Antimicrobial Agents
Confronted with an extensive and expanding array of antibiotics, the clinician must be well versed in the use of antibiotics in the day-to-day care of patients. New developments in antibiotic use include home parenteral therapy, new dosing regimens (as for gentamicin and clindamycin), antibiotic-resistant bacteria, and new antibiotics. The discussion of mode of action, pharmacokinetics, and antibiotic excretion in breast milk now appear on the Web site for this textbook. Relatively few antibiotics are contraindicated in pregnant and lactating women (Table 23.1).
PENICILLINS
Penicillin was initially isolated from the mold Penicillium notatum by Fleming in 1929 but was not introduced into clinical practice until 1941. The basic chemical structure of penicillin consists of three components: a thiazolidine ring, the β-lactam ring, and a side chain that largely determines the antibacterial spectrum and pharmacologic properties of each penicillin.
The various semisynthetic penicillins are derived from the penicillin nucleus, 6-aminopenicillanic acid (6-APS). The penicillins can be divided into eight major classes on the basis of their antibacterial activities (Table 23.2).
Natural Penicillins
The common natural penicillins are penicillin G and penicillin V (penicillin phenoxymethyl). Penicillin G is available as penicillin G potassium, penicillin G sodium, penicillin G procaine, and penicillin G benzathine.
Spectrum of Activity
The penicillins are bactericidal antibiotics that interfere with cell wall formation by affecting the formation of the mucopeptide portion of the cell wall. Penicillin G is active against a wide range of bacteria, predominantly Gram-positive organisms. Among the Gram-positive, facultative, or aerobic cocci, penicillin G is highly active against group A streptococci. Although most Streptococcus pneumoniae strains remain extremely sensitive, resistant pneumococcal strains occur frequently in the United States. Group B α-hemolytic streptococci are 100% sensitive to penicillin G but are approximately 10-fold less sensitive than the group A streptococci. In addition, groups C and G β-hemolytic streptococci and the α-hemolytic streptococci such as Streptococcus viridans and nonenterococcal group D streptococci are sensitive to penicillin G. The anaerobic Gram-positive cocci such as Peptostreptococcus sp are highly susceptible to penicillin G. On the other hand, enterococcal group D streptococci are resistant to penicillin G, as are all Staphylococcus aureus strains, whose resistance is caused by β-lactamase (penicillinase) production.
Among Gram-positive bacilli, Corynebacterium diphtheriae, Bacillus anthracis, and many strains of Listeria monocytogenes are sensitive to penicillin G. Anaerobic Gram-positive spore-forming bacilli such as Clostridium perfringens and most other Clostridium sp are penicillin G-sensitive. In addition, penicillin G is active against most anaerobic non-spore-forming bacilli such as Actinomyces, Eubacterium, Bifidobacterium, Propionibacterium, and Lactobacillus species.
Among the Gram-negative cocci, Neisseria meningitides remains very sensitive to penicillin G. However, Neisseria gonorrhoeae susceptibility has dramatically decreased, so that penicillin has not been used to treat this organism for over 20 years. Gram-negative anaerobic cocci such as Veillonella sp are also sensitive to penicillin G.
Among Gram-negative bacilli, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Salmonella, Shigella, Citrobacter spp and Pseudomonas aeruginosa, and other Pseudomonas species are all resistant to penicillin G. Although penicillin G is active against many Gram-negative anaerobes such as Fusobacterium and some Bacteroides species, resistant species are Bacteroides fragilis, Prevotella bivia (formerly Bacteroides bivius), and Bacteroides disiens.
Treponema pallidum is sensitive to penicillin G. The mycoplasmas, rickettsiae, fungi, and protozoa are completely penicillin resistant, whereas chlamydiae are relatively resistant.
The spectrum of activity of the phenoxypenicillins—penicillin V, phenethicillin, propicillin, and phenbenicillin—is generally similar to that described for penicillin G. However, penicillin G is more active against streptococci, pneumococci, and N. meningitides.
Dosage and Route
When oral therapy with penicillin is desired, penicillin V (penicillin phenoxymethyl), because of its greater acid stability than penicillin G, is the usual choice in a dosage of 250 to 500 mg (400,000 to 800,000 units) every 6 to 8 hours. Penicillin V may be given with meals. Based on kinetic studies, one recommended a dose in pregnancy of 1 million units every 6 hours instead of their usual dosing interval of every 8 hours.
Crystalline penicillin G is available to be administered intramuscularly or intravenously. When given intramuscularly, it reaches peak serum concentrations 15 to 30 minutes after injection; a dose of 1 million units results in a peak serum level of 12 μg/mL. By 3 to 4 hours, serum concentrations are negligible. Crystalline penicillin G is usually given in dosages ranging from 300,000 to 1,000,000 units every 6 hours by the intramuscular route, but it can be given as frequently as every 2 hours. Crystalline penicillin G may be administered intravenously by either intermittent bolus infusion or continuous infusion. The
intermittent infusion of high concentrations of penicillin G is generally preferred. A rapid infusion of 5 million units of crystalline penicillin G results in peak serum concentrations of 400 μg/mL within a few minutes. By 4 hours after injection, the serum concentration falls to 3 μg/mL. Intravenous therapy is administered in a dose of 1 million to 5 million units every 2 to 6 hours, depending on the severity of the clinical infection.
intermittent infusion of high concentrations of penicillin G is generally preferred. A rapid infusion of 5 million units of crystalline penicillin G results in peak serum concentrations of 400 μg/mL within a few minutes. By 4 hours after injection, the serum concentration falls to 3 μg/mL. Intravenous therapy is administered in a dose of 1 million to 5 million units every 2 to 6 hours, depending on the severity of the clinical infection.
TABLE 23.1 ▪ ANTIMICROBIAL AGENTS CONTRAINDICATED IN PREGNANT AND LACTATING WOMEN | |||||||||||||||||||||||||||||||||||
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Repository penicillins for intramuscular injection are penicillin G procaine and penicillin G benzathine. With penicillin G procaine, peak serum levels occur 1 to 3 hours after injection, and detectable levels are usually present for up to 24 hours. The standard dose of penicillin G procaine is 600,000 to 1,200,000 units intramuscularly every 6 to 12 hours. When injected intramuscularly, penicillin G benzathine results in a slow release of penicillin, which lasts for 2 to 4 weeks. After injection of 2.4 million units of penicillin G benzathine, 0.12 μg/mL of penicillin can be detected 14 days after injection. The usual dose is 1.2 million to 2.4 million units, and the interval of dosing depends on the clinical indication.
TABLE 23.2 ▪ CLASSIFICATION OF PENICILLINS | |||||||||||||||||||||||||||||||||||
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Side Effects
Although penicillin is one of the least toxic antimicrobial agents, it is commonly responsible for hypersensitivity reactions. These hypersensitization reactions include rash, urticarial reactions, anaphylactic reactions, serum sickness, contact dermatitis, and angioedema. Local reactions may occur such as swelling, pain, and redness at the site of injection or phlebitis after intravenous infusion.
Direct penicillin toxicity may occur with massive doses (60 million to 100 million units daily). Neurologic toxicity with convulsions and coma may result, particularly in patients with renal insufficiency, underlying central nervous system (CNS) disease, or hyponatremia. Interstitial nephritis or hemolytic anemia may occur with large doses of penicillin G. Rarely, administration of penicillin G has been associated with development of thrombocytopenic purpura, glossitis, and stomatitis.
Penicillin V may result in gastrointestinal side effects such as nausea, vomiting, and diarrhea. Hypersensitivity reactions may occur as noted for penicillin G.
Cost
Penicillin G and penicillin V are inexpensive antimicrobial agents. Thus, for microorganisms susceptible to these agents, the penicillins remain the drug of choice.
Use in Pregnancy
Penicillin G rapidly crosses the placenta and achieves therapeutic levels in cord blood and, after several hours, in amniotic fluid. No adverse effects on the fetus have been demonstrated with the use of penicillin G, and this drug is considered safe to use during pregnancy. Similarly, penicillin V has not been linked with adverse fetal effects. Small amounts of either penicillin G or penicillin V are excreted in breast milk, and both are considered compatible with breast-feeding.
Metabolism
Penicillin G is primarily excreted in the urine. In patients with normal renal function, more than 70% of the injected dose is excreted within 6 hours. Ninety percent of penicillin G excretion occurs by tubular excretion and 10% by glomerular filtration. This renal tubular secretion can be partly blocked by probenecid, resulting in a doubling of serum levels of penicillin. Approximately 5% of penicillin G is excreted in the bile. The penicillin not excreted in urine or bile is inactivated in the liver, with penicilloic acid as the major end product. The phenoxypenicillins are also excreted
in urine and bile. During the first 6 hours after oral intake, 20% to 40% of the dose of penicillin V can be recovered from urine.
in urine and bile. During the first 6 hours after oral intake, 20% to 40% of the dose of penicillin V can be recovered from urine.
Penicillin G is widely distributed in the body. High concentrations of penicillin G are present in blood, liver, bile, skin, intestines, and kidneys. Low concentrations occur in joint fluid, pericardial fluid, and pleural fluid. Peritoneal fluid contains high concentrations. Small amounts of penicillin G are distributed to brain, nerve, dura, bone marrow, bone, pancreas, adrenal glands, or spleen. Whereas penicillin G poorly penetrates the blood-brain barrier in the presence of normal meninges, when the meninges are inflamed, cerebrospinal fluid (CSF) levels of penicillin G are adequate.
Indications in Obstetrics and Gynecology
Penicillin G is the drug of choice for infections caused by group A streptococci and for prevention and treatment of infections caused by group B β-hemolytic streptococci. Because of its activity against aerobic and anaerobic streptococci, Clostridium species, and many of the Bacteroides species, penicillin G was commonly used in combination with an aminoglycoside as initial therapy for mixed aerobic-anaerobic soft tissue pelvic infections. However, recognition of the role of penicillin-resistant anaerobes has resulted in a diminished role for penicillin G in polymicrobial infections.
When enterococcal infection is a concern, penicillin G should be combined with an aminoglycoside because penicillin plus an aminoglycoside has a synergistic effect on the enterococcus.
As described in Chapter 5, penicillin G in the form of penicillin benzathine is the drug of choice for the treatment of syphilis.
Penicillin G is the drug of choice for the treatment of actinomycosis, which may be found associated with intrauterine device usage. Similarly, it is the drug of choice for most clostridial infections (except C. difficile).
Antistaphylococcal Penicillins
The emergence of β-lactamase-producing S. aureus led to major efforts for the development of antibiotics resistant to the hydrolysis of β-lactamase enzymes. This resulted in a large variety of semisynthetic penicillins derived from 6-amniopenicillanic acid. The narrow-spectrum penicillinase-resistant penicillins include methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, and flucloxacillin.
Spectrum of Activity
In 1961, methicillin was the first antistaphylococcal penicillin introduced into clinical medicine. Although it is active against pneumococci and streptococci, its efficacy against these organisms is many-fold less than that of penicillin G. Methicillin is active against most strains of S. aureus, but increasingly, methicillin-resistant S. aureus (MRSA) has been reported. MRSA is resistant by virtue of altered penicillin-binding proteins. MSRA is also resistant to penicillin G, the cephalosporins, and other penicillinase-resistant penicillins such as nafcillin, oxacillin, cloxacillin, and dicloxacillin. MRSA had been associated predominantly with hospital-acquired infections, but in the last 10 years, MRSA infections have now been community acquired as well and appear in otherwise healthy pregnant women and newborns. The isoxazolyl penicillins—oxacillin, cloxacillin, and dicloxacillin—have a spectrum of activity similar to that of methicillin. Nafcillin also has a similar antibacterial spectrum. Its stability in the presence of staphylococcal penicillinase is comparable to that of methicillin but greater than that of the isoxazolyl penicillins.
Dosage and Route
Methicillin is administered only by the intravenous route. The dosage can be varied depending on the site and severity of the infection. For infections of moderate severity, 1 g every 4 hours is generally used, and for serious infections such as endocarditis, a dose of 2 g every 2 to 3 hours may be given. After an intravenous injection of 1 g of methicillin, a peak serum level of 60 μg/mL is obtained. There is a rapid fall in serum levels, to 7 μg/mL by 1 hour and less than 1 μg/mL by 2 to 3 hours. The peak level can be doubled by doubling the dose.
Although oral oxacillin is available, it is absorbed erratically. Oxacillin may be given in a dosage of 250 to 500 mg every 4 to 6 hours, intravenously or intramuscularly, for mild to moderate infections. The dosage for severe infections is 1 g intravenously every 4 to 6 hours. Peak serum levels after a single intramuscular injection of oxacillin (500 mg) reach 14 to 16 μg/mL.
Cloxacillin and dicloxacillin are analogs of oxacillin. They are acid stable and thus well absorbed after oral ingestion. After an oral dose of 500 mg of cloxacillin, a peak serum level of 8 μg/mL is reached in 30 to 60 minutes. Dicloxacillin produces serum levels that are twice as high as those of cloxacillin. Serum levels of flucloxacillin are similar to those seen with dicloxacillin. The usual oral adult dosage of these penicillins is 500 mg every 6 hours. For dicloxacillin, a dosage of 125 to 250 mg every 6 hours may suffice.
Oxacillin, cloxacillin, and flucloxacillin can be given intramuscularly or intravenously, although dicloxacillin can be given intramuscularly. For mild infections, 250 mg every 6 hours is recommended. For moderate infections, the usual dosage is 1 g every 4 hours, and in severe infections, this is increased to 2 g every 4 hours.
Nafcillin is poorly absorbed and is unreliable when used orally. It can be given either intramuscularly or intravenously. The usual adult dosage is 1 g every 4 hours but can be increased to 2 g every 4 hours for severe infections. After a 1-g intramuscular injection, a peak serum level of 8 μg/mL of nafcillin is reached in about 1 hour. By 6 hours, the level is 0.5 μg/mL.
Side Effects
Methicillin, isoxazolyl penicillins, and nafcillin are contraindicated in penicillin-allergic patients because they can produce any of the hypersensitivity reactions described for penicillin G. Methicillin has been associated with drug fever and leukopenia. In addition, interstitial nephritis may result from the use of large doses of intravenous methicillin. Most patients recover from the methicillin-associated interstitial nephritis after stopping the agent.
The isoxazolyl penicillins may produce nausea and diarrhea with oral administration. Oxacillin may cause fever, nausea, and vomiting in association with abnormal liver function test results. Neutropenia has been noted as well. With very large doses, neurotoxicity occurs, particularly in patients with impaired renal function.
Nafcillin has been reported to cause nephropathy and neutropenia on rare occasion.
Cost
The penicillinase-resistant penicillins are more expensive drugs than are penicillin G. They should be used only in the treatment of staphylococcal strains resistant to penicillin G.
Use in Pregnancy
All of the penicillinase-resistant penicillins are capable of crossing the placenta. No untoward effects on the fetus have been described.
Metabolism
Methicillin is excreted in urine, both by glomerular filtration and by tubular secretion. Up to 80% of an injected dose can be recovered from urine. A small percentage (2% to 3%) of the administered drug is excreted in bile. The unexcreted methicillin is inactivated in the body by the liver. Methicillin is widely distributed throughout the body.
Isoxazolyl penicillins are mainly excreted in the urine, with dicloxacillin and flucloxacillin present in larger amounts than cloxacillin, of which 30% of an oral dose is excreted in the urine. Oxacillin is excreted in smaller amounts than cloxacillin. Excretion occurs by glomerular filtration and tubular secretion. These penicillins are also excreted in the bile to a small extent. Inactivation of the isoxazolyl penicillins probably occurs in the liver.
After administration of nafcillin, 30% of the dose can be recovered from the urine. Between 5% and 10% of a dose is excreted in bile. The remainder of the nafcillin is inactivated in the liver. Nafcillin reaches high concentrations in the CSF of patients with normal meninges and in those with inflamed meninges.
Indications in Obstetrics and Gynecology
The penicillinase-resistant penicillins are indicated solely for the treatment of infections caused by S. aureus. Examples include wound and episiotomy infection, mastitis, endocarditis, osteomyelitis, and toxic shock syndrome. Because infections caused by MRSA now appear in the community and are not readily distinguishable from other infections, it is recommended that a specimen for culture and sensitivity be sent even from community-acquired infections. One characteristic of MRSA infections is that an inappropriate antibiotic has usually been chosen initially.
Aminopenicillins
The aminopenicillins are semisynthetic derivatives of 6-APS and include ampicillin, amoxicillin, and antibiotics structurally related to ampicillin-amoxicillin, such as epicillin, cyclacillin, hetacillin, pivampicillin, talampicillin, bacampicillin, and metampicillin.
Spectrum of Activity
Ampicillin and amoxicillin have identical spectra. They are active against most of the bacteria that are sensitive to penicillin G. However, they are also active against some of the Gram-negative bacteria that are resistant to penicillin G. Like penicillin G, they are bactericidal antibiotics that inhibit cell wall synthesis.
Against aerobic Gram-positive cocci, ampicillin is generally as effective as penicillin G. Thus, group A and group B β-hemolytic streptococci, most S. pneumoniae, and the β-hemolytic streptococci of the viridans group are susceptible. Nearly all S. aureus organisms are resistant to ampicillin. Unlike penicillin G, ampicillin is effective against enterococcal strains of the group D streptococci. The anaerobic Gram-positive cocci such as Peptostreptococcus species are almost always sensitive to ampicillin.
Among Gram-positive aerobic bacilli, C. diphtheriae, B. anthracis, and L. monocytogenes are generally susceptible to ampicillin. Ampicillin is active against anaerobic Gram-positive spore-forming bacilli such as clostridia and anaerobic Gram-positive non-spore-forming bacilli such as Actinomyces, Eubacterium, Bifidobacterium, Propionibacterium, and Lactobacillus species.
Ampicillin is effective against some of the Enterobacteriaceae. Although E. coli is often sensitive, increasing resistance by this organism has made ampicillin an unreliable empiric choice for therapy. Unless it is a β-lactamase-producing strain, Proteus mirabilis is susceptible to ampicillin. Enterobacter, Klebsiella, Serratia, Citrobacter, and indole-positive Proteus strains are generally resistant to ampicillin. Salmonellae are usually sensitive, but resistant strains have occurred. On the other hand, Shigella species tend to be resistant.
Among the other Gram-negative aerobic bacteria, P. aeruginosa is always resistant to ampicillin. Haemophilus influenzae type b was generally sensitive to ampicillin, but plasmid-mediated ampicillin resistance has occurred. Because of the prevalence of penicillinase-producing N. gonorrhoeae (PPNG) strains, ampicillin (like penicillin) has not been used to treat gonorrhea in over 20 years. N. meningitides organisms remain sensitive. Similar to the pattern with penicillin G, many of the Bacteroides and Fusobacterium species are ampicillin sensitive. The notable exceptions are B. fragilis group, P. bivia, and Prevotella disiens. Mycoplasmas and rickettsiae are ampicillin resistant and chlamydiae are relatively resistant, but Chlamydia trachomatis cervicitis may be treated with amoxicillin, which is an alternative treatment in pregnancy.
Dosage and Route
The usual oral dosage of ampicillin is 250 to 500 mg every 6 hours. After oral administration of 500 mg, peak serum levels of 3 μg/mL are obtained at approximately 2 hours, and the drug is still detectable at 6 hours. Doubling the dose results in a doubling of the serum level. Oral absorption of ampicillin is significantly lowered if it is taken with meals. For amoxicillin, the usual dosage is 250 mg, three times a day.
An intramuscular preparation of ampicillin is available but rarely necessary. The usual dosage is 0.5 to 1.0 g every 6 hours. After a 500-mg injection, a peak serum level of 10 μg/mL is achieved in 1 hour, and levels persist for 4 hours.
The usual intravenous dosage is 1 to 2 g every 4 to 6 hours by intermittent infusion, depending on the severity of the clinical infection.
Amoxicillin is significantly better absorbed than ampicillin when given orally, and peak serum levels are approximately 2 to 2.5 times those achieved with a similar dose of ampicillin. The usual adult dosage of amoxicillin is 250 to 500 mg every 6 to 8 hours.
Side Effects
Ampicillin and the other aminopenicillins may cross-react with other penicillins and therefore should not be used in patients with a history of penicillin allergy. Any of the hypersensitivity reactions described for penicillin G may occur with ampicillin. The incidence of rash in ampicillin users is much greater than that reported with use of penicillin G. Five percent to 7% of patients treated with ampicillin develop a diffuse macular rash. However, these rashes are specific for ampicillin and do not represent a true penicillin allergy.
Gastrointestinal side effects such as nausea and diarrhea occur commonly but are generally not serious. Because of their enhanced gastrointestinal absorption, the aminopenicillins,
except ampicillin, are associated with fewer gastrointestinal side effects. More rarely, pseudomembranous colitis has been reported with ampicillin use. Unusual side effects noted in ampicillin treatment include nephropathy, agranulocytosis, and encephalopathy.
except ampicillin, are associated with fewer gastrointestinal side effects. More rarely, pseudomembranous colitis has been reported with ampicillin use. Unusual side effects noted in ampicillin treatment include nephropathy, agranulocytosis, and encephalopathy.
Ampicillin may impair the absorption of oral contraceptives and thus can be associated with breakthrough bleeding. Monilia vaginitis may develop secondary to ampicillin suppression of the normal vaginal microflora.
Cost
Ampicillin is a relatively inexpensive antibiotic, in both oral and parenteral forms. For oral amoxicillin, the cost is similar. The other aminopenicillins are more costly than ampicillin, and the additional cost may limit their use.
Use in Pregnancy
Ampicillin has been used extensively in pregnancy. Because no adverse fetal effects have been associated with ampicillin, the drug is considered safe for use in pregnancy. In pregnant woman, serum levels of ampicillin are approximately 50% of those obtained in nonpregnant women. This is the result of the significant increases in plasma volume and renal clearance of ampicillin that occur in pregnancy. Shorter dosing intervals or an increased dose has been recommended.
Ampicillin rapidly crosses the placenta, and after a single maternal dose, peak cord blood levels are 40% of the peak maternal levels. In turn, amniotic fluid levels are initially lower than those in the umbilical cord but increase to therapeutic levels over several hours. Use of amoxicillin/ampicillin is compatible with breast feeding, and these drugs are excreted in small amounts of breast milk.
Experience with the aminopenicillins other than ampicillin/amoxicillin in pregnancy is limited, to date.
Metabolism
Like penicillin G, ampicillin is largely excreted in urine as the result of glomerular filtration and tubular secretion. After oral administration, 75% of a dose is excreted in the urine. The remainder of an ampicillin dose is either excreted in the bile or inactivated in the liver.
Ampicillin is evenly distributed throughout body tissues, with levels in the kidneys and liver being significantly greater than serum levels. Although only very low levels can be detected in normal CSF, high levels of ampicillin are achieved in the CSF with inflamed meninges.
Indications in Obstetrics and Gynecology
Ampicillin may be used in the therapy for asymptomatic bacteriuria, acute cystitis, and acute pyelonephritis in pregnant and nonpregnant women, provided there is demonstrated in vitro susceptibility of the infecting organism. Because of increasing resistance of E. coli, ampicillin should not be used by itself in the empiric treatment of urinary tract infection.
Although in the past ampicillin alone or in combination with an aminoglycoside was commonly used for the treatment of mixed aerobic-anaerobic soft tissue pelvic infections such as endomyometritis, pelvic cellulitis, or pelvic inflammatory disease (PID), the recognition of the need to provide therapy against Gram-negative anaerobes in such infections has resulted in a more widespread use of “triple therapy” (ampicillin, clindamycin, and gentamycin).
Ampicillin is an alternate to penicillin for prevention and treatment of group B streptococcal infections. Ampicillin is also the optimal drug for the treatment of L. monocytogenes infections.
Finally, ampicillin has been used effectively as a prophylactic antibiotic with cesarean sections and vaginal hysterectomy. Because of enhanced oral absorption, amoxicillin has replaced oral ampicillin in the treatment of UTIs.
Antipseudomonal Penicillins
The antipseudomonal group of penicillins include the carboxypenicillins—carbenicillin and ticarcillin—and the ureidopenicillin azlocillin. The major importance of these antimicrobial agents is their activity against Pseudomonas species. However, they are all susceptible to β-lactamase enzymes produced by Gram-negative and Gram-positive organisms.
Spectrum of Activity
The spectrum of activity of carbenicillin is similar to that of ampicillin, but it does possess activity against P. aeruginosa and certain indole-positive Proteus species. Carbenicillin is less active than ampicillin against the facultative streptococci. Klebsiella pneumoniae is resistant. At high concentrations, carbenicillin is also active against anaerobic bacteria including B. fragilis, although not to the extent of clindamycin, chloramphenicol, metronidazole, or cefoxitin. Carbenicillin acts synergistically with aminoglycosides to inhibit P. aeruginosa. This is clinically important because resistance to carbenicillin often develops among P. aeruginosa during therapy. The antibacterial spectrum of ticarcillin is similar to that of carbenicillin with the exception that it is 2 to 4 times more active against P. aeruginosa. However, strains of P. aeruginosa that are highly resistant to carbenicillin are also resistant to ticarcillin. Azlocillin is a ureidopenicillin whose main advantage is its significantly enhanced activity against P. aeruginosa, compared with that of carbenicillin or ticarcillin. All three of these agents are ineffective against β-lactamase-producing S. aureus.
Dosage and Route
Carbenicillin is not absorbed after oral administration and is available in intramuscular or intravenous forms. An oral form, carbenicillin indanyl sodium, is available but is useful only for UTIs because adequate serum concentrations are not achieved. For the treatment of systemic Pseudomonas infections or anaerobic infection, intravenous intermittent doses of carbenicillin (5 g every 3 to 4 hours) are required (total 30 to 40 g daily). Parenteral carbenicillin for Pseudomonas UTIs requires 1 to 2 g every 4 to 6 hours. The usual adult dosage for oral carbenicillin (provided as carbenicillin indanyl sodium) is 0.5 to 1.0 g every 6 hours.
After an intramuscular dose of 1 g, peak carbenicillin serum levels of 20 μg/mL are achieved in 1 hour, and no drug is detectable by 4 hours. Although these serum levels are inadequate for Pseudomonas or anaerobic infections in soft tissue, the urine levels reach 2,000 to 4,000 μg/mL, which are sufficient for the treatment of Pseudomonas UTI. With an intravenous infusion of 70 to 100 mg of carbenicillin per kilogram of body weight, serum levels of 150 to 200 μg/mL can be obtained; these levels are sufficient, in many instances, for the treatment of soft tissue Pseudomonas or anaerobic infections.
With ticarcillin, an adult dosage of 18 to 24 g per 24 hours is recommended for systemic Pseudomonas infections or anaerobic infections; this is given as a 3-g dose every 3 to 4 hours. For treatment of UTIs, a dosage of 1 g every 6 hours is recommended. After a 1-g dose of ticarcillin intramuscularly, a mean peak serum level of 35 μg/mL is achieved in 1 hour, and by 6 hours, it is 6 μg/mL. After a 3-g intravenous
infusion, mean serum levels postinfusion are 239 μg/mL, and at 4 hours, they are 94 μg/mL.
infusion, mean serum levels postinfusion are 239 μg/mL, and at 4 hours, they are 94 μg/mL.
Side Effects
Carbenicillin, ticarcillin, and azlocillin may provoke any of the hypersensitivity reactions that occur with penicillin G. High doses of carbenicillin may result in neurotoxicity. Each gram of carbenicillin contains 4.7 mEq of sodium. With the use of the required large dosage of 30 to 40 g per day, the potential for sodium overload may occur in patients with cardiac or renal disease. In addition, hypokalemia may occur as a result of this sodium overload. Finally, carbenicillin rarely is associated with bleeding as the result of diminished platelet adhesiveness.
In high doses, ticarcillin also may result in neurotoxicity, electrolyte disturbances similar to those described with carbenicillin, and altered platelet function. The lower required dose of ticarcillin (compared with that of carbenicillin) is associated with a lower sodium load and less platelet dysfunction.
Cost
The antipseudomonal penicillins are costly antimicrobial agents because of the large doses required.
Use in Pregnancy
Carbenicillin, ticarcillin, and azlocillin have not been used extensively during pregnancy. Like other penicillins, they are most likely safe to use during pregnancy. However, they should be used in pregnant women only when no safe alternative is available.
Metabolism
Carbenicillin is excreted via the kidney, with about 95% of a parenteral dose excreted into the urine during the first 6 hours after administration. It is excreted via glomerular filtration and tubular secretion. A small amount (less than 1%) of carbenicillin is excreted in the bile or inactivated in the liver. Similarly, ticarcillin and azlocillin are also primarily excreted via the kidneys.
Indications in Obstetrics and Gynecology
The clinical role for carbenicillin and ticarcillin in obstetrics and gynecology is now very limited. Although clinical studies have demonstrated relatively good efficacy with these agents (as single agents or in combination with aminoglycosides) in the treatment of mixed aerobic-anaerobic soft tissue infections of the pelvis, the introduction of the ureidopenicillins, mezlocillin and piperacillin, into clinical practice has significantly reduced their usefulness.
Although Pseudomonas infections of soft tissue are rare on obstetric and gynecologic services, when these infections do occur, azlocillin is an appropriate therapeutic agent. Its major advantage over aminoglycosides is a decreased potential for nephrotoxicity or ototoxicity. For serious Pseudomonas infection, azlocillin should be combined with an aminoglycoside.
Extended-Spectrum Penicillins
Ureidopenicillins, such as mezlocillin (Mezlin) and piperacillin (Pipracil), have replaced the carboxypenicillins (carbenicillin and ticarcillin). Compared with carbenicillin and ticarcillin, the ureidopenicillins have extended coverage against the Enterobacteriaceae, a diminished sodium load, and increased bioavailability in CSF, amniotic fluid, and cord blood. In addition, they provide increased activity against many aerobic and anaerobic Gram-positive cocci, including enterococci.
Spectrum of Activity
Piperacillin is active against most clinically important Gram-negative facultative bacteria, particularly indole-positive Proteus species, Klebsiella, many Serratia marcescens, and P. aeruginosa; E. coli, P. mirabilis, Enterobacter, Citrobacter, Salmonella, and Shigella species are sensitive to low concentrations of piperacillin. Piperacillin demonstrates activity against Gram-positive aerobic bacteria, including the enterococcus. In addition, virtually all clinically important anaerobes, including B. fragilis and P. bivia, are sensitive to piperacillin.
The major defect in the spectrum of these agents is lack of coverage for S. aureus, 10% of E. coli, and some Klebsiella species (particularly with piperacillin, which covers only half of Klebsiella strains).
Dosage and Route
Piperacillin (Pipracil) is available for intramuscular or intravenous (preferred) administration. The usual adult dosage is 3 to 4 g every 4 to 6 hours as an intravenous infusion (total, 12 to 18 g per day). After a 30-minute intravenous infusion of 4 g of piperacillin, peak serum levels of 215 μg/mL are reached; by 1 hour, the level is 105 μg/mL, and it falls to 15μg/mL by 4 hours.
Side Effects
As with other penicillins, mezlocillin and piperacillin have been associated with hypersensitivity reactions, nausea, diarrhea, CNS irritability with large doses, and local reactions such as phlebitis.
A major advantage of mezlocillin and piperacillin over carbenicillin and ticarcillin is a significant decrease in sodium load. The ureidopenicillins contain 1.85 mEq/g of sodium, compared with 5.23 mEq/g for carbenicillin and 5.20 mEq/g for ticarcillin. This dramatically reduces the risk of congestive heart failure in patients with cardiovascular compromise.
Cost
Both mezlocillin and piperacillin are expensive antimicrobial agents because of the need for large doses, frequent intravenous administration, and a moderately expensive per-gram cost.
Use in Pregnancy
Because of altered protein binding, the ureidopenicillins can enter cord blood and amniotic fluid in therapeutic concentrations. Experience with these agents in pregnancy is very limited. As penicillins, they are probably safe for use during pregnancy, but long-term follow-up studies are unavailable.
Metabolism
Like other penicillins, both mezlocillin and piperacillin are primarily excreted by the kidneys. Approximately 55% of a mezlocillin dose appears in urine within 6 hours, and 26% is excreted in the bile. For piperacillin, nearly 80% of a dose is excreted in urine within 24 hours. Excretion also occurs via the biliary route for piperacillin. Both mezlocillin and piperacillin are widely distributed throughout body tissues. Although little of either drug penetrates the CSF in normal
patients, mezlocillin and piperacillin both achieve satisfactory levels in the CSF with inflamed meninges.
patients, mezlocillin and piperacillin both achieve satisfactory levels in the CSF with inflamed meninges.
Indications in Obstetrics and Gynecology
Clinical investigations have confirmed the efficacy of these agents in the treatment of mixed pelvic infections with clinical cure rates usually, but not always, similar to those achieved using standard regimens such as clindamycin plus gentamicin. These results suggest mezlocillin and piperacillin can be used as reasonable single-agent therapy for many polymicrobial infections in obstetrics and gynecology. Yet, they have not been evaluated as thoroughly as other regimens (e.g., clindamycin-gentamicin, and cefoxitin, or cefotetan).
Penicillin-β-Lactamase Inhibitor Combinations
This approach to developing new antimicrobial agents that are resistant to degradation by β-lactamase enzymes involves developing compounds that inhibit these enzymes and combining them with older β-lactam antibiotics. This results in an enhanced spectrum of activity against a wide variety of aerobic and anaerobic bacteria. Three enzyme inhibitors, clavulanic acid, sulbactam, and tazobactam, have been developed, and their combination with penicillins has led to the introduction of clinically available agents: amoxicillin-clavulanic acid (Augmentin), ticarcillin-clavulanic acid (Timentin), sulbactam-ampicillin (Unasyn), and piperacillin-tazobactam (Zosyn).
Amoxicillin-Clavulanic Acid (Augmentin)
The addition of clavulanic acid, a suicide inhibitor of β-lactamases, to amoxicillin has resulted in an antimicrobial agent (Augmentin) that has a markedly increased spectrum of activity against a wide variety of aerobic and anaerobic bacteria. Augmentin has demonstrated success in the treatment of skin infections caused by β-lactamase-producing S. aureus, otitis media caused by H. influenzae, UTIs caused by β-lactamase-producing E. coli and Klebsiella, and PPNG.
However, it is available only as an oral agent. Augmentin plus doxycycline is suggested as an alternative oral regiment for PID, but its use may be limited by a high incidence of nausea and vomiting.
Ticarcillin-Clavulanic Acid (Timentin)
Timentin is the combination of ticarcillin (3 g) and clavulanic acid (100 mg). The addition of clavulanic acid, a β-lactamase inhibitor, to ticarcillin resulted in a combination compound that has markedly enhanced activity. Compared with ticarcillin alone, Timentin has increased activity against S. aureus, E. coli, Klebsiella, B. fragilis, and other β-lactamase-producing Bacteroides. Timentin has demonstrated excellent in vitro activity against the B. fragilis group of organisms, which was equivalent to that of imipenem. However, enterococci and MRSA remain relatively resistant.
The pharmacology of ticarcillin is not significantly altered by the addition of clavulanic acid and thus is similar to that discussed already. Both drugs have a serum half-life of about 1 hour after intravenous infusion. Sixty percent to 90% of ticarcillin and 35% to 45% of clavulanic acid are excreted unchanged in the urine. Renal insufficiency leads to accumulation, so dosage adjustment is necessary for patients with renal impairment. After intravenous infusion, both ticarcillin and clavulanic acid are widely distributed, with peak serum levels of 400 μg/mL for ticarcillin and 11 μg/mL for clavulanic acid. The dosage of Timentin (3 g of ticarcillin and 100 mg of clavulanic acid) is every 4 to 6 hours, depending on the severity of infection. This combination can inactivate aminoglycosides and should not be infused at the same time as an aminoglycoside.
Side effects are rare and usually mild. Among the most common are phlebitis, rash, diarrhea, mild elevations in liver function test results, and, rarely, hematologic abnormalities such as eosinophilia, leukopenia, thrombocytopenia, or anemia.
The cost per day for Timentin (3.1 g every 6 hours) is high. In comparative studies, Timentin was found to be as effective as clindamycin-gentamicin. These results make Timentin a reasonable choice for many polymicrobial infections, but there has been more variability in cure rate than is seen with comparable regimens.
Ampicillin-Sulbactam (Unasyn)
The addition of sulbactam to ampicillin significantly extended the antibacterial spectrum of ampicillin to include β-lactamase-producing strains of H. influenzae, N. gonorrhoeae, many anaerobes (including B. fragilis, B. bivius, and B. disiens), E. coli, Klebsiella, Enterobacter aerogenes, S. aureus, and S. epidermidis. However, ampicillin-sulbactam is not active against P. aeruginosa, Enterobacter cloacae, or Serratia species.
Administration of ampicillin and sulbactam together has no effect on the pharmacokinetics of these agents. The serum half-life for both drugs is approximately 1 hour. After intravenous infusion, ampicillin and sulbactam are widely distributed, and after a 500-mg infusion of each agent, serum levels rapidly peak at about 30 μg/mL for ampicillin and 43 μg/mL for sulbactam. Eighty-five percent of both drugs is excreted in urine within 24 hours. Small amounts of both drugs appear in breast milk. Ampicillin-sulbactam is available as 1 g of sulbactam to every 2 g of ampicillin. The usual dosage is 0.5 to 1 g of sulbactam plus 1 to 2 g of ampicillin every 6 hours. As with ampicillin itself, the kinetics of ampicillin-sulbactam is altered in pregnancy. There is more rapid elimination and a shorter serum half-life.
The most common side effects have generally been nausea, vomiting, diarrhea, or allergic reactions. Minor elevations in liver function test results have been infrequently reported.
Based on the efficacy in clinical trials and the moderate cost, ampicillin-sulbactam is also a reasonable choice for treatment of polymicrobial infections. In combination with doxycycline, it is one of the alternative parenteral CDC regimens for PID. Among the penicillin β-lactamase combinations, it is the most widely studied.
Piperacillin-Tazobactam (Zosyn)
Another combination is piperacillin-tazobactam (Zosyn). Tazobactam is also an irreversible β-lactamase inhibitor. In a large multicenter comparative trial, Zosyn (3 g of piperacillin and 375 mg of tazobactam) compared favorably with clindamycin-gentamicin in various pelvic infections.
CEPHALOSPORINS
Cephalosporins are classified according to their chemical structure, differences in pharmacology, β-lactamase resistance, and spectrum of activity. The most commonly used classification system is by generations according to antimicrobial activity (Table 23.3).
TABLE 23.3 ▪ CLASSIFICATION OF CEPHALOSPORINS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Spectrum of Activity
The first-generation cephalosporins are primarily active against a wide variety of aerobic Gram-positive cocci (including S. aureus, but excluding the enterococcus). They possess moderate activity against N. gonorrhoeae (exclusive of PPNG strains) and some aerobic Gram-negative rods, including commnity acquired E. coli, P. mirabilis (indole negative), K. pneumoniae, and Moraxella catarrhalis. Resistant aerobic Gram-negative organisms include Enterobacter, Pseudomonas, and Serratia species. First-generation cephalosporins have poor activity against H. influenzae and methicillin-resistant staphylococci (despite in vitro sensitivity) and penicillin-resistant pneumococci. Although some anaerobes are susceptible to cephalosporins, other antibiotics are preferable because of their broader activity, especially against the Bacteroides and Prevotella groups of bacteria, which produce β-lactamase enzymes. C. trachomatis and the genital mycoplasmas are resistant.
TABLE 23.4 ▪ DOSAGE AND PHARMACOKINETICS OF FIRST-GENERATION CEPHALOSPORINS | ||||||||||||||||||||||||||||||||||||||||||||
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The mechanism of action of cephalosporin antibiotics is quantitatively and qualitatively similar to that of penicillin. Cephalosporins interfere with cell wall synthesis. In particular, cephalosporins interfere with the biosynthesis of peptidoglycan in the cell wall by binding to and inactivating penicillin-binding proteins.
Four mechanisms of microbial resistance to the cephalosporins have been described: (i) alteration and decreased affinity of penicillin-binding proteins; (ii) production of β-lactamases that inactivate the agent; (iii) changes in the bacterial outer cell wall (loss of porin channels) that limit the ability of the drug to reach the penicillin-binding proteins; and (iv) enhanced efflux of the drug from the periplasmic space.
Dosage and Route
First-generation cephalosporin antibiotics include oral and parenteral agents; the dosage and pharmacokinetics of the first-generation cephalosporins are summarized in Table 23.4. Oral cephalosporins are very well absorbed from the gastrointestinal tract. When parenteral cephalosporins are administered by either the intramuscular or intravenous route, they are readily absorbed and widely distributed.
Since excretion of most cephalosporins is delayed in patients with diminished renal function, the dose should be decreased modestly for these persons. Although cefazolin achieves serum concentrations that are significantly higher than those of the other cephalosporins, all these compounds achieve concentration adequate to inhibit most cephalosporin-susceptible bacteria.
Side Effects
The cephalosporins are generally very well tolerated. Fever, eosinophilia, serum sickness, and rashes occur rarely, and transient neutropenia has been observed. Although Coomb positivity is commonly observed in patients receiving cephalosporins, particularly cephalothin, hemolytic anemia is extremely uncommon.
Cross-reactivity may exist between penicillins and cephalosporins. Although precise incidence data are not available, persons who have had an immediate hypersensitivity reaction to penicillin, manifested by urticaria, wheezing, or anaphylaxis, are at greater risk for the development of similar reactions after cephalosporin administration. Cephalosporins are contraindicated in such individuals.
Cost
The first-generation cephalosporins are relatively inexpensive agents. Thus, for perioperative prophylaxis and treatment of microorganisms susceptible to these agents, first-generation cephalosporins are appropriate.
Placental Transfer
Cephalosporins cross the placenta rapidly after intravenous injection to the mother and achieve adequate levels in cord blood and amniotic fluids. To date, no adverse fetal effects have been reported for this group of antibiotics.
Metabolism
Cefazolin is excreted by the renal route, and excretion is delayed in the presence of diminished renal function.
Indications in Obstetrics and Gynecology
The first-generation cephalosporins are among the most commonly used group of antibiotics in hospitals in this country. In obstetrics and gynecology as well as other specialties, they have been frequently used as prophylactic agents. They are also active and effective agents in the treatment of staphylococcal (non-MRSA) and a limited number of Gram-negative infections.
Yet, there are no situations in which they are clearly the drugs of choice for therapy. In most situations, other antibiotics are clearly preferable. Thus, for a penicillin-sensitive organism, penicillin should be used, and for treating infections caused by S. aureus, a penicillinase-resistant penicillin should be used.
In a number of situations, however, the first-generation cephalosporin antibiotics are valuable. The first of these is in the patient with delayed-type penicillin hypersensitivity. A cephalosporin may be used safely in most of these patients in place of penicillins for staphylococcal and nonenterococcal streptococcal infections. The second situation may be in treating some urinary tract infections. Depending on the susceptibility pattern of causative microorganism, a first-generation cephalosporin may be a good choice for the empiric treatment of pyelonephritis in pregnancy. In patients with severe pyelonephritis and shock or with multiple previous infections, a broader spectrum of therapy is indicated. The oral first-generation cephalosporins may be appropriate for many skin and soft tissue infections.
First-generation cephalosporins have been studied widely for prophylaxis and are now considered the drugs of choice by many experts for prophylaxis in obstetric and gynecologic procedures (see Chapter 24).
Second-Generation Cephalosporins
The second-generation cephalosporins actually contain two distinct groups: the true cephalosporins and the cephamycins (see Table 23.3). These groups have different spectra of activity. Cefoxitin (Mefoxin) and cefamandole (Mandol) became available in late 1978. Both have an extended spectrum of activity compared with first-generation cephalosporins. As a result of this expanded spectrum of activity, particularly against anaerobes by cefoxitin, effective single-agent antimicrobial therapy for polymicrobic intra-abdominal and pelvic infections became available and revolutionized the approach to treatment of these mixed aerobic-anaerobic infections. Most of these second-generation cephalosporins are not commonly used in pelvic infections. Thus, among the second-generation drugs, only cefoxitin and cefotetan are discussed in detail.
Spectrum of Activity
Second-generation cephalosporins have enhanced activity against Gram-negative bacteria while maintaining some activity against Gram-positive cocci. Like the penicillins and other cephalosporins, the second-generation cephalosporins are bactericidal, inhibiting cell wall synthesis. The true cephalosporins among the second-generation agents have significantly improved activity against H. influenzae, M. catarrhalis, N. meningitides, and N. gonorrhoeae compared with first-generation drugs. They provide comparable to improved activity against staphylococci and nonenterococcal streptococci. With their activity against S. pneumoniae, H. influenzae, and M. catarrhalis, true second-generation cephalosporins have been widely used for the treatment of respiratory tract infections in hospitalized patients. Cefuroxime was commonly used to treat meningitis caused by penicillin-susceptible S. pneumoniae, H. influenzae, and N. meningitides. However, third-generation cephalosporins have generally replaced cefuroxime because they eradicate bacteria from the CNS more rapidly. Similarly, cefuroxime has been replaced for the treatment of community-acquired pneumonia because of the increased prevalence of penicillin-resistant S. pneumoniae.
The cephamycins provide significantly enhanced activity against anaerobic bacteria, particularly the B. fragilis group, Bacteroides species, Prevotella species, and Porphymonas species, compared with first-generation cephalosporins and the true cephalosporins among the second-generation cephalosporins. Cefotetan, in particular, has enhanced activity against many Enterobacteriaceae: Cefoxitin and cefotetan have good activity against Neisseria species but decreased activity against staphylococci, compared with first-generation cephalosporins or the true cephalosporins among the second-generation cephalosporins. In addition, Pseudomonas species are highly resistant to all of these agents. N. gonorrhoeae, including penicillinase-producing strains, is susceptible to cefoxitin and cefotetan. Gram-positive anaerobic organisms are susceptible to these agents (as well as to penicillin and older cephalosporin antibiotics).
Against Gram-negative anaerobes, cefoxitin and cefotetan clearly have better activity than first-generation cephalosporins. True second-generation cephalosporins are not as active against the B. fragilis group as cefoxitin or cefotetan. However, up to 15% of B. fragilis strains may be resistant to cephamycins.
The antimicrobial spectra of cefonicid, ceforanide, and cefuroxime are very similar to that of cefamandole. These agents are not active against the B. fragilis group of organisms or other β-lactamase-producing Bacteroides such as B. bivius, B. disiens, or the pigmented Bacteroides. Thus, their use in obstetrics and gynecology is limited. Cefaclor is an oral agent that is more active against Gram-negative bacilli than the oral first-generation cephalosporin cephalexin. As with older cephalosporins, C. trachomatis and the genital mycoplasmas are resistant to the second-generation cephalosporins.
Dosage and Route
The dosages and pharmacokinetics of the true second-generation cephalosporins and cephamycins are summarized in Table 23.5.
TABLE 23.5 ▪ DOSAGE AND PHARMACOKINETICS OF SECOND-GENERATION CEPHALOSPORINS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Because these agents are excreted mainly in the urine, the dose should be reduced somewhat in patients with renal impairment.
Side Effects
These drugs, like other cephalosporins, are generally well tolerated. One of the problems with some antibiotics in this class is local irritation on intramuscular or intravenous injection. Pain on intramuscular injection is more common with cefoxitin, although it can be decreased by diluting the drug with 0.5% lidocaine solution.
Cefamandole and cefotetan contain a methyltetrazolethiol (MTT) side chain that inhibits the conversion of inactive to active prothrombin. Thus, these drugs have been associated, on occasion, with hypoprothrombinemia and bleeding. Cefoxitin has been associated infrequently with pseudomembranous colitis.
Cost
These agents were relatively expensive, but many (e.g., cefoxitin) are now off patent and the costs of these drugs are lower. In most settings, the cost per day is lower for cefotetan because of its twice-daily dosing schedule, versus four times daily for cefoxitin. However, this drug is currently not marketed in the United States.
Use in Pregnancy and Placental Transfer
Pharmacokinetic studies in pregnant women demonstrated that cefoxitin serum levels were similar to those in nonpregnant women. Amniotic fluid levels of cefoxitin were 2 to 6 μg/mL between 1 and 5 hours after infusion demonstrating rapid placental transfer. Cefoxitin, cefotetan, and cefamandole have been widely used in pregnancy and the puerperium and are considered safe for use in pregnancy.
Metabolism
As with other cephalosporins, these antibiotics are excreted mainly by the kidney. Approximately 75% of an intravenous dose can be recovered in the urine within 8 hours. Probenecid inhibits tubular secretion and results in higher blood levels.
Indications in Obstetrics and Gynecology
The extended activity of cefoxitin, especially against B. fragilis group, Prevotella spp, and other anaerobes has made it an attractive single-agent therapy for obstetrics and gynecologic infections. In the late 1980s, cefoxitin emerged as the most commonly used single-agent antimicrobial used for the treatment of pelvic infections. Multiple studies demonstrated its safety and efficacy in a variety of genital infections with overall cure rates greater than 90%. These included endomyometritis, PID (in combination with doxycycline), posthysterectomy pelvic infection, and pelvic abscesses. In several studies, cefotetan has been demonstrated to have clinical efficacy equivalent to that of cefoxitin for the treatment of obstetric and gynecologic infections.
Because of activity against N. gonorrhoeae, including penicillinase-producing species, and anaerobic bacteria, including the Bacteroides groups, cefoxitin and cefotetan have been recommended by the CDC as part of combination therapy for PID and cefoxitin (with Probenicid) is an alternative choice for uncomplicated N. gonorrhoeae.
Although cefoxitin and cefotetan have been shown to be effective for prophylaxis, they have no advantage over older less-expensive agents such as cefazolin. Because these agents may be used for therapy and are more expensive than older agents, their use for prophylaxis obstetric and gynecology has been questioned. (The use of prophylactic antibiotics is discussed more fully in Chapter 24.)
Because of its activity against S. pneumoniae, H. influenzae, and M. catarrhalis, cefuroxime was commonly used in the treatment of community-acquired bacterial pneumonia. As noted above, cefuroxime is no longer recommended as empiric treatment for community-acquired pneumonia. Oral second-generation cephalosporins (cefuroxime axetil, cefaclor, cefprozil, and loracarbef) are used to treat various mild to moderate community-acquired infections, including skin and soft tissue infection and UTI. However, more cost-effective or narrow-spectrum treatment is available for these indications. Thus, the primary use of oral second-generation cephalosporins is for the treatment of respiratory tract infections.
In summary, among the second-generation cephalosporins, cefoxitin and cefotetan have the most appropriate antimicrobial
spectra for treating pelvic infections. They are well tolerated and achieve high concentrations in serum. In most clinical trials, efficacy has been very good. Cefoxitin or cefotetan is a reasonable initial choice for mild to moderate pelvic infections such as endomyometritis, PID (in combination with doxycycline), and cuff cellulites after hysterectomy.
spectra for treating pelvic infections. They are well tolerated and achieve high concentrations in serum. In most clinical trials, efficacy has been very good. Cefoxitin or cefotetan is a reasonable initial choice for mild to moderate pelvic infections such as endomyometritis, PID (in combination with doxycycline), and cuff cellulites after hysterectomy.
Third-Generation Cephalosporins
Modification of the side chains provides the third-generation cephalosporins with changes in spectrum and alterations in metabolism. In general, the third-generation cephalosporins are less active than the first-generation agents against Gram-positive cocci but are significantly more active against the Enterobacteriaceae. The third-generation cephalosporins are not as active against the B. fragilis group of bacteria, as are cefoxitin and cefotetan. On the other hand, they are more active against a broader spectrum of Gram-negative aerobic and facultative bacteria. In addition, as noted in Table 23.6, several of these agents have antipseudomonal activity.
TABLE 23.6 ▪ ANTIBIOTIC SENSITIVITIES OF COMMON PATHOGENS RECOVERED FROM OBSTETRIC AND GYNECOLOGIC INFECTIONS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Spectrum of Activity
Although all of these compounds possess very broad activities, they should not be considered interchangeable. Particularly in regard to the array of organisms involved in pelvic infections, there are important in vitro differences in activity.
For aerobic streptococci, these agents have activity that is inferior to that of penicillin G or ampicillin and the first-generation cephalosporins. Within the group of third-generation cephalosporins, cefotaxime, ceftizoxime, and ceftriaxone have greater intrinsic activity than cefoperazone and ceftazidime. Yet, with usual doses, all of these agents provide sufficient coverage for all aerobic streptococci except enterococci.
For S. aureus, an anti-staphylococcal penicillin or a first-generation cephalosporin would be preferable. With the exception of ceftazidime, these agents are effective against methicillin-sensitive S. aureus. Methicillin-resistant staphylococci are not susceptible to the third-generation agents.
Activity against N. gonorrhoeae is excellent for ceftriaxone, cefotaxime, ceftazidime, cefoperazone, and moxalactam. All of these inhibit penicillinase-producing species. Among the third-generation cephalosporins, ceftriaxone has
the best activity against N. gonorrhoeae, including PPNG strains, and this agent is recommended by the CDC for treatment of gonococcal infection.
the best activity against N. gonorrhoeae, including PPNG strains, and this agent is recommended by the CDC for treatment of gonococcal infection.
Activity of these agents against aerobic Gram-negative rods is impressive, especially for E. coli, K. pneumoniae, and P. mirabilis. Enterobacter species have higher MIC90 values, but these are generally within the susceptible range, except for cefoperazone. Many aminoglycoside-resistant strains are susceptible to low concentrations of the third-generation cephalosporins. P. aeruginosa occurs infrequently in pelvic infections, and activity of these new agents varies widely. Ceftazidime is the most active.
The third-generation cephalosporins, in general, have high antibacterial potency, wide spectrum of activity, low risk for toxicity, and favorable pharmacokinetics (e.g., enhanced CSF drug levels). They are especially useful for treatment of infections caused by Gram-negative bacteria (especially Enterobacteriaceae) that are resistant to other β-lactamase-mediated resistance. In particular, new Amp C β-lactamases and ESBLs that inactivate third-generation cephalosporins threaten the use of these agents.
Gram-positive anaerobic cocci are inhibited by the third-generation cephalosporins. C. perfringens usually has low MIC values, whereas C. difficile is resistant.
Among the anaerobic Gram-negative species, P. bivia and P. disiens are susceptible to cefoperazone and cefotaxime, but the B. fragilis group has a more variable response. High rates of resistance to third-generation cephalosporins have been demonstrated by the B. fragilis group. The poor activity against the B. fragilis group has limited the usefulness of third-generation cephalosporins as single-agent therapy for polymicrobic pelvic infections.
None of these agents are active against either C. trachomatis or the genital mycoplasmas.
Dosage, Route, and Metabolism
Initially third-generation cephalosporins were available only for parenteral administration. More recently, oral forms have become available. They possess different routes of metabolism and different half-lives. Table 23.7 summarizes the dosage and pharmacokinetics of the third-generation cephalosporins.
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