Bacterial cell wall synthesis; penicillin binding proteins (PBPs); cephalosporin antibiotic

Cephalexin (10 μg/mL) inactivates an enzyme known as penicillin-binding protein (PBP), which disturbs the synthesis of the polymer peptidoglycan (PG) [1]. Numerous Gram-positive and Gram-negative microbes are inhibited by cephalexin, which has MIC values of 2, 2, 2, 2, 4, 4.4 and 5.7 μg/mL for Proteus rettgeri, respectively [2].

Cephalexin (0-50 mg/kg; oral; 3.5 hr) exhibits antibacterial action against male Swiss-Webster mice infected with microorganisms [2].

Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.[1]

Animal/Disease Models: Bacterially infected male Swiss-Webster mice [2]
Doses: 0-50 mg/kg
Route of Administration: po (po (oral gavage)) 3.5 hrs (hrs (hours))
Experimental Results: Against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus and several Antimicrobial activity against Gram-negative bacteria in mice.

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Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin.[2]

Absorption, Distribution and Excretion
Well absorbed from the upper gastrointestinal tract with nearly 100% oral bioavailability. Cephalexin is not absorbed in the stomach but is absorbed in the upper intestine. Patients taking 250mg of cephalexin reach a maximum plasma concentration of 7.7mcg/mL and patients taking 500mg reach 12.3mcg/mL.
Cephalexin is over 90% excreted in the urine after 6 hours by glomerular filtration and tubular secretion with a mean urinary recovery of 99.3%. Cephalexin is unchanged in the urine.
5.2-5.8L.
Clearance from one subject was 376mL/min.
LESS THAN 10 TO 15%...IS BOUND TO PLASMA PROTEIN, & PLASMA DRUG CONCN FALL RAPIDLY... MORE THAN 90%...IS EXCRETED UNALTERED IN URINE WITHIN 6 HR, PRIMARILY BY RENAL TUBULAR SECRETION. ...THERAPEUTICALLY EFFECTIVE CONCN ARE STILL ACHIEVED IN URINE OF PT WITH DECR RENAL FUNCTION.
CEPHALEXIN...IS WELL ABSORBED FROM GI TRACT. PEAK PLASMA CONCN, REACHED @ ABOUT 1 HR AFTER INGESTION OF DRUG, ARE APPROX 9 & 18 UG/ML AFTER ORAL DOSES OF 250 & 500 MG, RESPECTIVELY. INGESTION OF FOOD MAY DELAY ABSORPTION.
CEPHALEXIN IS ALSO EXCRETED INTO BILE.
BOTH ABSORPTION & EXCRETION OF CEPHALEXIN ARE IMPAIRED IN NEW-BORN INFANTS, WHERE 24-HR URINARY RECOVERY OF ANTIBIOTIC ACCOUNTED FOR 5-66% OF DAILY ORAL DOSE.
For more Absorption, Distribution and Excretion (Complete) data for CEPHALEXIN (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
Cephalexin is not metabolized in the body.

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Biological Half-Life
The half life of cephalexin is 49.5 minutes in a fasted state and 76.5 minutes with food though these times were not significantly different in the study.
LESS THAN 10 TO 15%...IS BOUND TO PLASMA PROTEIN, & PLASMA DRUG CONCN FALL RAPIDLY, T/2 OF CEPHALEXIN NORMALLY BEING ABOUT 40 MIN.
/IN RATS/ RATIOS OF BONE TO SERUM CONCN AVG...1:9 FOR CEPHALEXIN DURING 0.25-4 HR AFTER /ORAL/ DOSING. DESPITE DIFFERENCES IN CONCN; T/2 IN BONE & SERUM WERE SIMILAR.
PEAK TIME, T/2 OF ELIMINATION, T/2 OF ABSORPTION, & VOL OF DISTRIBUTION WERE ALL SIMILAR FOLOWING ADMIN OF EITHER 1 OR 2 G OF CEPHALEXIN.
The serum half-life of cephalexin is 0.5-1.2 hr in adults with normal renal function. The serum half-life of the drug is reported to be about 5 hr in neonates and 2.5 hr in children 3-12 mo of age. In one study, the serum half-life was 7.7 hr in adults with creatinine clearances of 9.2 ml/min and 13.9 hr in adults with creatinine clearances of 4 ml/min.

Interactions
PROBENECID IS EFFECTIVE IN SLOWING URINARY CLEARANCE & ENHANCING DURATION OF SYSTEMIC ANTIMICROBIAL ACTIVITY /OF CEPHALEXIN/.
...CEPHALOSPORINS...MAY BE AFFECTED BY CONCURRENT USE OF...SULFINPYRAZONE. DIMINISHED TUBULAR SECRETION...RESULT IN HIGHER & MORE SUSTAINED SERUM LEVELS & HENCE, INTENSIFICATION OF DRUG ACTIVITY. /CEPHALOSPORINS/
FUROSEMIDE MAY ENHANCE NEPHROTOXICITY OF CEPHALOSPORINS. /CEPHALOSPORINS/
Hypoprothrombinemia induced by large doses of salicylates and/or cephalosporins, and the gastrointestinal ulcerative or hemorrhagic potential of nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, or sulfinpyrazone may increase the risk of hemorrhage. /Cephalosporins/
For more Interactions (Complete) data for CEPHALEXIN (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 MOUSE ORAL 1.6-4.5 G/KG /MONOHYDRATE/
LD50 MOUSE INTRAPERITONEAL 0.4-1.3 G/KG /MONOHYDRATE/
LD50 RAT ORAL GREATER THAN 5.0 G/KG /MONOHYDRATE/
LD50 RAT INTRAPERITONEAL GREATER THAN 3.7 G/KG /MONOHYDRATE/

[1]. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell. 2014 Dec 4;159(6):1300-11.

[2]. Cefadroxil, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother. 1977 Feb;11(2):324-30.

Therapeutic Uses
Cephalosporins
/CEPHALEXIN/ HAS ANTIBACTERIAL SPECTRUM SIMILAR TO THAT OF PENICILLINS... AGAINST COCCI & GRAM-POSITIVE BACILLI, PENICILLIN G IS USUALLY MORE EFFECTIVE. ...MOST PENICILLINASES DO NOT AFFECT CEPHALEXIN...
...CEPHALOSPORINS ARE HIGHLY EFFECTIVE IN THERAPY OF VARIETY OF MILD-TO-SEVERE INFECTIONS DUE TO BOTH GRAM-POSITIVE & GRAM-NEGATIVE MICROORGANISMS. /CEPHALOSPORINS/
...CEPHALOSPORIN IS...DRUG OF 1ST CHOICE...FOR KLEBSIELLA INFECTIONS. ... THEY ARE...VALUABLE SECONDARY AGENTS, & THEY FREQUENTLY APPEAR AS ALTERNATIVE CHOICES TO PENICILLIN. /CEPHALOSPORINS/
For more Therapeutic Uses (Complete) data for CEPHALEXIN (9 total), please visit the HSDB record page.

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Drug Warnings
PHYSICIAN MUST ALTER EITHER DRUG DOSAGE OR INTERVAL BETWEEN DOSES WHEN RENAL FUNCTION IS IMPAIRED.
CEPHALOSPORINS SHOULD NOT BE USED TO TREAT BACTERIAL MENINGITIS. THIS IS TRUE FOR ALL CAUSATIVE MICROORGANISMS. ...PENETRATION OF CEPHALOSPORINS INTO CSF IS POOR. /CEPHALOSPORINS/
INFECTIONS DUE TO ENTEROCOCCI ARE USUALLY UNAFFECTED BY THESE CMPD... ENTEROCOCCAL ENDOCARDITIS CANNOT BE CURED WITH CEPHALOSPORIN EVEN WHEN IT IS GIVEN CONCURRENTLY WITH GENTAMICIN OR STREPTOMYCIN. /CEPHALOSPORINS/
ENTEROBACTER (AEROBACTER) INFECTIONS ARE, AS A RULE, RESISTANT TO THESE CMPD. /CEPHALOSPORINS/
For more Drug Warnings (Complete) data for CEPHALEXIN (20 total), please visit the HSDB record page.

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Pharmacodynamics
Cephalexin (also called Cefalexin) is a first generation cephalosporin antibiotic. It is one of the most widely prescribed antibiotics, often used for the treatment of superficial infections that result as complications of minor wounds or lacerations. It is effective against most gram-positive bacteria through its inihibition of the cross linking reaction between N-acetyl muramicacid and N-acetylglucosamine in the cell wall, leading to cell lysis.

C16H17N3O4S

347.89

347.093

C, 55.32; H, 4.93; N, 12.10; O, 18.42; S, 9.23

15686-71-2

Cephalexin hydrochloride;59695-59-9;Cephalexin monohydrate;23325-78-2;Cephalexin hydrochloride monohydrate;105879-42-3;Cephalexin (lysine);53950-14-4;Cephalexin-d5;2101505-56-8; 15686-71-2 (free); 38932-40-0 (sodium)

27447

White to light yellow solid powder

1.5±0.1 g/cm3

727.4±60.0 °C at 760 mmHg

196-198°C

393.7±32.9 °C

0.0±2.5 mmHg at 25°C

1.700

0.65

3

6

4

24

600

3

CC1=C(N2[C@@H]([C@@H](C2=O)NC(=O)[C@@H](C3=CC=CC=C3)N)SC1)C(=O)O

ZAIPMKNFIOOWCQ-UEKVPHQBSA-N

InChI=1S/C16H17N3O4S/c1-8-7-24-15-11(14(21)19(15)12(8)16(22)23)18-13(20)10(17)9-5-3-2-4-6-9/h2-6,10-11,15H,7,17H2,1H3,(H,18,20)(H,22,23)/t10-,11-,15-/m1/s1

(6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Cephacillin; Cefalexin; Keflex; Cepexin; Carnosporin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~10 mg/mL (~28.79 mM)

Solubility in Formulation 1: 25 mg/mL (71.97 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with heating and sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)