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Cephalosporins

Introduction:

The word antibiotics come from the word - antibiosis which means against life.

Cephalosporins are one of the most commonly used antibiotics in clinical practice.

It was first discovered formed from "Cephalosporium acremonium" from a sewage outfall in Sardinia in 1948 by an Italian scientist "Giuseppe Brotzu".
 
 


Many different types of cephalosporins have been developed since its first identification.

Structure of Cephalosporins.

In cephalosporins, the β-lactam ring is bonded to a six-membered dihydrothiazine ring, or cepham.



First generation cephalosporins were created by modifying the R1 site of the cephalosporin structure. The succeeding generations of cephalosporins have been synthetically produced with modifications at the R1 and R2 sites. These changes in the R site also differentiate the spectrum of activity amongst the cephalosporins.



Mechanism of action of Cephalosporins

Since the cephalosporin also has the same beta lactam ring like penicillin – it acts by inhibiting the transpeptidation reaction. This impairs the peptidoglycan synthesis which plays an important role in maintaining the cellular integrity.

During replication, a bacterium removes “tiles” circumferentially to allow cell division via a pinching-like action, while quickly placing new “tiles” at the ends of what have become two bacteria. This process requires enzyme – This process requires enzymes to interlock replacement tiles. Such enzymes are the targets of beta-lactam antibiotics and are called penicillin-binding proteins (PBPs). Antibiotic action requires binding to PBPs, preventing them from closing the vulnerable ends on dividing bacteria and causing the natural intrabacterial hyperosmotic pressure to rupture the bacteria. Thus, beta-lactam antibiotics are bactericidal.

Classification of Cephalosporins:

Most of the available cephalosporins are semi-synthetic derivatives of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related cephamycin compounds (derived from Streptomyces spp) are regarded as members of the cephalosporin class.

In clinical practice, these antibiotics are grouped into five "generations" based upon their spectrum of activity against aerobic and facultative gram-negative bacilli and gram-positive bacteria.

In general, lower-generation cephalosporins have more gram-positive activity and higher-generation cephalosporins more gram-negative activity. The fourth-generation drug cefepime is the exception, with gram-positive activity equivalent to first-generation and gram-negative activity equivalent to third-generation cephalosporins.

Additional advanced cephalosporins include a siderophore cephalosporin (cefiderocol) and cephalosporin combinations with beta-lactamase inhibitors.

First generation of cephalosporins

All the cephalosporin drugs that have FA/PHA/PHRA belong to 1st generation except – cefaclor which belongs to 2nd generation.

The drugs in 1st generation are –

Cephalexin

cefazolin

Cefalothin

Cefadroxil

Cephalexin

Cephradine

Spectrum of activity of 1st generation cephalosporin:

Gram Positive organisms

Gram negative organisms

Anaerobes

Active against – Streptococci and MSSA

 

 

 

Inactive against -MRSA,

Enterococcus,

Penicillin resistant pneumococcus and Listeria.

 

Active against –

Gm-ve rods like E. coli, Klebsiella, Proteus but not against Serratia, Indole positive Proteus, Pseudomonas. Enterobacter.

 

Inactive against Gm -ve cocci like Meningococcus, Gonococcus, Hemophilus

 

 

Active against common anaerobes but inactive against Bacteroides.

 


Never prescribe 1st generation cephalosporins for CNS infection as they cannot penetrate the meninges even when inflamed.

 Oral first-generation cephalosporins, including cephalexin, cefadroxil, and Cephradine, are well absorbed. Therapeutic concentrations occur in most tissues, including pleura, synovial fluids, and bone, but not middle ear fluid. Cefadroxil has a half-life of more than 1 hour and is administered every 12 hours versus every 6 to 8 hours for cephalexin.

IV- cefazolin

Indications:

Can used for MSSA and penicillin sensitive streptococci but rarely used as first line therapy.

 In fact, cefazolin is the cephalosporin of choice for surgical prophylaxis. Cefazolin with high biliary concentrations is still used for surgical prophylaxis and for treatment of abdominal infections.  One of the non-FDA approved indication is to use first-generation cephalosporins for endocarditis prophylaxis for those who are susceptible and undergoing a dental or respiratory procedure.

 

Second generation of Cephalosporins

Drugs are –

Second generation cephalosporins are broken up into two groups: true second generation cephalosporins and the cephamycins. The true second generation cephalosporins include cefuroxime and cefprozil, while the cephamycins include cefoxitin, cefotetan, and cefmetazole.

Cefaclor

Cefuroxime

Cefotitan

Cefmetazole

Cefoxitin

Cefprozil

Spectrum of activity of second generation:

Because of greater stability against beta-lactamases of gram-negative bacteria, enhanced activity occurs among second-generation cephalosporins against many Enterobacteriaceae, H influenzae, and Moraxella catarrhalis, but they have less gram-negative activity than do third generation cephalosporins.

Second-generation cephalosporins retain good activity against gram-positive organisms, including some strains of PNSP, but have less S aureus activity compared with their first-generation counterparts.

Cefaclor has no PNSP activity.

In the first subgroup, cefuroxime is available parenterally and orally, and is more active than cefazolin in vitro against strains of Enterobacter and indole-positive Proteus.

Cefoxitin, a cephamycin, is classified with second-generation cephalosporins but demonstrates more anaerobic activity, especially for Bacteroides fragilis.

Cefoxitin also offers activity against rapidly growing nontuberculous mycobacteria and often is included in multiple-drug combination regimens to treat serious nontuberculous mycobacterial infections.

Pharmacokinetics of some drugs:

Compared with cefaclor and Cefprozil, which are well absorbed orally, the bioavailability of cefuroxime axetil is less than 50% but is enhanced when taken with food.

Cefuroxime axetil suspension is less bioavailable than the tablet form, and dosage adjustments are necessary between these two forms.

Cefuroxime axetil is hydrolyzed rapidly in the GI tract and in serum to its active parent compound, cefuroxime.

Use of second generation in CNS infections?

Therapeutic concentrations of second-generation cephalosporins are achieved in most tissues, including pleural and synovial fluids and bone. Of parenteral second-generation cephalosporins, cefuroxime penetrates CSF but is not recommended for treating meningitis due to its potential for delayed CSF sterilization, therapeutic failures, and more frequent hearing loss compared with ceftriaxone.

Clinical use:

Similar to first generation and they are not always the first choice.

Otitis media, pharyngitis, sinusitis –

Because of the anaerobic coverage, cefoxitin is used prophylactically in multiple surgeries, including cardiac, biliary, appendectomy, small intestine, colorectal, head and neck, hysterectomy, and urologic.

Cefoxitin can also be prescribed for use in treating pelvic inflammatory disease (PID), moderate severity DFIs, human and animal bites, early localized or early disseminated Lyme or Lyme-induced arthritis, and mild-to-moderate severity IAIs.

Third generation cephalosporins:

Drugs of 3rd generation are –

Third generation cephalosporins are the most prescribed cephalosporins and are the first generation to be considered an extended-spectrum cephalosporin or broad spectrum.

Drugs with -ime or -ten or -one at the end are 3rd generations with the exception of cefuroxime which belongs to 2nd generation.

Cefixime

Ceftazidime

Cefpodoxime

Cefotaxime

Ceftizoxime

Ceftriaxone

Cefoperazone

Ceftibuten

 

Moxalactam and cefdinir do not follow this rule but belong to 3rd generation.

They are effective against both gram-positive and gram-negative organisms, but their optimum activity is mostly against gram-negative organisms.

Spectrum of activity:

Marked by stability to the common beta-lactamases of gram-negative bacilli, and these compounds are highly active against Enterobacteriaceae (E. coliProteus mirabilis, indole-positive ProteusKlebsiellaEnterobacterSerratiaCitrobacter), Neisseria, and H. influenzae. They are the therapy of choice for gram-negative meningitis due to susceptible Enterobacteriaceae.

The third-generation cephalosporins are less active against most gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, methicillin-resistant staphylococci, and Acinetobacter

Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third-generation cephalosporins as well.

Based on the activity against pseudomonas 3rd gen are sometimes grouped as

Poorly active against Pseudomonas:

Ceftriaxone and cefotaxime:

Ceftriaxone:

Ceftriaxone is bactericidal for gram negative pathogens, specifically all H influenzae (including beta-lactamase-producing strains);

M catarrhalis;

most E coli,

Klebsiella pneumoniae,

Morganella, Neisseria, Proteus, and Enterobacter sp; Serratia marcescens;

and Acinetobacter sp

It also is active against all group A and group B streptococci and nearly all S pneumoniae, including PNSP outside the CSF.

MSSA, S epidermidis, other coagulase negative staphylococci, MRSA, and all enterococci are considered resistant.

Ceftriaxone has minimal anaerobic activity.

Pharmacokinetics

Unlike other cephalosporins, ceftriaxone is highly protein-bound. This effect prolongs its half-life (5.5 to 8.7 hours beyond the neonatal period and 9.0 to 15.5 hours in the neonate), allowing once- or twice-daily dosing.

It penetrates bone, joint, muscle, skin, and middle ear, with approximately 10% reaching the CSF through inflamed meninges.

Up to 70% is excreted unchanged in urine, with the rest excreted unchanged into bile (stool has very high concentrations).

Side effects of Ceftriaxone:

<5% CASES

Thrombocytosis, leukopenia, allergic reactions

Candida superinfection like diaper dermatitis

Diarrhea with eosinophilia

Pseudomembranous colitis

Jaundice in infants because of Biliary sludging and pseudolithiasis. Also they tend to displace bilirubin bound to albumin.

Rare but serious side effects is hemolysis which is often life threatening and occur in patients with no prior h/o cephalosporin allergy.

Fatal reactions due to calcium-ceftriaxone precipitates in the lungs and kidneys of neonates have been reported. Ceftriaxone should not be reconstituted or mixed with a calcium-containing product (eg, Ringer's or Hartmann's solution or parenteral nutrition). In addition, ceftriaxone should be avoided in infants aged ≤28 days if they are receiving or expected to receive intravenous calcium-containing products. However, ceftriaxone and calcium-containing products may be used concomitantly in patients aged >28 days, provided that the infusion lines are thoroughly flushed between infusions.  

Clinical use:

Meningitis

Gonorrhea

PIDs

CAP

IAI

 

Cefotaxime:

Cefotaxime and ceftriaxone are used in similar clinical scenarios because of similar spectra. Advantages of cefotaxime over ceftriaxone include no bilirubin displacement from albumin (preferred neonatal drug), better in vivo activity against MSSA, and no sludging in the gallbladder.

Require frequent dosing of 6-8 hourly as they have shorter half life.

Side effects –

Allergy -rash

Diarrhea

Candida superinfection

Active against Pseudomonas:

Ceftazidime has activity against most community acquired gram-negative pathogens and P aeruginosa. It has been effective in treating P aeruginosa meningitis.

Ceftazidime is the only cephalosporin with a Food and Drug Administration (FDA)-approved indication for the inpatient treatment of febrile neutropenia, however, its use is not recommended due poor pneumococcal and MSSA activity and no activity against MRSA, methicillin resistant S epidermidis, or enterococci. Further, the drug can induce the production of high-level cephalosporinases among mostly nosocomial gram-negative pathogens, including Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter (SPACE) species. Thus, should be should be reserved for use in infections proven or highly suspected to be due to P. aeruginosa.

Oral 3rd generation cephalosporins:

Cefdinir and cefpodoxime have balanced gram-positive and gram-negative spectra. Cefdinir is very palatable; cefpodoxime is bitter. Both are active against MSSA and some PNSP.

Cefpodoxime and cefdinir are used primarily for treating acute otitis media, acute bacterial sinusitis, and as once or twice-daily regimens for penicillin-allergic patients who have group A streptococcal pharyngitis.

Cefixime and ceftibuten are similar in spectra, dose, and dosing schedules, but cefixime has slightly more gram-positive activity. Ceftibuten is less active against M catarrhalis. Both have excellent activity against coliform bacteria and are more stable to beta-lactamases than other oral cephalosporins.

Ceftibuten and cefixime are excellent for treating urinary tract infections or respiratory infections due to beta-lactamase-producing ntHi.

Adverse effects:

Cefdinir can produce a “bloodlike” appearance in stools when infants consume iron-containing foods. Both cefdinir and cefpodoxime are associated with about an 8% diarrhea rate, with cefpodoxime associated with higher emesis rate.

Fourth generation cephalosporins:

Drugs with PI in the name like

Cefepime

Cefpirome

Its in vitro activity resembles that of cefazolin combined with ceftazidime, with effectiveness against MSSA, S pyogenes, S pneumoniae (PNSP outside CSF), E coli, H influenzae, M catarrhalis, N gonorrhoeae, P aeruginosa, Morganella morganii, Proteus mirabilis, Citrobacter, Enterobacter, Klebsiella, Providencia, and Serratia sp. It has no activity against MRSA, enterococci, ESBL- or Amp-C beta-lactamase-producing gram-negative organisms, or multidrug-resistant Acinetobacter sp.

It has a positively charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli.

Cefepime is as active as ceftazidime for P. aeruginosa, and is active against some ceftazidime-resistant isolates. As with the anti-pseudomonal penicillins, cefepime should generally be given in combination with an aminoglycoside for treatment of serious P. aeruginosa infection when susceptibilities are unknown. 

Side effects

At high doses in renal insufficiency can cause seizures (nonconvulsive status epilepticus).

Candida superinfection.

 

Fifth generation cephalosporin:

The fifth generation cephalosporins, otherwise known as anti-methicillin-resistant S. aureus (MRSA) cephalosporins, include ceftaroline and ceftibiprole

 Ceftaroline is a fifth-generation cephalosporin whose active metabolite has a spectrum of in vitro activity similar to ceftriaxone but with improved gram-positive activity.

In particular, ceftaroline has higher affinity for PBP2a in methicillin-resistant staphylococci, and has activity against MRSA, as well as vancomycin-intermediate Staphylococcus aureus (VISA) and hetero-VISA.  In addition, ceftaroline has activity for Streptococcus pneumoniae that is intermediate or resistant to penicillin or ceftriaxone.

Ceftaroline is not active for enterococci nor against AmpC-overproducing or ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosaAcinetobacter baumannii, or Bacteroides fragilis

Ceftobiprole is a cephalosporin available in Canada and some European countries (but not the United States) that is also capable of binding to penicillin binding protein 2a, the protein conferring S. aureus resistance to beta-lactam antibiotics .

It can also bind penicillin binding protein 2x in penicillin-resistant S. pneumoniae. It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it also has activity against enterococci. In addition, ceftobiprole appears to have a low potential for selection of resistance.

 

Other Cephalosporins:

This siderophore cephalosporin has activity against multidrug-resistant gram-negative bacteria, including extended-spectrum beta-lactamase- or carbapenemase-producing organisms and multidrug-resistant P. aeruginosaA. baumanniiStenotrophomonas maltophilia, and Burkholderia cepacia.

In addition to enhanced stability against beta-lactamases, it has a novel mechanism for transport across the outer membrane that can overcome the effect of membrane permeability mutations, as seen in P. aeruginosa. Cefiderocol is thought to have poor gram-positive and anaerobic activity.

In the United States, cefiderocol has been approved by the Food and Drug Administration for use in adults with complicated urinary tract infections (UTIs) and/or pyelonephritis due to highly resistant gram-negative organisms when there are no alternative treatment regimen.

Ceftolozane-Tazobactum

Ceftazidime-avibactam

 All of the cephalosporins except ceftriaxone require dose modification in the presence of severe renal failure.

Mechanism of resistance of Cephalosporins.

1. Lactamases

2. Outer membrane

3. PBP alteration


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