Penicillins, Cephalosporins, and Other β-Lactams



Penicillins, Cephalosporins, and Other β-Lactams


Sumathi Nambiar

William J. Rodriguez



The Penicillins


Introduction

Alexander Fleming discovered penicillin in 1928 (1). In the 1940s, penicillin became available for use in clinical practice. Batchelor and coworkers (2) isolated the 6-aminopenicillanic acid nucleus from Penicillium chrysogenum, which served as the basis for the development of semisynthetic penicillins. Subsequently, penicillins with expanded spectrum of activity including some gram-negative organisms were developed (Table 29.1).


Natural Penicillins


Structure–Activity Relationship

All penicillins contain the 6-aminopenicillanic acid nucleus, which is composed of a β-lactam ring and a five-member thiazolidine ring to which is attached a side chain. The penicillin nucleus is the chief structural requirement for biologic activity. The side chain determines many of the antibacterial and pharmacologic characteristics of a particular type of penicillin (3). Penicillins generally exist as sodium or potassium salts.


Mechanism of Action

Penicillins exert bactericidal action against penicillin-susceptible microorganisms during the stage of active replication. Penicillin interferes with bacterial cell wall synthesis by reacting with one or more penicillin-binding proteins (PBPs). The PBPs, such as transpeptidases, carboxypeptidases, and endopeptidases, are bacterial enzymes involved in cell wall synthesis. Bacteria produce four types of PBPs, and they structurally resemble serine proteases (4). The transpeptidase activity of PBPs is essential for cross-linking adjacent peptidoglycan, and the carboxypeptidases are important for the modification of peptidoglycan. PBPs account for approximately 1% of membrane proteins. They vary in the amounts present, in their role in cell wall assembly, and in their affinity for binding to β-lactam antibiotics (5).


Resistance

Penicillin resistance is mediated mainly through production of β-lactamase, which covalently binds to the β-lactam bond to form an acyl enzyme intermediate, which undergoes rapid hydrolysis, thus destroying the activity of the drug. Gram-positive β-lactamases, such as the staphylococcal penicillinase, are exoenzymes that destroy penicillins before they reach the target PBPs. The β-lactamases of gram-negative bacteria are cell associated and are located in the periplasmic space between the cytoplasmic membrane and the lipopolysaccharide outer membrane. Alteration of PBPs accounts for penicillin resistance among pneumococci, some strains of Haemophilus influenzae, and some Neisseria spp.


Pharmacokinetics

Metabolism and disposition vary significantly among the various penicillins and also vary with the age of the patients. They are not well absorbed from the gastrointestinal tract, with the exception of phenoxymethyl penicillin (penicillin V) and amoxicillin. Penicillin V is acid stable and is available only for oral use. Penicillin G is not acid stable and hence is generally used parenterally. Penicillins bind to serum proteins, mainly albumin. Penicillins are primarily excreted in the urine in the unchanged form. Tubular secretion accounts for most of the urinary penicillin, and glomerular filtration accounts for only a small fraction. Penicillin does not penetrate well into the cerebrospinal fluid (CSF) in the absence of meningeal inflammation. Repository penicillins such as procaine penicillin or benzathine penicillin provide tissue depots. Procaine penicillin is absorbed over several hours and benzathine penicillin over several days.


Spectrum of Activity


Gram-Positive Cocci

Includes most streptococci, and susceptible strains of staphylococci, enterococci, and pneumococci. Tolerance to penicillin among group B streptococcal isolates has
been reported (6,7). Penicillin acts synergistically with gentamicin or tobramycin against many strains of enterococci.








Table 29.1 Types of Penicillins
































Natural Penicillins Aminopenicillins Penicillinase-Resistant Penicillins Extended-Spectrum Penicillins
Penicillin G Amoxicillin Cloxacillin Carbenicillin
Penicillin V Ampicillin Dicloxacillin Ticarcillin
Penicillin G procaine   Oxacillin Piperacillin
Penicillin G benzathine   Nafcillin Mezlocillin
    Methicillin Azlocillin


Gram-Positive Bacilli

Corynebacterium diphtheriae, Bacillus anthracis, Actinomyces, Erysipelothrix rhusiopathiae, and Listeria monocytogenes.


Gram-Negative Bacteria

Non-β-lactamase-producing strains of Neisseria gonorrhoeae, and H. influenzae, Neisseria meningitidis, Streptobacillus moniliformis, and Pasteurella multocida.


Anaerobic Bacteria

Clostridia spp., Peptostreptococcus, and Propionibacteria.


Spirochetes

Treponema pallidum, Borrelia burgdorferi, and Spirillum minus.


Clinical Uses

Penicillin is effective in the treatment of infections caused by group A streptococci, group B streptococci, meningococci, Actinomyces, and T. pallidum (Tables 29.2 to 29.4) (8,9). It is also the treatment of choice for infections due to susceptible Streptococcus pneumoniae, enterococci, and gonococci. Infections other than meningitis that are due to penicillin-resistant S. pneumoniae may not be associated with a less favorable clinical outcome or increased mortality compared with those for penicillin-susceptible infections when treated with high-dose penicillin (10). The breakpoints for penicillin in the treatment of pneumococcal pneumonia were recently updated, whereas the breakpoint for meningitis remains unchanged (11). Infections due to anaerobic mouth flora are generally susceptible to penicillin G. Penicillin V is the drug of choice for prophylaxis against rheumatic carditis and against infections in patients with anatomic or functional asplenia. In patients with poor compliance, intramuscular benzathine penicillin can be used every 3 to 4 weeks. Benzathine penicillin is the drug of choice for primary, secondary, and early or late latent syphilis (except neurosyphilis). For infants with congenital syphilis, penicillin G or procaine penicillin is recommended (12).








Table 29.2 Pharmacokinetic Properties of Selected Penicillins (5,8)

























































Generic Name Half-Life (hr) Protein Binding (%) Route of Excretion
Penicillin G 0.5–1.2 55–65 Renal
Penicillin V 1 80 Renal
Oxacillin 0.5–1.2 90–95 Renal, hepatic
Cloxacillin 0.5 90–95 Renal, hepatic
Dicloxacillin 0.8–1 96–98 Renal, hepatic
Nafcillin 0.5 87–90 Hepatic, renal
Ampicillin 1 15–25 Renal
Amoxicillin 1 17–20 Renal
Ticarcillin 1.0–1.2 45–65 Renal
Piperacillin 0.5–1.3 22 Renal


Adverse Reactions

Allergic reactions are the major side effects associated with the penicillins. Severe and occasionally fatal anaphylaxis has also occurred. This relates to the ability of penicillins to act as haptens and combine with proteins. The most important antigenic component of the penicillins is the penicilloyl determinant produced by opening of the β-lactam ring. Anaphylactic reactions are estimated to occur in 0.01% to 0.05% of persons receiving penicillins. In patients with a history of life-threatening reactions to penicillin it may be prudent to avoid other β-lactam agents. However, if no other options are available, a trial of desensitization may be attempted. The following hypersensitivity reactions have been described: skin rashes ranging from maculopapular eruptions to exfoliative dermatitis, urticaria, and reactions resembling serum sickness, including chills, fever, edema, arthralgia, and prostration. The Jarisch–Herxheimer reaction has been reported in patients treated for syphilis.

Hematologic toxicity including Coombs-positive hemo-lytic anemia, leukopenia, and thrombocytopenia has been reported with penicillin use. Penicillins bind to the adenosine diphosphate receptor site in platelets and thereby
interfere with platelet aggregation. Clinically significant bleeding is not common.








Table 29.3 Penicillin Dosing Recommendations: Neonates (mg/kg/dose or u/kg/dose) (9)




































































    Infants 0–4 wk of Age Infants <1 wk of Age Infants ≥1 wk of Age
Antibiotic Route BW <1,200 g BW 1,200–2,000 g BW >2,000 g BW 1,200–2,000 g BW >2,000 g
Penicillin Ga, aqueous i.v., i.m. 25,000–50,000 q12 h 25,000–50,000 q12 h 25,000–50,000 q8 h 25,000–50,000 q8 h 25,000–50,000 q6 h
Ampicillin (mg/kg)a i.v., i.m. 25–50 q12 h 25–50 q12 h 25–50 q8 h 25–50 q8 h 25–50 q6 h
Procaine penicillin (u) i.m. · · · 50,000 q24 h 50,000 q24 h 50,000 q24 h 50,000 q24 h
Ticarcillin (mg/kg) i.v., i.m. 75 q12 h 75 q12 h 75 q8 h 75 q8 h 100 q8 h
Nafcillin (mg/kg) i.v., i.m. 25 q12 h 25 q12 h 25 q8 h 25 q8 h 25–35 q6 h
Oxacillin (mg/kg) i.v., i.m. 25 q12 h 25–50 q12 h 25–50 q8 h 25–50 q8 h 25–50 q6 h
BW, Body weight; i.m., Intramuscular; i.v., intravenous; q6 h, every 6 hr; q8 h, every 8 hr; q12 h, every 12 hr; q24 h, every 24 hr; u, units.
aFor meningitis, larger dosage is recommended.

Sodium overload and hypokalemia can occur with massive doses of penicillin secondary to the large dose of nonreabsorbable anion in the distal renal tubules. Patients given continuous intravenous therapy with penicillin G potassium in high dosage (10 million to 100 million units daily) may suffer severe or even fatal potassium poisoning, particularly if renal insufficiency is present.

Neurologic toxicity in the form of seizures has been reported following the use of massive doses of penicillin.








Table 29.4 Penicillin Dosing Recommendations: Pediatric Patients Excluding Neonates (mg/kg/day or u/kg/day) (9)



























































































































    Daily Dose  
Antibiotic Route Mild–Moderate Infections Severe Infections Frequency of Administration (i.e., in Divided Doses)
Penicillin G i.m., i.v. 25,000–50,000 U 250,000–400,000 U q4–6 h
Penicillin V p.o. 25,000–50,000 U Inappropriate q6–8 h
Penicillin G, benzathine i.m. <27.3 kg (60 lb): 600,000 U    
    ≥27.3 kg: 1,200,000 U Inappropriate q1–3 wk
Penicillin G, procaine i.m. 25,000–50,000 U (max. adult dose 48,000,000 u/24 hr) Inappropriate q12–24 h
Oxacillin i.m., i.v. 100–150 mg/kg 150–200 mg/kg q4–6 h
Dicloxacillin p.o. 25–50 mg/kg Inappropriate q6 h
Nafcillin i.m., i.v. 50–100 mg/kg 100–150 mg/kg q6 h
Ampicillin i.m., i.v. 100–150 mg/kg 200–400 mg/kg q6 h
  p.o. 50–100 mg/kg Inappropriate q4–6 h
Amoxicillin p.o. 25–50 mg/kg Inappropriate q8 h
Ticarcillin i.m., i.v. 100–200 mg/kg 200–300 mg/kg q4–6 h
Piperacillin i.m., i.v. 100–150 mg/kg 200–300 mg/kg q4–6 h
Amoxicillin–clavulanic acida p.o. 90 mg/kg Inappropriate q12 h
Ticarcillin–clavulanic acidb i.m., i.v. 100–200 mg/kg 200–300 mg/kg q6 h
Piperacillin–tazobactamb i.m., i.v. 100 mg piperacillin/12.5 mg tazobactam/kgc 240 mg q8 h
Ampicillin–sulbactamb i.m., i.v. 100–150 mg/kg 200–400 mg/kg q6 h
i.m., Intramuscular; i.v., intravenous; p.o., oral; q1–3 wk, every 1–3 weeks; q4–6 hr, every 4–6 hr; q6 h, every 6 hr; q6–8 h, every 6–8 hr; q8 h, every 8 hr; q12 h, every 12 hr; q12–24 h, every 12–24 hr.
aAmoxicillin:clavulanate 14:1, approved for infants and children ≥3 mo.
bBased on the penicillin component.
cFor 2–9 month old, 80 mg piperacillin/10 mg tazobactam/kg/day in three divided doses (Product label, http://dailymed.nlm.nih.gov.easyaccess1.lib.cuhk.edu.hk/dailymed/drugInfo).


Drug Interactions

Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin and tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. The clinical significance of this interaction is
not well documented. Penicillin blood levels may be prolonged by concurrent administration of probenecid, which blocks the renal tubular secretion of penicillins. Penicillins can interact with oral contraceptives (13,14).


Aminopenicillins


Structure–Activity Relationship

Aminopenicillins have a free amino group at the alpha position on the β-lactam ring of the penicillin nucleus, thereby increasing their ability to penetrate the outer membranes of gram-negative organisms.


Mechanism of Action

The mechanism of action is similar to that of penicillins.


Resistance

Aminopenicillins are inactivated by the β-lactamases produced by either gram-positive or gram-negative bacteria.


Pharmacokinetics

Aminopenicillins are cleared by the kidney. Ampicillin achieves therapeutic concentrations in most body fluids including CSF pleural, joint, and peritoneal fluids after parenteral administration. Amoxicillin has better absorption and bioavailability and hence is the preferred oral aminopenicillin. The absorption of amoxicillin is not affected by food.


Spectrum

Compared with penicillin G, ampicillin has increased in vitro efficacy against most strains of enterococci and L. monocytogenes as well as against some gram-negative pathogens, such as non-β-lactamase producing strains of H. influenzae and N. gonorrhoeae. Some strains of Escherichia coli, Shigella sonnei, and Salmonella including strains of S. typhi are resistant.


Clinical Uses

Amoxicillin is the drug of choice for acute otitis media (15,16) (Tables 29.2 to 29.4). Oral amoxicillin is also the drug of choice for treatment of some clinical manifestations of Lyme disease like erythema migrans, isolated facial palsy, and arthritis (17). Parenteral ampicillin is widely used in neonates with sepsis because of its activity against Listeria. Amoxicillin is used in combination with clarithromycin and a proton pump inhibitor like omeprazole or lansoprazole for the treatment of Helicobacter pylori infections (18,19). A report from the Food and Drug Administration (FDA) provides information on the pharmacokinetics and dosing of amoxicillin for use in the prophylaxis of postexposure inhalational anthrax (15 mg per kg per dose given every 8 hours) (20).


Adverse Events

The incidence of hypersensitivity reactions with aminopenicillins is similar to that of natural penicillins. There is a slightly higher incidence of maculopapular rash associated with ampicillin use in patients with intercurrent viral illnesses, especially due to Epstein–Barr virus.


Antistaphylococcal Penicillins


Structure–Activity Relationship

These are semisynthetic penicillin derivatives synthesized by the acylation of 6-aminopenicillanic acid to prevent the attachment of staphylococcal penicillinases to the β-lactam ring. Methicillin contains a dimethoxyphenyl group on the penicillin nucleus, and nafcillin is a naphthyl analogue of methicillin. Cloxacillin and dicloxacillin contain chlorine atoms, which increase gastrointestinal absorption and antibacterial activity as well as serum half-life and protein binding.


Mechanism

The penicillinase-resistant penicillins also act by binding to PBPs and preventing cell wall synthesis. They are resistant to the action of bacterial penicillinases by steric hindrance of the acyl side chain, thereby preventing opening of the β-lactam ring.


Resistance

Resistance to semisynthetic penicillins among staphylococci is related to the presence of the mecA gene, which results in the synthesis of a unique PBP, PBP2a, which has low affinity for methicillin and other β-lactam antibiotics.


Spectrum

This group of penicillins is effective against β-lactamase-producing isolates of Staphylococcus aureus and coagulase-negative staphylococci. They retain most of the activity of the penicillins but are much less active compared with penicillin G against penicillin-susceptible organisms, including non–penicillinase-producing staphylococci and streptococci. Enterococci, gram-negative cocci, L. monocytogenes, and anaerobes are resistant to these penicillins.


Pharmacokinetics

Unlike the natural penicillins, nafcillin is predominantly excreted through the biliary system, and hence accumulation can occur in jaundiced neonates. Although nafcillin is available in oral formulations, absorption is erratic. The isoxazolyl penicillins oxacillin, cloxacillin, and dicloxacillin are absorbed after oral administration but adversely affected by food. Serum levels after absorption are higher with cloxacillin and dicloxacillin than with oxacillin. They are excreted primarily by the kidneys with some biliary excretion. Cloxacillin and dicloxacillin are highly protein bound.


Clinical Indications

Methicillin is acid labile, is the least active member of this group of penicillins, and is most likely to cause interstitial nephritis, and hence is no longer used. Semisynthetic
penicillins are commonly used in the empiric treatment of skin and skin structure infections and bone and joint infections where S. aureus is a likely pathogen (Tables 29.2 to 29.4).


Adverse Events

Interstitial nephritis manifesting clinically as fever, rash, eosinophilia, proteinuria, eosinophiluria, and hematuria is more commonly reported with methicillin use. Elevated aspartate aminotransferase levels and cholestasis usually without jaundice have been reported with oxacillin use. Liver enzymes usually return to normal after discontinuation of therapy.


Drug Interactions

Drug interactions involving nafcillin and both cyclosporine and warfarin have been reported (21,22,23,24).


Extended-Spectrum Penicillins


Structure–Activity Relationship

Carbenicillin is an α-carboxypenicillin. It differs from ampicillin in that an α-carboxyl group is substituted for the α-amino group. Indanyl carbenicillin is a α-carboxy ester of carbenicillin. Ticarcillin is the 3-thienyl analogue of carbenicillin. The acylampicillins are semisynthetic penicillins and include ureidopenicillins (mezlocillin and azlocillin) and piperacillin. Mezlocillin and azlocillin are ureidopenicillins and have a ureido group at the α position. Piperacillin is a piperazine analogue of ampicillin.


Resistance

The extended-spectrum penicillins are susceptible to hydrolysis by β-lactamases of both gram-positive and gram-negative bacteria.


Spectrum

The extended-spectrum penicillins have a broader spectrum of activity than natural penicillins and aminopenicillins. Carbenicillin has greater stability against Pseudomonas and some β-lactamase-producing Enterobacteriaceae but is less active than ampicillin against Streptococcus pyogenes, S. pneumoniae, and Enterococcus faecalis. Ticarcillin has similar spectrum of activity as carbenicillin but is more active against Pseudomonas aeruginosa. Piperacillin is similar to ampicillin in activity against gram-positive species. It has good activity against anaerobic cocci and bacilli. It also has activity against members of the Enterobacteriaceae family and P. aeruginosa. Some extended-spectrum penicillins are less active than natural penicillins and aminopenicillins against anaerobic bacteria. In contrast to carbenicillin and ticarcillin, acylampicillins have activity against enterococci.


Pharmacokinetics

The extended-spectrum penicillins are administered parenterally, with the exception of indanyl carbenicillin. As a sodium ester, indanyl carbenicillin is acid stable. However, serum or tissue levels are not adequate for the treatment of systemic infections and its use was limited to the treatment of uncomplicated urinary tract infections. The extended-spectrum penicillins have minimal CSF penetration. Primary route of elimination is renal via glomerular filtration and tubular secretion. The ureidopenicillins show dose-related nonlinear kinetics.


Clinical Indications

The extended-spectrum penicillins are effective against a variety of gram-negative organisms and in combination with aminoglycosides are synergistic against many gram-negative bacilli (Tables 29.2 to 29.4). They are generally used clinically in combination with a β-lactamase inhibitor.


Adverse Events

Hypersensitivity reactions occur similar to those with natural penicillins. Because these agents are negatively charged ions, hypokalemia can result from leaching of anions in the distal renal tubule. Platelet dysfunction and prolonged bleeding times have been observed with the use of extended-spectrum penicillins. They can inhibit platelet aggregation by binding to the adenosine diphosphate receptor on platelets. Mezlocillin is the least likely to affect bleeding times.


Drug Interactions

Extended-spectrum penicillins can interact with warfarin, thereby decreasing its anticoagulant effects. Piperacillin can potentiate the action of nondepolarizing blocking agents. Some extended-spectrum penicillins have been shown to interact in solution with aminoglycosides, causing degradation of the aminoglycosides. It is recommended that these drugs not be mixed in solution and their administration be separated by 30 to 60 minutes.


β-Lactamase Inhibitors

The β-lactamase inhibitors are compounds that inhibit many β-lactamases and additionally have weak antibacterial activity. They are available as fixed-combination preparations with a β-lactam antibiotic. Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and cephalosporins. It contains a β-lactam ring attached to an oxazolidine ring. Sulbactam is a synthetic penicillinate sulfone derived from 6-aminopenicillanic acid and contains a β-lactam ring. Tazobactam is a synthetic penicillanic acid sulfone.


Mechanism of Action

Clavulanic acid, sulbactam, and tazobactam possess the ability to inactivate a wide variety of β-lactamases by irreversibly binding to the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for
transferred drug resistance to penicillins and cephalosporins. Clavulanic acid acts by both transient reversible complex formation and irreversible inactivation. Against E. coli-derived β-lactamase, reversible complex formation has been shown to proceed at a faster rate than terminal inactivation. In the presence of excess clavulanic acid, all enzymes will accumulate into one of several irreversibly inactivated forms (25,26). The mechanism of action of sulbactam and tazobactam is similar to that of clavulanic acid (27,28).

Clavulanic acid is the most efficient inhibitor of staphylococcal β-lactamase and is also an effective inhibitor of chromosomally mediated β-lactamase liberated by Klebsiella pneumoniae, Proteus mirabilis, P. vulgaris, Moraxella catarrhalis, Bacteroides fragilis, and TEM plasmid-mediated β-lactamase. It less readily inhibits chromosomally mediated β-lactamase of Citrobacter species, Enterobacter species, indole-positive Proteus species, and Serratia marcescens (29). Overall, sulbactam is the least active of the three agents (30). No significant difference in activity between the inhibitors exists with respect to anaerobes; therefore, they should be considered comparable with respect to extending anaerobic coverage to their partner antibiotic in treating mixed infections (31).

β-lactamase inhibitors can act as inducers of certain β-lactamases, thus rendering organisms that produce the enzyme less susceptible to the partner antibiotic (32). This effect is most pronounced with clavulanic acid and occurs at concentrations at or above those achievable in vivo (23). Tazobactam does not induce chromosomally mediated β-lactamases at tazobactam levels achieved with the recommended dosage regimen (33). β-lactamase inhibitors also have some intrinsic antibacterial activity. Clavulanic acid demonstrates good activity against B. fragilis, Acinetobacter species, and Legionella pneumophilia (34). Tazobactam has very low-level binding to PBPs and has the least intrinsic antibacterial activity (30).


Pharmacokinetics

Clavulanic acid is well absorbed orally and provides adequate inhibitory activity in most body fluids except CSF and sputum (35,36). Sulbactam is available in oral and parenteral formulations. In the United States, it is available only for parenteral use. Tazobactam is also available only in a parenteral formulation.


Penicillins and β-Lactamase Inhibitor Combinations

Penicillins and β-lactamase inhibitor combinations used clinically include ampicillin + sulbactam, amoxicillin + clavulanic acid, ticarcillin + clavulanic acid, and piperacillin + tazobactam.


Pharmacokinetics

Amoxicillin serum concentrations achieved with amoxicillin + clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration. Penetration of ticarcillin into bile and pleural fluid has been demonstrated. Penetration of both ampicillin and sulbactam into CSF in the presence of inflamed meninges has been demonstrated after intravenous administration of ampicillin and sulbactam. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into CSF is low in individuals with noninflamed meninges, as with other penicillins (33). The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound.


Clinical Uses


Amoxicillin + Clavulanic Acid

Amoxicillin + clavulanic acid is useful in children with acute otitis media and other respiratory tract infections caused by β-lactamase-producing strains of H. influenzae and M. catarrhalis. It can be used to treat animal or human bites. Various formulations of this combination are available, with the ratio of amoxicillin to clavulanate varying (4:1, 7:1, and 14:1). The 12-hourly regimen is associated with significantly less diarrhea.

It is approved by the FDA for use in pediatric patients for the following infections: lower respiratory tract infections, otitis media, sinusitis, skin and skin structure infections, and urinary tract infections. A different dosing regimen is recommended for patients younger than 3 months of age.


Ampicillin + Sulbactam

The safety and effectiveness of ampicillin + sulbactam have been established for pediatric patients 1 year of age and older for skin and skin structure infections. The safety and effectiveness have not been established for pediatric patients for intra-abdominal infections.


Ticarcillin + Clavulanic Acid

Ticarcillin + clavulanic acid is approved by the FDA for use in patients from 3 months to 16 years of age. It is not approved for the treatment of septicemia and/or infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b. It is currently approved for the following indications: septicemia, including bacteremia; lower respiratory infections; bone and joint infections; skin and skin structure infections; urinary tract infections; gynecologic infections; and intra-abdominal infections.


Piperacillin + Tazobactam

Piperacillin + tazobactam is approved for use in pediatric patients 2 months of age or older with appendicitis and/or
peritonitis. The dosing regimens vary for children 9 months of age or older, weighing up to 40 kg, and with normal renal function and for those between 2 and 9 months of age (Table 29.4). Pediatric patients weighing more than 40 kg and with normal renal function should receive the adult dose. There are no dosage recommendations for pediatric patients with impaired renal function.


Cephalosporins

The first source of cephalosporins was Cephalosporium acremonium, a fungus isolated in 1948 by G. Brotzu from the sea near a sewer outlet off the Sardinian coast.


Structure–Activity Relationship

All cephalosporins are semisynthetic derivatives of a 7-aminocephalosporanic acid nucleus. Like penicillins, cephalosporins possess a β-lactam ring. Modifications of the carbon-3 and carbon-7 positions of the 7-aminocephalosporanic acid nucleus have yielded the three generations. Modifications around this nucleus have stabilized the β-lactam ring to hydrolysis by penicillinases. Modifications around the carbon-3 position are associated with changes in the metabolism or improved pharmacokinetics, and modifications around the carbon-7 position affect β-lactamase stability and antimicrobial activity (37,38,39,40). The cephamycins are similar to cephalosporins, but have a methoxy group at position 7 of the β-lactam ring of the 7-aminocephalosporanic acid nucleus. The cephamycins will be discussed along with the second-generation cephalosporins.

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics
  2. Drugs for Hyperbilirubinemia
  3. Psychopharmacology in Children and Adolescents
  4. Glucocorticoids

Stay updated, free articles. Join our Telegram channel
Tags:
Sep 7, 2016 | Posted by in PEDIATRICS | Comments Off on Penicillins, Cephalosporins, and Other β-Lactams

Full access? Get Clinical Tree
Get Clinical Tree app for offline access