methicillin, the elimination half life of oxacillin in patients with renal impairment is much shorter, so that a high parenteral dosage of oxacillin (1 g every 4–6 hours) has been recommended for the treatment of severe infections in anuric patients [23].

Impaired hepatic function

There are no useful data on the effect of hepatic impairment on the isoxazolyl kinetics, and therefore no information on dosage modification.
 

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
child TDLo intravenous 2550mg/kg/17D (2550mg/kg) BLOOD: AGRANULOCYTOSIS Journal of Pediatrics. Vol. 90, Pg. 668, 1977.
guinea pig LD50 unreported 120mg/kg (120mg/kg)   Gigiena i Sanitariya. For English translation, see HYSAAV. Vol. 42(9), Pg. 10, 1977.
infant TDLo intravenous 3800mg/kg/19D (3800mg/kg) BLOOD: AGRANULOCYTOSIS Journal of Pediatrics. Vol. 89, Pg. 769, 1976.
man TDLo intravenous 3800mg/kg/19D (3800mg/kg) BLOOD: AGRANULOCYTOSIS Journal of Pediatrics. Vol. 89, Pg. 769, 1976.
Link to PubMed
mouse LD50 intravenous 1490mg/kg (1490mg/kg)   Pharmaceutical Chemistry Journal Vol. 1, Pg. 245, 1967.
mouse LD50 oral 6500mg/kg (6500mg/kg)   "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982Vol. -, Pg. 95, 1982.
mouse LD50 unreported 28gm/kg (28000mg/kg)   Gigiena i Sanitariya. For English translation, see HYSAAV. Vol. 42(9), Pg. 10, 1977.
rat LD50 unreported 10gm/kg (10000mg/kg)   Gigiena i Sanitariya. For English translation, see HYSAAV. Vol. 42(9), Pg. 10, 1977.
women TDLo intravenous 40mg/kg/7H-I (40mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE" Annals of Pharmacotherpy. Vol. 33, Pg. 1060, 1999.
women TDLo intravenous 5560mg/kg/20D (5560mg/kg) BLOOD: AGRANULOCYTOSIS Southern Medical Journal. Vol. 70, Pg. 1245, 1977.
women TDLo oral 200mg/kg/10D- (200mg/kg) GASTROINTESTINAL: OTHER CHANGES Southern Medical Journal. Vol. 77, Pg. 532, 1984.

Gastrointestinal side-effects

Oral administration of isoxazolyl penicillins may cause nausea and diarrhea, which only occasionally necessitates cessation of treatment. Antibiotic-associated colitis due to Clostridium difficile can be caused by these drugs; toxin-producing C. difficile was isolated from the feces of one child who developed watery diarrhea with i.v. oxacillin therapy, and from another child who developed diarrhea following 4 days of oral dicloxacillin [24].

Drug fever

This can occur with methicillin and other anti-staphylococcal penicillins; it is abrupt in onset and the patient usually appears otherwise relatively well. It rapidly resolves when the drug is stopped, and may recur later if another penicillin analog is administered [25].

Hepatotoxicity

Oxacillin occasionally causes fever, nausea, and vomiting associated with abnormal liver function tests, mainly elevated serum glutamic oxaloacetic transaminase (SGOT) levels [26-27]. Increases in liver enzymes are seen more commonly [28]. Liver biopsy may show a nonspecific hepatitis [29]. Some patients remain asymptomatic and anicteric, showing only elevated serum enzymes and sometimes eosinophilia [30].Hepatotoxicity due to oxacillin appears to be common in HIV-infected patients. In one series, 81% of such patients receiving oxacillin developed liver damage [31]. Rash is a frequent accompaniment of oxacillin hepatotoxicity [32]. Hepatotoxicity may be more common with oxacillin than other isoxazolyl penicillins, because it is cleared to a greater extent through the liver and biliary tract. It is a not infrequent reaction, especially with higher doses, and is probably a hypersensitivity reaction [27]. When oxacillin is administered intravenously to children in the outpatient setting, hepatotoxicity and rash are much more commonly observed (22% and 32%, respectively) than with nafcillin (0% and 10%, respectively) [32].

Neurotoxicity

This may occur if very large doses are given i.v., especially to patients with renal failure. A patient with acute bacterial endocarditis and impaired renal function convulsed while receiving 16 g oxacillin i.v. per day [33]. In this patient, predose oxacillin serum level was 270 mg/ml, serum level 1 hour after a dose was 340 mg/ml, and the CSF level was 70 mg/ml. 

Neutropenia

This has been noted particularly with oxacillin [32], but it can occur with the other isoxazolyl penicillins and with all b-lactam antibiotics. Four children developed marked neutropenia during the third week of treatment with i.v. oxacillin in a dose of 200 mg or more per kg per day [34]. In all cases the white cell count returned to normal when the drug was stopped. Oxacillin and other b-lactam antibiotics probably exert a toxic effect on the maturation of neutrophils [35], but antibody-mediated suppression of granulopoiesis may also be a factor, at least in some patients [36]. Acute agranulocytosis has been described in two patients receiving oxacillin therapy; both recovered when the drug was withdrawn [37-38]. 

Pharmacokinetic

Bioavailability 30%
Protein binding 94.2 +/- 2.1%
Metabolism  
Half-life 20 to 30 minutes
Cmax (mg/ml) 5.6 mg/ml (500mg per os)
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion urinary

Absorption

Oxacillin shows dose linearity with dose. The presence of food in the stomach interferes with absorption.

Distribution

Oral administration
When a 0.5-g oral dose of oxacillin is given, a peak serum level of about 4 mg/ml is reached in 30–60 minutes [39]. Thereafter, the serum concentration falls, but significant levels are maintained for 4–6 hours.

Parenteral administration
The peak serum level after i.m. oxacillin is twice that obtained when the same dose is given orally. Peak serum levels of oxacillin, cloxacillin, dicloxacillin, and flucloxacillin after a single i.m. injection of 0.5 g are similar (14–16 mg/ml) [40].

Newborn and premature infants
After a single i.m. injection of oxacillin in a dose of 20 mg/kg to newborn infants (aged 8–15 days), the mean peak serum concentration was 51.5 mg/ml and the mean serum half-life 1.6 hours. In infants aged 20–21 days, the peak level was 47 mg/ml and the mean serum half-life 1.2 hours [41].

Drug distribution of isoxazolyl penicillins is similar to that of other b-lactams. Detectable levels are found in most organs of the body except cerebrospinal fluid (CSF) in the absence of inflammation. However, only unbound interstitial fluid drug is active, and highly protein-bound drugs such as the isoxazolyl penicillins have restricted penetration to interstitial fluid as measured by microdialysis [42]. Indeed, free plasma concentrations are similar or the same as interstitial fluid in many tissues, and can be used to predict active tissue concentration in the absence of inflammation [43]. Tissue penetration does increase in the presence of inflammation. 

Therapeutic concentrations of oxacillin [44] have been detected in pleural fluid. Oxacillin, like other penicillins, does not penetrate into human polymorphonuclear leukocytes [45]. These drugs are excreted in breast milk and cross the placenta 46]. The levels in uninflamed CSF are very low [47], but both oxacillin and methicillin reach therapeutic concentrations in he CSF of rabbits with experimental staphylococcal meningitis [48]. After subconjunctival injection of 100 mg of oxacillin in the infected eyes of rabbits, tissue concentrations are high in the cornea, iris, and anterior chamber fluid, and these concentrations are higher than those achieved with methicillin. Oxacillin, like methicillin, penetrates poorly into the vitreous humor [49].

Excretion

Isoxazolyl penicillins are mainly excreted in the urine. Oral oxacillin is excreted to a lesser extent via the kidney, partly because of its poorer absorption and partly because more oxacillin is cleared by other mechanisms.

In patients with markedly impaired renal function, metabolites may represent up to 50% of the total serum level. In healthy subjects, 10–23% of these penicillins excreted in urine are in the form of metabolites. Isoxazolyl penicillins are excreted by both glomerular filtration and tubular secretion. Probenecid can delay their excretion by partly blocking renal tubular secretion.

Isoxazolyl penicillins are eliminated by the biliary tract to some extent; this is more marked with oxacillin than with cloxacillin. All the isoxazolyl penicillins are inactivated to some degree in the body, probably in the liver. Oxacillin is more rapidly destroyed in the body than the others, and therefore has little tendency to accumulate in patients with renal failure [50].

Metabolism

Isoxazolyl penicillins have relatively few drug interactions, and none are considered predictable. There are occasional reports of interaction between oxacillin and methotrexate, with the former reducing the clearance of methotrexate and in one case leading to significant methotrexate toxicity [51].

Mechanism of Action

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, Oxacillin inhibits the third and last stage of bacterial cell wall synthesis. The principal target appears to be the bifunctional enzyme PBP2. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that Oxacillin interferes with an autolysin inhibitor.

Antibacterial activity

The antibacterial spectrum of the isoxazolyl penicillins is similar to that of methicillin and nafcillin. Isoxazolyl penicillins are active against Gram-positive cocci, such as wild-type Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, viridans streptococci, and many species of Gram-positive bacteria, but Enterococcus species and Bacillus cereus are resistant. The Neisseria species are the only Gram-negative bacteria susceptible to these drugs.

The isoxazolyl penicillins are considerably less active than penicillin G against bacteria which are susceptible to penicillin G. However, they
are 4- to 8-fold more active than methicillin against S. aureus. Oxacillin has about the same activity as cloxacillin against S. aureus but dicloxacillin is slightly more active [52].

Table 1 shows the minimum inhibitory concentration (MIC) of the four isoxazolyl penicillins against some selected bacteria, and Table 2 shows the MIC distributions of a number of species. The MICs of cloxacillin, oxacillin, and flucloxacillin against staphylococci are increased 10-fold if the test is performed in 95% human serum instead of nutrient broth [40,53].
 

Table 1. In vitro activity of isoxazolyl penicillins.

Species Agent N. of strains MIC50 MIC90 Range Emerging resistance
Staphylococcus aureus Cloxacillin 11 0.125 0.25 0.06-0.25 Y
Staphylococcus aureus PenS Oxacillin 20 0.8 1.6 0.8-1.6 Y
Cloxacillin 23 0.25 0.5 0.06-0.5 Y
Staphylococcus aureus PenR Oxacillin 15 0.4 0.8 ≤0.2-1.6  
Oxacillin 25 0.25 0.5 ≤0.125-1 Y
Staphylococcus aureus Oxacillin 100 0.25 0.5 0.125-64  
Staphylococcus aureus methicillin susceptible Oxacillin 69 0.25 0.5 0.03-1 Y
Oxacillin 15 0.5 1 0.25-2 Y
Oxacillin 49 0.2 0.4 0.2-0.4 Y
Oxacillin 11 0.125 0.25 0.125-0.5 Y
Staphylococcus aureus methicillin resistant Oxacillin 33 1.6 100 ≤0.2->100  
Oxacillin 19 64 >64 4->64  
Oxacillin 15 128 >128 64->128  
Oxacillin 50 >50 >50 >50  
Oxacillin 12 >128 >128 >128  
Oxacillin 14 128 >128 128->128  
Staphylococcus epidermidis methicillin susceptible Oxacillin 16 ≤0.2 0.8 ≤0.2-3.1 Y
Oxacillin 45 0.06 0.25 ≤0.03-2 Y
Staphylococcus epidermidis methicillin resistant Oxacillin 29 3.1 25 ≤0.2-25  
Oxacillin 38 16 >64 4->64  
Staphylococcus epidermidis Oxacillin 26 1 64 0.125->128 Y
Staphylococcus haemolyticus Oxacillin 13 100 >100 ≤0.2->100 Y
Streptococcus pyogenes Cloxacillin 14 100 >100 ≤0.2->100  
Oxacillin 10 ≤0.06 ≤0.06 ≤0.06  
Streptococcus pneumoniae Cloxacillin 16     0.125-0.25 Y
Streptococcus pneumoniae penicillin resistant Oxacillin 9 8 64 4-64  
Streptococcus agalactiae Oxacillin 10 0.5 0.5 0.5-4  
Streptococcus Gp C & G Oxacillin 10 ≤0.06 ≤0.06 ≤0.06  
Viridans Streptococcus spp. penicillin susceptible Oxacillin 29 0.5 1 ≤0.06-2 Y
Viridans Streptococcus spp. penicillin resistant Oxacillin 10 32 32 4-64  
Enterococcus faecalis Cloxacillin 15     32-64  
Oxacillin 30 16 32 8-64  
Enterococcus faecium Oxacillin 10 >128 >128 128->128  
Bacillus anthracis Cloxacillin 13     0.5  
Bacillus spp. (non cereus) Oxacillin 35 0.25 16 ≤0.125->16 Y
Neisseria gonorrhoeae Cloxacillin 25     0.75->4  
Neisseria meningitidis Cloxacillin 2     0.25-1  
Moraxella catarrhalis Cloxacillin 7     0.25-2  

Table 2. MIC distributions for isoxazolyl penicillins.

Species Agent

MIC (mg/ml)

    ≤0.03 0.06 0.125 0.25 0.5 1 2 4 8 >16
Staphylococcus aureus Oxacillin 17 190 1240 4852 7773 1478 283      
      1 10 9 5 1 1 25
      3 79 14          
      1 10 21 4        
Cloxacillin   1 31 2 2          
Dicloxacillin   6 8  22            
Staphylococcus aureus, penicillin susceptible Oxacillin   3 26 13  2          
Cloxacillin     26 29 10          
Dicloxacillin   3 33 27 2          
Flucloxacillin   2 43 14 6          
Staphylococcus capitis Oxacillin   3 22 94 28 3        
Staphylococcus epidermidis Oxacillin   84 566 884 137 366        
      23 6 0 10 7 8 5 40
      5 44 29 15 1 12 2 7
Cloxacillin         3 1        
Dicloxacillin   2 4 14 9 3        
Staphylococcus haemolyticus Oxacillin   10 34 61 50 18        
      5 12  8 2     2 46
Staphylococcus hominis Oxacillin   13 78 104 23 23        
      22 10 2       1
Staphylococcus lugdunensis Oxacillin   3
 
6 38 83 28 7      
Staphylococcus saprophyticus Oxacillin     9 6 23 59        
        1 5 31 2      
Staphylococcus simulans Oxacillin   1 12 24 6 3        
Staphylococcus warneri Oxacillin   1 7 48 42 7        
Staphylococcus xylosus Oxacillin         1 4 7 14 14  
Actinomyces israelii Oxacillin         1 4 14 10 2  
Dicloxacillin         1 1 9 17 2 2

Penicillin-tolerant S. aureus

These strains have a deficiency in an autolytic enzyme on their cell surface, which appears to be necessary before any penicillins, including
penicillinase-resistant penicillins, can exert a bactericidal effect. Oxacillin tolerance in S. aureus can also be due to enhanced secretion of an autolysin inhibitor, such as lipoteichoic acid [54]. Tolerance seems to be quite common, and was found in 30–60% of strains isolated from blood cultures [55-56]. S. aureus cultures are heterogeneous with regard to tolerance; the majority of cells are not tolerant to the antibiotic tested, and the remainder are tolerant to varying degrees [55, 57-58]. Tolerance of S. aureus strains to oxacillin may disappear after storage of the organism in the laboratory [59]. With many strains tolerance may be demonstrable in the laboratory only at an acid pH of 6.22 but not at pH of 7.15 [60]. It is uncertain whether such pH-induced tolerance has any clinical relevance.

Other pharmacological effects

 Oxacillin is a penicillin b-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually gram-positive, organisms. The name "penicillin" can either refer to several variants of penicillin available, or to the group of antibiotics derived from the penicillins. Oxacillin has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of Oxacillin results from the inhibition of cell wall synthesis and is mediated through Oxacillin binding to penicillin binding proteins (PBPs). Oxacillin is stable against hydrolysis by a variety of b-lactamases, including penicillinases, and cephalosporinases and extended spectrum b-lactamases.


Medicinal Chemistry

CAS number: 66-79-5  EINECS: 200-635-5

Molecular Formula:  C19H19N3O5S

Average mass: 423.418 Da

Monoisotopic mass:  423.086486066 Da

Systematic name: 2S,5R,6R)-3,3-dimethyl-6-(5-methyl-3-phenyl-1,2-oxazole-4-amido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: [H][C@]12SC(C)(C)[C@@H](N1C(=O)[C@H]2NC(=O)C1=C(C)ON=C1C1=CC=CC=C1)C(O)=O

Std. InChI: 1S/C19H19N3O5S/c1-9-11(12(21-27-9)10-7-5-4-6-8-10)15(23)20-13-16(24)22-14(18(25)26)19(2,3)28-17(13)22/h4-8,13-14,17H,1-3H3,(H,20,23)(H,25,26)/t13-,14+,17-/m1/s1

ACD/LogP: 2.53±0.34 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -0.52 ACD/LogD (pH 7.4): -1.20
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: 8 #H bond donors: 2
#Freely Rotating Bonds: 4 Polar Surface Area: 138.04 Å2
Index of Refraction: 1.685 Molar Refractivity: 106.2±0.4 cm3
Molar Volume: 279.3±5.0 cm3 Polarizability: 42.1±0.5 10-24cm3
Surface Tension: 79.2±5.0 dyne/cm Density: 1.6±0.1 g/cm3
Flash Point: 370.9±31.5 °C Enthalpy of Vaporization: 106.2±3.0 kJ/mol
Boiling Point: 689.7±55.0 °C at 760 mmHg Vapour Pressure: 0.0±2.3 mmHg at 25°C

 

Major Impurities:

Appearance:

Melting point: 188°C

Optical rotation:

Solubility: 13.9 mg/L (water)

logP: 2.38

pKa: 2.72
 

Stability:

 


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