Methicillin was the ﬁrst penicillinase-resistant semi-synthetic penicillin to be derived from the penicillin nucleus, 6-aminopenicillanic acid (6-APA) . Meticillin is a narrow-spectrum b-lactam antibiotic of the penicillin class that was developed by Beecham in 1959. It was previously used to treat infections caused by susceptible Gram-positive bacteria, in particular, b-lactamase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins, but it is no longer clinically used.
Meticillin was used to treat infections caused by certain Gram-positive bacteria including Staphylcoccus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, methicillin is not as effective against these organisms due to increasing resistance.
The following provides susceptibility data on a few medically significant bacteria:
Staphylococcus aureus - 0.125 mg/mL
- >100 mg/mL
Dosage and Administration
Meticillin is unstable in acids, so it is ineffective if given orally. Methicillin can be administered i.m. or i.v. The dose can be varied widely according to the site and severity of infection. For infections of moderate severity, a commonly used adult dosage is 1 g 4-hourly. For serious infections, the dose is often doubled or increased even further. Daily doses of up to 25 g have been given i.v. for several weeks without toxic effect.
Newborn infants and children
The usual dose of meticillin for children is 100 mg/kg body weight per day, given in four or six divided doses. Renal excretion of meticillin in newborn infants is decreased. A dose of 25 mg/kg body weight every 12 hours should be given to infants weighing less than 2000 g and who are 07 days old. For infants still weighing less than 2000 g, but who are 830 days old, the dose of 25 mg/kg should be given 8-hourly. For infants weighing more than 2000 g, the dose is 25 mg/kg given 8-hourly to those aged 07 days, and the same dose 6-hourly to those aged 830 days [3-4]. After the age of one month, meticillin should be administered in doses recommended for older children.
S. aureus infections
Meticillin is useful for the treatment of S. aureus infections (proven or suspected) due to b-lactamase-producing staphylococci which are resistant to penicillin G. Originally, this antibiotic was regarded as the drug of ﬁrst choice for severe staphylococcal infections, such as septicemia, endocarditis, pneumonia, meningitis, osteomyelitis, and septic arthritis. It is effective for the treatment of penicillin-resistant staphylococcal infections , including staphylococcal septicemia and endocarditis . It was extensively used for these infections for some years after its discovery. All other parenteral b-lactamase-resistant penicillins, such as oxacillin, cloxacillin, dicloxacillin, ﬂucloxacillin, and nafcillin, have the same therapeutic efﬁcacy as methicillin .
Staphylococcus epidermidis infections
Meticillin was used for severe hospital-acquired S. epidermidis infections, such as prosthetic valve endocarditis, provided that the strain was sensitive. For the reasons given above, one of the isoxazolyl penicillins or nafcillin are now preferred for these infections. Meticillin, other penicillinase-resistant penicillins, and cephalosporins are no longer suitable for immediate emergency treatment of severe hospital-acquired S. epidermidis infections, as >50% of hospital strains are meticillin resistant.
Adverse reactions to meticillin, particularly renal reactions, are more common than with other antistaphylococcal penicillins. For this reason, meticillin is no longer marketed for human use.
These should be anticipated in patients known to be sensitive to the penicillins. However, not all patients allergic to penicillin G react to meticillin. In a study of eight consecutive patients with histories of penicillin G anaphylaxis, it was shown that all tolerated usual i.m. doses of methicillin without reaction . Antecedent skin testing with penicillin G in these patients gave positive reactions, while similar tests with meticillin were negative. Skin testing with these reagents is not recommended. Severe allergic reactions to meticillin and to other semisynthetic penicillins may be less common than to penicillin G. Nevertheless, it should be assumed that patients allergic to other penicillins will be sensitized to meticillin, and it should be avoided in such subjects. All hypersensitivity reactions which occur with penicillin G can be provoked by meticillin. In a study of 124 children who received methicillin for 10 days or longer, the frequency of skin rashes, either maculopapular or urticarial, was 6% .
This advers effect can occur with meticillin. 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 .
Leukopenia is fairly common during
methicillin therapy. It was observed in 16 of 124 children who received
methicillin for 10 days or longer, and it usually occurred 1020 days after
starting treatment . Some patients developed a decrease in both neutrophils
and lymphocytes, others an absolute neutropenia (less than 500/mm3).
The white cell count usually reverted to normal in a few days after cessation of
methicillin. The leukopenia may worsen if another penicillin, such as oxacillin,
is substituted for methicillin. No serious problems resulting from leukopenia
have been encountered. Similar to that described with penicillin G,
Coombs-positive hemolytic anemia can also be caused by meticillin.
Sometimes hematuria may be the sole
manifestation of nephropathy, and in such cases it may be difﬁcult to
distinguish whether this is due to the drug or to the patients disease, such as
staphylococcal septicemia . Hematuria and dysuria may also result in some
methicillin-treated patients because the drug occasionally causes a hemorrhagic
cystitis, possibly by direct chemical irritation [8, 14-15]. This complication
is distinct from meticillin-induced interstitial nephritis, and its presence can
be conﬁrmed by cystoscopy. In meticillin cystitis, hematuria may disappear when
a few doses of the drug are omitted, and therapy is resumed with a lower daily
dose in association with an increase in ﬂuid intake. As in the case of
meticillin-induced interstitial nephritis, it is preferable to discontinue
meticillin when this complication occurs. Most patients recover slowly and
completely from meticillin interstitial nephritis after cessation of the drug.
Corticosteroid therapy should be considered for severe cases.
The clinical picture suggests that a delayed hypersensitivityreaction may be involved in methicillin nephritis . Immunoﬂuorescent studies in one patient showed that dimethoxphenyl-penicilloyl, the hapten group of methicillin, was ﬁrmly bound to kidney tissue together with immunoglobulin . In another patient, a methicillin antigen, assumed to be dimethoxyphenyl-penicilloyl, was ﬁxed in a linear pattern along the renal tubular basement membrane together with IgG and the C3 component of complement. This patient also had a serum autoantibody, which was reactive with tubular basement membranes of normal human and monkey kidneys . Methicillin nephritis therefore may be an example of drug-induced autoimmunity. Methicillin acts as a hapten and alters the antigenicity of the tubular basement membrane; resultant autoantibodies react not only against the drug, but also against the tissue antigen . Meticillin nephritis appears to be a common complication when large doses of the drug are given for extended periods [19-20]. This side-effect was more common with methicillin than with other penicillins .
Meticillin is not absorbed when administered orally. The estimated elimination half-life of methicillin is around 30 minutes. Meticillin has relatively low protein binding to serum albumin. Depending on the type of assay binding ranges from 37% to 49% .
Meticillin is not orally absorbed.
After a 1-g i.m. dose, a mean peak serum level of 18 mg/ml is reached after 30 minutes, and this level falls to 34 mg/ml after 3 hours . After an i.v. injection of 1 g meticillin over a 5-minute period, a peak serum level of about 60 mg/ml is reached. This peak level is doubled by doubling the dose. Subsequently, there is a rapid fall in the serum level to about 7 mg/l after 1 hour, and after 23 hours the level is usually less than 1 mg/ml. Usually meticillin cannot be detected in the serum after 4 hours.
Meticillin is widely distributed in various body ﬂuids. Antibacterial levels which equate with those in serum occur in pleural, pericardial, and ascitic ﬂuids , and in septic joint effusions . The drug reaches high concentrations in the pus and bone of patients with acute osteomyelitis . As with other penicillins, only low methicillin concentrations are attained in normal CSF, but these may be moderately high in patients with meningitis.
Meticillin is excreted in urine in an unchanged active form . Very high urine concentrations of meticillin are attained, provided renal function is normal. It is excreted by both glomerular ﬁltration and tubular secretion, and up to 80% of an injected dose can be recovered from urine. Probenecid delays renal tubular secretion. Some 23% of an injected dose is excreted in bile. This is not reabsorbed, and is subsequently destroyed in the gut. The fraction of meticillin which is not excreted is inactivated in the body. Like penicillin G, it still disappears from the blood at a signiﬁcant, but reduced, rate in anuric patients. The liver is an important extrarenal site for inactivation of the penicillins, including meticillin.
Mechanism of Action
Like other b-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. It does this by binding to and competitively inhibiting the transpeptidase enzyme used by bacteria to cross-link the peptide (D-alanyl-alanine) used in peptidogylcan synthesis.
The activity of methicillin is similar to that of penicillin G. Methicillin is active against Gram-positive bacteria and also against Gram-negative cocci, such as meningococci and gonococci. Gonococci with altered penicillin-binding proteins have elevated minimum inhibitory concentrations (MICs) to methicillin, as well as penicillin G. Methicillin is some 20- to 50-fold less active than penicillin G against bacteria susceptible to both drugs. The MICs of methicillin against some key bacteria are listed in Tables 1 and 2. Methicillin inhibits the growth of both penicillin susceptible and penicillinase-producing staphylococci.
Table 1. In vitro activity of methicillin.
Table 2. MIC distributions for methicillin among key staphylococcal species .
Methicillin-resistant Staphylococcus aureus
Staphylococcal resistance to
methicillin is not due to the destruction of the antibiotic by a bacterial
enzyme such as a b-lactamase, but it is acquired in a
different manner. There is no penetration barrier to methicillin in
methicillin-resistant S. aureus (MRSA) strains. Instead
Other pharmacological effects
Meticillin is insensitive to b-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ortho-dimethoxyphenyl group directly attached to the side-chain carbonyl group of the penicillin nucleus increase the b-lactamase resistance, since those enzymes are relatively intolerant to the steric hindrance of the side-chain . Thus, it is able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by b-lactamases.
CAS number: 61-32-5 EINECS: 200-505-8
Molecular Formula: C17H20N2O6S
Average mass: 380.415497 Da
Monoisotopic mass: 380.104218 Da
Systematic name: (2S,5R,6R)-6-[(2,6-Dimethoxybenzoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Std. InChI: 1S/C17H20N2O6S/c1-17(2)12(16(22)23)19-14(21)11(15(19)26-17)18-13(20)10-8(24-3)6-5-7-9(10)25-4/h5-7,11-12,15H,1-4H3,(H,18,20)(H,22,23)/t11-,12+,15-/m1/s1
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