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Meticillin

Methicillin was the first penicillinase-resistant semi-synthetic penicillin to be derived from the penicillin nucleus, 6-aminopenicillanic acid (6-APA) [1]. Meticillin is a narrow-spectrum b-lactam antibiotic of the penicillin class that  was developed by Beecham in 1959.[2] 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.

Therapeutic use

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
Methicillin resistant Staphylococcus aureus (MRSA) - 15.6 mg/mL - >1000 mg/mL
Streptococcus pneumoniae 0.39 mg/mL

Meticillin is no longer used to treat patients. Compared to other b-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare side-effect of penicillins. However, it serves a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other beta-lactamase-resistant penicillins.

Dosage and Administration

Adults

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 0–7 days old. For infants still weighing less than 2000 g, but who are 8–30 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 0–7 days, and the same dose 6-hourly to those aged 8–30 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 [5], including staphylococcal septicemia and endocarditis [6]. 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 [19].

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.

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
man TDLo oral 11gm/kg/32D-I (11000mg/kg) KIDNEY, URETER, AND BLADDER: "CHANGES IN TUBULES (INCLUDING ACUTE RENAL FAILURE, ACUTE TUBULAR NECROSIS)"

KIDNEY, URETER, AND BLADDER: INTERSTITIAL NEPHRITIS
New England Journal of Medicine. Vol. 279, Pg. 1245, 1968.
man TDLo unreported 229mg/kg/8D-I (229mg/kg) KIDNEY, URETER, AND BLADDER: URINE VOLUME INCREASED

KIDNEY, URETER, AND BLADDER: HEMATURIA
Antimicrobial Agents and Chemotherapy Vol. -, Pg. 765, 1961.
mouse LD50 intracrebral 38340mg/kg (38.34mg/kg)   Journal of Antibiotics, Series B. Vol. 16, Pg. 40, 1963.
mouse LD50 intravenous 3720mg/kg (3720mg/kg)   Antibiotiki. Vol. 10, Pg. 629, 1965.

Adverse effects

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.

Hypersensitivity reactions

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 [7]. 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% [8].

Drug fever

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 [8].

Hematologic
Adverse hematologic effects occur in approximately 7% of treated patients and appear to be associated with higher doses given for long periods of time. Recovery generally occurs within one to two weeks. Hematologic adverse effects reported with methicillin include neutropenia, leukopenia, and thrombocytopenia. Agranulocytosis has been reported rarely.

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 10–20 days after starting treatment [8]. 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.

Hepatic
Meticillin therapy has resulted in transient increases in liver function tests. As with the isoxazolyl penicillins, elevation of serum glutamic
oxaloacetic transaminase has been occasionally observed during meticillin therapy [9].

Hypersensitivity
Hypersensitivity reactions to methicillin include rash (2% to 6%), eosinophilia (up to 38%), pruritus, fever, chills, and myalgias. Meticillin is contraindicated in patients who are allergic to penicillin.

Local
Local reactions include thrombophlebitis associated with intravenous administration, and pain at injection site if given intramuscularly.

Renal
Acute renal failure and interstitial nephritis have been associated with meticillin therapy and can be caused by large i.v. doses [10-12]. These problems occur most frequently after prolonged therapy (longer than ten days). Acute interstitial nephritis may be accompanied by rash, fever, dysuria, proteinuria, eosinophilia, and hematuria.Microscopic changes in the kidneys consist of patchy but usually heavy interstitial infiltrate with lymphocytes, plasma cells, and eosinophils, i.e. interstitial changes without glomerular abnormalities.

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 patient’s disease, such as staphylococcal septicemia [13]. 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 frequency of acute interstitial nephritis is higher with meticillin than other penicillinase-resistant penicillins and has been reported in up to 17% of patients. Acute renal failure generally occurs after ten days and with doses of methicillin greater than 200 mg/kg/day. Renal function slowly returns towards normal after discontinuation of meticillin, but irreversible decreases in renal function have been observed.

The clinical picture suggests that a delayed hypersensitivityreaction may be involved in methicillin nephritis [16]. Immunofluorescent studies in one patient showed that dimethoxphenyl-penicilloyl, the hapten group of methicillin, was firmly bound to kidney tissue together with immunoglobulin [10]. 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 [17]. 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 [18]. 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 [21].

Pharmacokinetic

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% [22].

Bioavailability 0%
Protein binding  
Metabolism hepatic 20-40%
Half-life 50-60 min
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion renal

Absorption

Meticillin is not orally absorbed.

Distribution

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 3–4 mg/ml after 3 hours [23]. 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 2–3 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 [24], and in septic joint effusions [25]. The drug reaches high concentrations in the pus and bone of patients with acute osteomyelitis [26]. As with other penicillins, only low methicillin concentrations are attained in normal CSF, but these may be moderately high in patients with meningitis.

Excretion

Meticillin is excreted in urine in an unchanged active form [27]. 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 2–3% 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.

Metabolism

 

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.

Antibacterial activity

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.

Species

 
Nr. of strains
tested
MIC
50
MIC
90
Range Emerging
resistance
Reference
Staphylococcus aureus, methicillin susceptible 23 1 2 0.5–2 Yes [28]
  51 1.56 3.13 0.39–3.13   [29]
Staphylococcus aureus, methicillin resistant 51 50  >100 6.25–>100   [29]
Staphylococcus epidermidis, methicillin susceptible 29 1.56  3.13 0.39–3.13 Yes [29]
Staphylococcus epidermidis, methicillin resistant 20 50 >100 6.25–>100 Yes [29]
Staphylococcus saprophyticus 20 8 8 0.5–8   [30]

Table 2. MIC distributions for methicillin among key staphylococcal species [31].

Species

MIC (mg/ml)

  0.5 1 2 4 8 16 32 64 128
Staphylococcus aureus, methicillin susceptible
 
  4 21 11          
Staphylococcus epidermidis, penicillin resistant   
 
2 10 33 37 21 4    6 3
Staphylococcus epidermidis, penicillin susceptible   8 9  34 3 4      

 

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
resistance is mediated through the acquisition of a gene that encodes an additional penicillin-binding protein (PBP), PBP2a (sometimes
designated PBP2'), which performs the functions of PBP2, but has much lower affinity for methicillin and most other b-lactams [32].
 

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.


Medicinal Chemistry

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

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)C3=C(C=CC=C3OC)OC)C(=O)O)C

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

ACD/LogP: 1.27±0.26 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -1.78 ACD/LogD (pH 7.4): -2.46
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: 5 Polar Surface Area: 130.47 Ε2
Index of Refraction: 1.639 Molar Refractivity: 94.4±0.4 cm3
Molar Volume: 262.6±5.0 cm3 Polarizability: 37.4±0.5 10-24cm3
Surface Tension: 67.4±5.0 dyne/cm Density: 1.4±0.1 g/cm3
Flash Point: 340.9±31.5 °C Enthalpy of Vaporization: 99.3±3.0 kJ/mol
Boiling Point: 640.0±55.0 °C at 760 mmHg Vapour Pressure: 0.0±2.0 mmHg at 25°C

 

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

logP: 1.22

pKa: 2.77
 

Stability:

 


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