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.
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 , conﬁrming that isoxazolyl penicillins alone can effectively cover
S. aureus and S. pyogenes in this
For moderately severe complicated skin and skin structure infections, oxacillin i.v. followed by dicloxacillin orally has been shown to be effective .
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 . The addition of gentamicin is often associated with increased nephrotoxicity . 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 .
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 . 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
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
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 . 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 .
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.
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 .
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 .
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 . Liver biopsy may show a nonspeciﬁc hepatitis . Some patients remain asymptomatic and anicteric, showing only elevated serum enzymes and sometimes eosinophilia .Hepatotoxicity due to oxacillin appears to be common in HIV-infected patients. In one series, 81% of such patients receiving oxacillin developed liver damage . Rash is a frequent accompaniment of oxacillin hepatotoxicity . 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 . 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) .
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 . 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.
This has been noted particularly with oxacillin , 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 . 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 , but antibody-mediated suppression of granulopoiesis may also be a factor, at least in some patients . Acute agranulocytosis has been described in two patients receiving oxacillin therapy; both recovered when the drug was withdrawn [37-38].
Oxacillin shows dose linearity with dose. The presence of food in the stomach interferes with absorption.
Newborn and premature infants
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 . 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 . Tissue penetration does increase in the presence of inﬂammation.
Therapeutic concentrations of oxacillin  have been detected in pleural ﬂuid. Oxacillin, like other penicillins, does not penetrate into human polymorphonuclear leukocytes . These drugs are excreted in breast milk and cross the placenta 46]. The levels in uninﬂamed CSF are very low , but both oxacillin and methicillin reach therapeutic concentrations in he CSF of rabbits with experimental staphylococcal meningitis . 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 .
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 .
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 .
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.
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
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.
Table 2. MIC distributions for isoxazolyl penicillins.
Penicillin-tolerant S. aureus
These strains have a deﬁciency in an
autolytic enzyme on their cell surface, which appears to be necessary before any
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.
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
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
Melting point: 188°C
Solubility: 13.9 mg/L (water)
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