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Pivmecillinam

Pivmecillinam is an orally active prodrug of mecillinam, an extended-spectrum penicillin antibiotic. Pivmecillinam is the pivaloyloxymethyl ester of mecillinam. Mecillinam is a 6-b-amidinopenicillanic acid [1-2] and in its hydrochloride dihydrate form, is suitable for i.m. or i.v. administration, but it is not absorbed when given orally. Pivmecillinam is only considered to be active against Gram-negative bacteria, and is used primarily in the treatment of lower urinary tract infections [3-4]. It has also been used to treat paratyphoid fever [5].

Therapeutic use

Mecillinam is active against most pathogenic Gram-negative bacteria, except Pseudomonas aeruginosa and some species of Proteus [6]. Several studies have also found it to be as effective as other antibiotics for treating Staphylococcus saprophyticus infection, even though it is Gram-positive, possibly because mecillinam reaches very high concentrations in urine [3].

Urinary tract infections

Mecillinam has been fairly extensively used for the treatment of urinary tract infections (UTIs). Escherichia coli infections respond very well and those caused by other Enterobacteriaceae, such as Klebsiella, Proteus, or Enterobacter spp., also usually respond satisfactorily [7-8]. The efficacy of mecillinam in both uncomplicated and complicated infections is similar to that of ampicillin or co-trimoxazole [8-10]. Bacteriologic success rate in patients with bacteriuria in pregnancy was 87% in one study, and the drug appeared safe as there were no drug-related fetal abnormalities [11]. Pivmecillinam was compared with pivampicillin in gynecologic patients with bacteriuria at the time of removal of an indwelling catheter 3–4 days after surgery. After treatment, all 17 patients in the pivmecillinam group, but only 6 of 14 patients in the pivampicillin group were cured [12]. Uncomplicated urinary tract infections caused by S. saprophyticus may occasionally respond to pivmecillinam treatment, but the drug is unlikely to be effective in infections caused by E. faecalis [13]. However, other authors who treated 15 women with S. saprophyticus bacteriuria, found on review 2–4 weeks after treatment, that only 11 patients were cured [14]. They suggested that mecillinam should not be used for treatment of urinary tract infections caused by this organism, which is resistant to mecillinam in vitro. Pivmecillinam or a pivmecillinam–pivampicillin combination have been compared for the treatment of urinary tract infections in patients with underlying urological abnormalities. Combination therapy was more successful in eradicating urinary pathogens [15-17]. Combination mecillinam and cefoxitin therapy was efficacious for the treatment of complicated urinary tract infections caused by multi-resistant Serratia marcescens strains [18]. Pivmecillinam in a single bed-time dose of 5–10 mg/kg appeared satisfactory for long term prophylaxis to girls with recurrent bacteriuria [19]. The markedly enhanced effect obtained when E. coli is exposed to mecillinam in conditions of low osmolality, suggests that it may be advisable to reduce urine osmolality by increased fluid intake, when mecillinam is used to treat urinary tract infections [20].

Salmonella infections

In a study, 26 patients with typhoid or paratyphoid fever; cure was obtained in 23 and the three others relapsed [21]. Results in 21 other patients treated with co-trimoxazole did not differ from the mecillinam-treated group, except in the frequency of convalescent excretion of salmonellae. Only three patients in the mecillinam-treated group had negative stools following treatment, compared with 13 out of 21 in the co-trimoxazole-treated group. Another study had less favorable results with only 7 of 12 typhoid fever patients being cured by mecillinam [22]. Two other patients with typhoid fever who were cured clinically by chloramphenicol, but had positive stool cultures after therapy, were given pivmecillinam 800 mg three times per day in an attempt to eradicate the organisms. Unexpectedly, while the patients were taking the drug, they had clinical relapses of the disease, confirmed by positive blood cultures [23] (Jones et al., 1982). These experiences suggest that mecillinam alone is unreliable for the treatment of typhoid fever. Mecillinam 800 mg was used with amoxicilin 750 mg, both given i.v. 6-hourly, to treat seven patients with enteric fever; treatment was continued until 48 hours after defervescence (4–10 days), when pivmecillinam 400 mg orally 6hourly plus probenecid was used to complete a total of 14 days’ chemotherapy. All patients responded initially, but after treatment one patient relapsed 20 days later and only one patient had six sequential negative stool cultures [24]. It was considered that this combination had no advantage over conventional therapy of enteric fever. Some authors treated 12 patients with typhoid by a combination of pivmecillinam and pivampicillin for 10–14 days; all responded to treatment and stool cultures were negative in eight patients who were available for follow-up. In four patients, the S. typhi strain was ampicillin resistant and, as expected, these strains showed relative resistance to mecillinam (MIC 1.3–2.5 mg/ml). Nevertheless, mecillinam and ampicillin were synergistic against these strains in vitro, which was compatible with the clinical outcome [25]. Similarly, 15 enteric fever patients were treated with fixed-dose combination tablets, each containing 100 mg of pivmecillinam and 125 mg of pivampicillin; the dosage was two tablets four times a day, but six patients received i.v. chemotherapy initially [26]. All patients responded satisfactorily, but they were not monitored for persistent fecal excretion of S. typhi. Twelve enteric fever patients were also treated with mecillinam alone; clinical response was satisfactory in only eight. Mecillinam may be suitable for the treatment of septicemias caused by other Salmonella spp. A mecillinam–ampicillin combination was used successfully to control septicemia in a patient with S. enteritidis endocarditis associated with a prosthetic heart valve [27]. Another group treated 12 chronic salmonella carriers (two S. typhi, two S. paratyphi B, and eight other Salmonella spp.), with oral pivmecillinam 300 mg four times daily, for 28 days [28]. The carrier state was eradicated in eight patients, but three of these also had a cholecystectomy. Mecillinam-resistant salmonellae emerged during treatment in the remaining four patients. In another study, a 6-week course of mecillinam eradicated the Salmonella carrier state from one of three long-term Salmonella carriers; a 6-week course of pivmecillinam and pivampicillin (plus oral probenecid in one patient) subsequently eliminated the carrier state in the other two patients [29].

Other diarrheal illnesses

In one trial, either oral pivmecillinam or oral mecillinam (which is not absorbed) appeared to be equally as effective as co-trimoxazole in adults and children with infections due to Vibrio cholerae and V. parahaemolyticus [30]. Oral pivmecillinam seems comparable to ampicillin for the treatment of shigella dysentery, and it may also prove to be effective for the treatment of this disease caused by ampicillin-resistant strains [31-32]. The combination of pivampicillin and pivmecillinam also eradicates the organism from most Shigella spp. carriers [33].

Other infections caused by Gram-negative bacilli

Parenterally administered, mecillinam may be suitable for the treatment of septicemias and other systemic infections caused by E. coli and other sensitive Enterobacteriaceae. Addition of mecillinam to cefazolin–carbenicillin for early therapy of septicemia caused by Gram-negative organisms in patients with serious underlying diseases did not improve results of treatment [34]. In a controlled study of infantile gastroenteritis caused by enteropathogenic E. coli, one group received mecillinam, another received co-trimoxazole, and a third group a placebo. Cure rates evaluated clinically on the third day were 79% for mecillinam, 73% for co-trimoxazole, and 7% in control subjects. Organisms were eliminated from the bowel in 53% of patients who received either antibiotic, but from none of those who received a placebo [35]. Some success has been obtained by combining mecillinam with other b-lactam antibiotics, such as carbenicillin, ticarcillin, cephalothin, cefamandole, or cefoxitin, for the treatment of severe infections, such as pyelonephritis, septicemia, and pneumonia caused by Gram-negative bacilli [36-37]. However, a combination of mecillinam plus ticarcillin or carbenicillin was only moderately effective as initial therapy for neutropenic, febrile cancer patients [38].

Chronic bronchitis

An amoxicillin–mecillinam combination (either amoxicillin 250 mg and pivmecillinam 200 mg or double the dose of both drugs, three times daily) has been compared with amoxicillin alone, 500 mg three times daily, in 10-day courses for the treatment of purulent exacerbations of chronic bronchitis [39]. By the seventh day of treatment, a greater improvement was noted in patients
receiving the combination therapy. At the end of treatment, results in patients receiving the lower dosage were the same as with amoxicillin, but clinical improvement was better in those receiving the higher doses of the combination; patients who were treated with amoxicillin alone later relapsed more frequently. Combination of amoxicillin and pivmecillinam may be superior to amoxicillin alone in chronic bronchitis caused by H. influenzae and organisms such as E. coli, the latter being sometimes a respiratory tract pathogen in debilitated patients. In another study of patients with acute exacerbations of chronic bronchitis, a pivmecillinam–pivampicillin combination was equally as effective as co-trimoxazole [40].

Dosage and Administration

Adults

For parenteral use, mecillinam hydrochloride dihydrate is available as a powder, containing 82% anhydrous mecillinam, which when dissolved in sterile water is suitable only for i.m. or i.v. administration. This should be administered i.v. in doses of 10 mg/kg (600 mg for adults), as a 15-minute infusion every 4 hours, for the treatment of severe systemic infections. For the treatment of urinary tract infections, 10 mg/kg administered i.v. 6-hourly is sufficient. The i.m. dosage of the drug is the same [41-42]. In clinical trials, somewhat different dosages have been used. Some authors [43] used 400 mg i.m. or i.v. every 6 hours to treat adults with typhoid fever; Others [34] prescribed mecillinam 600 mg i.v. 6-hourly for the treatment of Gram-negative septicemias; and as much as 800 mg i.v. 6-hourly in combination with amoxicillin for the initial treatment of typhoid fever, has been used [44]. Pivmecillinam is available in capsules of 150 or 200 mg, each containing 68% anhydrous mecillinam, suitable for oral administration. Depending on the nature and severity of the infection, pivmecillinam can be given in adult doses of 200–400 mg three or four times daily [11, 26, 28-29]. Probenecid, in an adult dose of 1 g daily, can also be administered to augment serum levels, when systemic infections, such as typhoid fever, are treated by oral pivmecillinam [44].

Newborn infants and children

In young children, 40 mg/kg body weight per day has been given i.m. to treat enteropathogenic E. coli gastroenteritis [35]. In young children, oral pivmecillinam has been used in a dosage of 80 mg/kg/day (twice the parenteral dose), administered in four divided doses, to treat E. coli gastroenteritis [35].

Impaired renal function

The serum half-life of mecillinam, normally 53 minutes, is prolonged to 334 minutes in patients with severe renal failure. When mecillinam was given in a dosage of 400 mg i.v. 6-hourly for 5 days to patients with severe renal failure, high serum concentrations were attained, but there was no further accumulation of the drug after the first few days. Accordingly, it was recommended that mecillinam can be given safely and in normal doses for short-term treatment of patients with renal failure, even when renal function is severely reduced. For long-term treatment, the mecillinam dose should be reduced in patients with severe renal failure [45]. Other authors recommend that the mecillinam dose should always be reduced in patients with severe renal failure [46-47]. In patients receiving treatment by chronic hemodialysis, the rate of removal of mecillinam is such that serum levels remain in the therapeutic range during the procedure. A booster dose of mecillinam is only necessary after dialysis for patients with severe infections. In between dialysis, the intervals between standard doses of the drug should be prolonged to avoid high potentially toxic mecillinam serum levels [47-48].

Toxicology

The adverse effect profile of pivmecillinam is similar to that of other penicillins. The most common side effects of mecillinam use are rash and gastrointestinal upset, including nausea and vomiting.

Prodrugs that release pivalic acid when broken down by the body — such as pivmecillinam, pivampicillin and cefditoren pivoxil — have long been known to deplete levels of carnitine [49-50]. This is not due to the drug itself, but to pivalate, which is mostly removed from the body by forming a conjugate with carnitine. Although short-term use of these drugs can cause a marked decrease in blood levels of carnitine [51], it is unlikely to be of clinical significance; long-term use, however, appears problematic and is not recommended [52-53].

 

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
mouse LD50 intraperitoneal 3500mg/kg (3500mg/kg) BLOOD: OTHER CHANGES Eksperimental'naya i Klinicheskaya Farmakoterapiya. Vol. 9, Pg. 91, 1980.
mouse LD50 intravenous 1200mg/kg (1200mg/kg)   Medicamentos de Actualidad. Vol. 16, Pg. 191, 1980.
mouse LD50 oral > 20gm/kg (20000mg/kg) LUNGS, THORAX, OR RESPIRATION: DYSPNEA

SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE

BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
Eksperimental'naya i Klinicheskaya Farmakoterapiya. Vol. 9, Pg. 91, 1980.
rat LD50 intraperitoneal > 4gm/kg (4000mg/kg) BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)

BEHAVIORAL: ATAXIA
Eksperimental'naya i Klinicheskaya Farmakoterapiya. Vol. 9, Pg. 91, 1980.
rat LD50 intravenous > 1500mg/kg (1500mg/kg)   Medicamentos de Actualidad. Vol. 16, Pg. 191, 1980.
rat LD50 oral > 10gm/kg (10000mg/kg) BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)

BEHAVIORAL: ATAXIA
Eksperimental'naya i Klinicheskaya Farmakoterapiya. Vol. 9, Pg. 91, 1980.

Gastrointestinal side-effects


Nausea, vomiting, upper gastrointestinal discomfort, and diarrhea occur in some patients treated with oral pivmecillinam [26, 28, 39].

Hypersensitivity reactions

Maculopapular or urticarial skin rashes appear to be uncommon. Two patients developed erythematous rashes while receiving pivmecillinam, which subsided within a few days after cessation of treatment [8, 54]. No rashes were encountered in several other clinical trials [26, 28, 43]. One patient who developed a skin rash after pivampicillin treatment was treated 2 weeks later by pivmecillinam without recurrence of the rash [12]. Nevertheless, it is wise to assume that mecillinam is cross-allergenic with other penicillins, and to avoid its use in patients with a previous history of penicillin allergy.

Carnitine deficiency

The pivaloyl moiety in pivmecillinam and other drugs with pivaloyl esters binds carnitine through conjugation of pivalioc acid with carnitine [49]. Carnitine is an essential metabolite in mitochondral metabolism of fatty acids. The main portion (>95%) of carnitine is stored in muscular tissues. Carnitine serum levels were found very low after prolonged treatment with a combination of pivampicillin and pivmecillinam in children with recurrent urinary tract infections [49]. Only one of these children had symptoms compatible with mild carnitine deficiency.
 

Pharmacokinetic data

Bioavailability  
Protein binding 5 to 10%
Metabolism Some hepatic metabolism
Half-life 1 to 3 hours
Cmax (mg/ml) 2.5 mg/ml following 400mg dose per os
tmax (hrs) 1.5hrs following 400mg dose per os
Distribution volume Vd  
Clearance  
Excretion Renal and biliary, mostly unchanged

Absorption

Mecillinam is not absorbed when given orally. Pivmecillinam is well absorbed after oral administration. The bioavailability increased 20% when pivmecillinam was ingested with or within 1 hour after standard breakfast compared with ingestion 1 hour before a standard breakfast [55]. On doubling the oral pivmecillinam dose, peak serum concentrations increase by approximately 50%, but the area under the curve is doubled. If pivmecillinam is given with food, its bioavailability is much the same [55]. As with other penicillins, concurrent administration of probenecid produces higher and more prolonged mecillinam serum levels [56].

Distribution

After a 400-mg dose (equivalent to 273 mg anhydrous mecillinam) to adults, a mean peak serum level of 2.5 mg/ml (expressed as anhydrous mecillinam) is reached approximately 1.5 hours after the dose. Thereafter, the serum level falls, but some mecillinam is still detectable in the serum 6 hours after administration.

The serum half-life is approximately 1 hour [57-58]. Higher serum levels after oral administration have been reported. A mean peak serum level as high as 5 mg/ml was detected after a 400-mg dose in older ambulatory subjects [56, 59]. Older patients are likely to have higher serum concentrations as renal excretion of the drug is slower, and physical activity after antibiotic administration also tends to produce higher serum levels [58]. After i.m. injection of a 335-mg dose of mecillinam hydrochloride dihydrate (equivalent to 273 mg anhydrous mecillinam) to adults, a mean peak serum level of 4.5–5.0 mg/ml (expressed as anhydrous mecillinam) is reached 30–45 minutes later. This peak level is approximately double that attained after an equivalent dose of oral pivmecillinam. Thereafter, the serum level falls more rapidly than that after oral pivmecillinam and the drug cannot be detected in the serum 6 hours after the dose [57]. Doubling the dose, doubles both the peak serum concentration and the area under the curve. If a 10 mg/kg dose (about 600 mg to adults and equivalent to 492 mg anhydrous mecillinam) is administered i.v. as an infusion over 15 minutes, the mean peak serum level, just after the infusion, is approximately 50 mg/ml; this falls to about 13 mg/ml 1 hour after the infusion, and at 4 hours it is 1.0–1.5 mg/ml (anhydrous mecillinam).

When this dose is administered 4-hourly to adults with normal renal function, there is no accumulation of the drug in the serum. The serum half-life of mecillinam is approximately 53 minutes [42, 60-61]. Mecillinam penetrates into human CSF in only marginal amounts in the absence of meningeal inflammation, being 1–10% of the concomitant serum concentration [41]. In animals, mecillinam is evenly distributed in body fluids and tissue and produces high concentrations in the kidneys, liver, and lungs, but low concentrations in the fetus and breast milk [56]. Serum protein binding of mecillinam is relatively low [47]. Biliary levels are higher than those in the serum, provided that the biliary tract is not obstructed. A study investigated 53 patients undergoing biliary surgery, all of whom received a single i.m. dose of 800 mg mecillinam 1 hour preoperatively; 11 patients were
jaundiced [62]. Serum and bile samples were obtained 1–3 hours after the administration of the drug. In nonjaundiced patients, the mean concentration of mecillinam in gallbladder bile was 40 mg/ml in 26 patients with normal gallbladder function, compared with 12 mg/ml in 16 patients with a nonfunctioning gallbladder; mean concentrations of mecillinam in the common bile duct bile and serum were 49 and 12 mg/ml, respectively, in these two groups. In the 11 jaundiced patients, the mean concentration in common bile duct bile was 8 mg/ml, and in gallbladder bile 12 mg/ml. In patients with marked jaundice, the concentration of mecillinam in gallbladder bile was less than 1 mg/ml.

Excretion

Mecillinam is excreted in the urine in an unchanged active form by both glomerular filtration and tubular secretion. Probenecid delays excretion by reducing renal tubular secretion [57]. After i.v. administration, as much as 67% of an administered dose is excreted in urine in the first 4 hours; approximately 71% of the dose can be recovered within 24 hours [60]. High urinary concentrations of active mecillinam, up to 3000 mg/ml during times of low urine flow, are attained after an i.v. dose of 10 mg/kg [42]. Unexcreted mecillinam is presumably inactivated in the body, similar to other penicillins. Three antibacterially inactive metabolites of mecillinam have been identified [57].

Metabolism

 

Mechanism of Action

Pivmecillinam interferes with the biosynthesis of the bacterial cell wall however its activity is slightly different from that of other penicillins and cephalosporins.

Antibacterial activity

Gram-negative bacteria

Mecillinam differs in its antibacterial activity from other penicillins, being much more active against Gram-negative than against Gram-positive organisms [63-65]. As shown in Table 1, it is highly active against most Enterobacteriaceae, such as Escherichia coli, Klebsiella, Salmonella, Shigella, Yersinia, and Citrobacter spp. Proteus mirabilis and P. vulgaris are usually sensitive, but Morganella morganii, Providencia rettgeri, and other Providencia spp. are less often so. Serratia marcescens may be mecillinam sensitive, but most strains are moderately or highly resistant [65]. Pseudomonas aeruginosa, Acinetobacter, and the anaerobic Gram-negative bacilli, such as Bacteroides fragilis, are mecillinam resistant [66-67]. Neisseria spp. are much less sensitive to mecillinam than to ampicillin (Table 1). Gonococci are relatively resistant and b-lactamase-producing strains are completely resistant [68]. Haemophilus influenzae is moderately resistant and ampicillin resistant strains are highly mecillinam resistant [65].

Gram-positive bacteria

Compared with ampicillin, mecillinam’s activity against these organisms is relatively low. All Enterococcus faecalis strains are highly resistant [65]. Staphylococcus saprophyticus is relatively resistant, but sufficiently high concentrations may be attained in the urine to inhibit this bacterium [13, 69].

Chlamydia

Mecillinam seems to be active against against Chlamydia trachomatis (MIC 0.25–0.5 mg/ml) and C. pneumoniae MIC (0.2 mg/ml) [70-71].

Table 1. In vitro susceptibility of mecillinam compared to ampicillin.

Organism MIC50 (mg/ml)
Mecillinam Ampicillin
Gram-positive    
Staphylococcus aureus (non penicillinase producer) 5.0 0.016
Streptococcus pyogenes 0.5 0.006
Streptococcus pneumoniae 1.6 0.016
Enterococcus faecalis 100 0.2
Staphylococcus saprophyticus 16-64 -
Clostridium perfringens 8.0-64 -
Gram-negative    
Neisseria gonorhoeae 0.125-8 0.005
haemophylus influenzae 16.0 0.16
Escherichia coli 0.016 0.50
Enterobacter cloacae 0.16 100
Klebsiella pneumoniae 0.1 100
Proteus mirabilis 0.1 0.5
Morganella morganii 0.13 100
Salmonella typhimurium 0.1 1.0
Shigella dysenteriae 0.05 1.0
Serratia marcescens 12.5-100 32
Pseudomonas aeruginosa 160 500
Bacteroides malanogenicus 0.25-16 0.5-4
Bacteroides fragilis 1-64 4-256

Emerging resistance and cross-resistance

Bacteria exhibiting cross-resistance between ampicillin and mecillinam are usually those which produce large amounts of b-lactamases. Although mecillinam can be inactivated by b-lactamases, it is generally more stable than ampicillin because of its relatively low affinity for them. The two drugs may also differ in their sensitivity to the various types of b-lactamases produced by individual organisms. Another reason why Enterobacteriaceae are more sensitive to mecillinam than to ampicillin is mecillinam’s superior ability to penetrate through the outer layers of the bacterial cell envelope [64, 72]. Mecillinam-resistant strains of many bacterial species can be readily selected in vitro by repeated passage in the presence of the antibiotic [2, 64]. Emergence of resistant strains was not a major problem when the drug was used to treat urinary tract infections [9, 12, 73]. It appears that short courses of treatment are unlikely to select resistant fecal organisms and lead to therapeutic failure [74]. Mecillinam-resistant variants can sometimes be demonstrated in urine containing therapeutic concentrations of the drug. The generation time of these resistant strains is 3.0–4.5 times as long as that of susceptible organisms, which may be why such resistant organisms do not usually colonize the urinary tract during chemotherapy [74]. Mecillinam-resistant strains have emerged during treatment of other infections, including those due to Salmonella spp. [28], E. coli [75], and K. pneumoniae [76]. These mecillinam-resistant variants were spherical in shape, and most of them were unstable and readily reverted to their mecillinam-sensitive rod-shaped form. Stable mutants of K. pneumoniae and E. coli were also detected, which were identical to the unstable variants with regard to form, growth rate, and sensitivity to mecillinam. Amongst Enterobacteriaceae isolated from patients in the community and hospitals, resistance to mecillinam is much less common than to ampicillin [73, 77-78]. Most ampicillin-resistant Enterobacteriaceae isolated from fecal flora or infected urines are mecillinam sensitive. This seems to include
strains of E. coli and K. pneumoniae that are extended-spectrum b-lactamase (ESBL)-producing [79]. In Swedish surveys, all Shigella spp. strains [80] and all Yersinia enterocolitica strains [81] were mecillinam sensitive. Some ampicillin-resistant Gram-negative bacilli are also mecillinam resistant [65, 82]. Most ampicillin-resistant Shigella isolates are mecillinam sensitive [83], and only occasionally have mecillinam-resistant S. flexneri and S. boydii strains been isolated, in which case the resistance appeared to be plasmid mediated [84-85]. However, ampicillin-resistant salmonellae show partial resistance to
mecillinam (Chau et al., 1981). In media with high osmolality and high conductivity, mecillinam’s minimum inhibitory concentration (MIC) values for some organisms are markedly increased [20, 86]. As mecillinam has been used to treat urinary tract infections, and as urine normally has a high osmolality and conductivity, this finding has clinical significance. If large inocula of bacteria are used for in vitro sensitivity testing, mecillinam’s MICs are markedly increased for all bacteria. With many
Gram-negative bacteria there is also a large difference (8- to 32-fold) between mecillinam’s MICs and its MBCs [65]. Instability of mecillinam in the assay medium may account for these differences and the drug probably has a bactericidal effect in vivo, similar to other penicillins.

Other pharmacological effects

The key pharmacokinetic and pharmacodynamic parameters that are linked to clinical efficacy are not known, but presumably are similar to other b-lactams – namely, time above the MIC. Mecillinam alone has a prolonged (>3 hours) post-antibiotic effect on E. coli. The combinations of mecillinam with ampicillin, aztreonam, ceftazidime, or piperacillin at most concentrations induce longer postantibiotic effect (PAEs) on E. coli than do the sum of the individual antibiotic PAEs. Thus, there is a synergistic PAE on Gram-negative bacteria when mecillinam is combined with these other antibiotics [87].

 


Medicinal Chemistry

CAS number: 32887-01-7 EINECS: 251-276-6

Molecular Formula: C21H33N3O5S
Average mass: 439.568787 Da
Monoisotopic mass: 439.214081 Da

Systematic name: [(2,2-Dimethylpropanoyl)oxy]methyl (2S,5R,6R)-6-[(1-azepanylmethylene)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
SMILES: O=C(OCOC(=O)C(C)(C)C)[C@@H]2N3C(=O)[C@@H](/N=C/N1CCCCCC1)[C@H]3SC2(C)C
Std. InChI: 1S/C21H33N3O5S/c1-20(2,3)19(27)29-13-28-18(26)15-21(4,5)30-17-14(16(25)24(15)17)22-12-23-10-8-6-7-9-11-23/h12,14-15,17H,6-11,13H2,1-5H3/t14-,15+,17-/m1/s1


Properties
Melting Point: 119°C

ACD/LogP: 2.968 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): 1.06 ACD/LogD (pH 7.4): 2.20
ACD/BCF (pH 5.5): 1.32 ACD/BCF (pH 7.4): 18.29
ACD/KOC (pH 5.5): 12.20 ACD/KOC (pH 7.4): 169.10
#H bond acceptors: 8 #H bond donors: 0
#Freely Rotating Bonds: 7 Polar Surface Area: 113.81 Ĺ2
Index of Refraction: 1.604 Molar Refractivity: 115.933 cm3
Molar Volume: 336.918 cm3 Polarizability: 45.959 10-24cm3
Surface Tension: 47.7809982299805 dyne/cm Density: 1.305 g/cm3
Flash Point: 305.176 °C Enthalpy of Vaporization: 86.894 kJ/mol
Boiling Point: 580.996 °C at 760 mmHg Vapour Pressure: 0 mmHg at 25°C

 

 


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