The selection of an appropriate antimicrobial agent to treat an infection is guided by a number of factors. Typically, empiric antimicrobial therapy is based on the epidemiology of the suspected infection, with therapy directed toward the most likely organisms. Laboratory studies, including Gram stain as well as culture and sensitivity testing, help to identify the pathogen and its susceptibility to a variety of antimicrobials. Although there may be several options, efficacy, toxicity, pharmacokinetic profile, and cost ultimately determine the agent of choice. The optimal dose and duration of the antimicrobial therapy are then determined by patient factors such as age, weight, and concurrent disease states as well as the site and severity of infection.
FACTORS IN SELECTING AN ANTIMICROBIAL REGIMEN
Before initiating antibiotic therapy, a systematic approach to identify the source and site of infection must be undertaken. A complete medical history and physical examination should be conducted to identify signs and symptoms consistent with the presence of infection. Identifying underlying medical or social conditions such as diabetes, immunosuppression (cancer, human immunodeficiency virus [HIV] infection), past medications, or intravenous (IV) drug use may help in identifying a predisposition toward infection or the most likely pathogen causing disease. In addition, determining where the infection was acquired (in the community vs. a nursing home or hospital setting) may also help limit the list of most likely pathogens. Health care-acquired pathogens may necessitate broad-spectrum empiric therapy to cover multidrug-resistant (MDR) pathogens.
Identifying the causative pathogen is the ultimate goal because it allows for optimal antibiotic selection and patient outcome. Specimens from the most likely body sites should be properly collected and sent to the microbiology laboratory. Depending on the body site involved, specimens will be stained (e.g., Gram stain) to determine morphology and cell wall structure (gram positive vs. gram negative and cocci vs. bacilli) and analyzed to detect white blood cells (which indicate inflammation and infection). The gold standard of diagnosis in infectious diseases is to be able to grow the causative organism in culture and perform antibiotic susceptibility testing to determine which agents are most likely to be effective in eradicating the pathogen. Susceptibility results often take 48 to 72 hours after cultures are obtained. Newer methods of testing can help identify specific pathogens (such as methicillin-resistant Staphylococcus aureus [MRSA] and Candida) more quickly.
Often, antibiotic therapy is initiated before culture and sensitivity testing is complete. Empiric antibiotic therapy is based on the premise of providing coverage for the most likely pathogens (Table 8.1). In general, the most likely organism is based on the suspected site of the infection. Table 8.2 outlines key pathogens and spectra of activity for the most commonly prescribed antibiotics.
In most patients treated initially with a parenteral antibiotic who are clinically improving, therapy should be switched to the oral route. This does not apply to certain infections, such as osteomyelitis and endocarditis, in which parenteral antibiotics are continued to ensure adequate concentrations at the infection site. This oral conversion should be based on the following criteria:
The patient is responding to therapy, as evidenced by a return to normal or a trend toward normal values in the patient’s temperature and white blood cell count.
TABLE 8.1 Infection and Most Likely Infecting Organism
E. coli, other gram-negative aerobic bacilli, Enterococcus spp., Staphylococcus saprophyticus
Hospital acquired
E. coli, other gram-negative aerobic bacilli, Enterococcus spp.
The patient can take oral medications and absorb them adequately.
An oral equivalent to the parenteral regimen exists. Not all parenteral agents are available orally. In choosing the oral equivalent, the goal is to select an agent (or agents) that provides a similar spectrum of antimicrobial activity and possesses good oral bioavailability. This may necessitate the use of oral agents that are from a different class from the parenteral agent.
The patient’s response to therapy should be monitored regularly. This includes monitoring both efficacy and toxicity. If the patient responds to the prescribed antibiotic regimen, the presenting signs and symptoms of the infection should resolve. Parameters to be considered for response regardless of the site of infection include vital signs, white blood cell count, and, if the culture proved positive for bacteria, subsequent negative cultures. Other signs and symptoms are specific to the body site involved. Monitoring for adverse events is specific to the agents prescribed. (Review the drug overview sections for common adverse events.) All patients should be taught how to recognize the most common adverse events, and they should be advised to notify their health care provider if an adverse reaction occurs. The following sections highlight antimicrobials used in practice and include pharmacokinetics, pharmacodynamics, mechanism of action, spectrum of activity, common clinical uses, adverse events, drug interactions, and antimicrobial resistance.
PENICILLINS
First isolated in 1928, the penicillins were used successfully to treat streptococcal and staphylococcal infections. Since then, many synthetic penicillins have been developed to address the emerging problem of resistance. Despite resistance, the penicillins remain an important class of antimicrobials. They are classified based on their spectra of activity.
Pharmacokinetics and Pharmacodynamics
Most of the penicillins are unstable in the acid environment of the stomach and must be administered parenterally. Those that are acid stable are given orally. They are widely distributed in the body and penetrate the cerebrospinal fluid (CSF) in the presence of inflammation. Most penicillins are excreted by the kidneys, and renal impairment necessitates dosage adjustment. The half-life of the penicillins in adults with normal renal function is 30 to 90 minutes. The penicillins are removed by hemodialysis, with the exception of nafcillin and oxacillin. The penicillins exhibit time-dependent bactericidal activity and a postantibiotic effect (PAE) against most gram-positive organisms. See Box 8.1 for information on PAE. Also, see Table 8.3 for dosing information.
TABLE 8.2 Sensitivity of Organisms to Specific Agents
+ = Poor to moderate activity; use only when known to be susceptible.
++ = Good activity; resistance in some strains and geographical location may limit use.
+++ = Excellent activity; generally reliable coverage for empiric therapy.
BOX 8.1 Postantibiotic Effect
The PAE is defined as “persistent suppression of bacterial growth after a brief exposure (1 or 2 hours) of bacteria to an antibiotic even in the absence of host defense mechanisms”. This delayed growth of bacteria results in an increased efficacy of the drugs and allows for less frequent dosing of medications, potentially lowering toxicity and improving compliance. The duration of the PAE is affected by the class of antibiotic, the relevant exposure time, and the specific bacterial species. Bacteriostatic agents, such as macrolides, clindamycin, streptogramins, tetracyclines, and linezolid, have long PAEs, whereas drugs with relatively slow bactericidal action (e.g., penicillins) have little to no PAE.
TABLE 8.3 Penicillin Dosages
Drug
Adult Dosages
Pediatric Dosages
Natural
penicillin G
2-4 million units IV q4-6h
100,000-400,000 units/kg/d IV divided q4-6h
penicillin G benzathine
1.2-2.4 million units IM at specified intervals
300,000-2.4 million units IM at specified intervals
penicillin G procaine
0.6-4.8 million units IM in divided doses q12-24h at specified intervals
25,000-50,000 units/kg/d IM divided 1-2 times/d
penicillin VK
250-500 mg PO q6h
25-50 mg/kg/d PO divided q6-8h
Aminopenicillins
ampicillin
1-2 g IV q4-6h
100-400 mg/kg/d IV divided 4-6h
amoxicillin-ampicillin
250-500 mg PO q8h
875-1,000 mg PO q12h
400-100 mg/kg/d PO divided q6-12h
Carboxypenicillins
ticarcillin sodium
3 g IV q4-6h
200-300 mg/kg/d IV divided q4-6h
Penicillinase Resistant
cloxacillin
250-500 mg PO q6h
50-100 mg/kg/d PO divided q6h
dicloxacillin
250-500 mg PO q6h
12.5-100 mg/kg/d PO divided q6h
nafcillin
500 mg-1 g IV q4-6h
50-200 mg/kg/d IV divided q4-6h
oxacillin
500-2 g IV q4-6h
100-200 mg/kg/d IV divided q4-6h
Ureidopenicillins
piperacillin
3-4 g IV q4-6h
200-300 mg/kg/d IV divided q4-6h
Note: Dosage adjustment of all above drugs required in patients with impaired renal function, with the exception of penicillinase-resistant penicillins.
Mechanism of Action and Spectrum of Activity
The mechanism of action of the penicillins is the inhibition of bacterial cell growth by interference with cell wall synthesis. Penicillins bind to and inactivate the penicillin-binding proteins (PBPs).
Clinical Uses
Although the use of penicillin itself is limited due to widespread resistance, the penicillin class is effective in many infections, including those of the upper and lower respiratory tract, urinary tract, and central nervous system (CNS) as well as sexually transmitted diseases. They are the agents of choice for treating gram-positive infections such as endocarditis caused by susceptible organisms. Both the carboxypenicillins and ureidopenicillins are useful in treating infections caused by Pseudomonas aeruginosa.
Adverse Events
There is a low incidence of adverse reactions with penicillin administration. Hypersensitivity reactions characterized by maculopapular rash and urticaria are most common. Gastrointestinal (GI) side effects are most common with oral administration. In the presence of severe renal dysfunction, high-dose penicillins have been associated with seizures and encephalopathy. Thrombophlebitis has occurred with IV administration. The Jarisch-Herxheimer reaction, characterized by fever, chills, sweating, and flushing, may occur when penicillin is used in treating spirochetes, in particular syphilis. Release of toxic particles from the organism precipitates the reaction. In rare cases, leukopenia, thrombocytopenia, and hemolytic anemia can occur with penicillins.
Drug Interactions
Drug interactions involving penicillins are rare. Probenecid has been shown to increase the half-life of the penicillins by inhibiting renal tubular secretion. Both the carboxypenicillins and ureidopenicillins have been shown to inactivate the aminoglycosides, and these agents should not be mixed in the same IV solution. Also, the parenteral carboxypenicillins have a high sodium content. Caution should be used in patients with fluid or sodium restrictions.
BETA-LACTAM/BETA-LACTAMASE INHIBITOR COMBINATIONS
Resistance to penicillin develops when the drug is inactivated by the enzymes known as penicillinases or beta-lactamases produced by bacteria. After several attempts over the years to prevent penicillin degradation by this enzyme, clavulanic acid became the first beta-lactamase inhibitor introduced and combined with a beta-lactam. Other beta-lactamase inhibitors, avibactam, sulbactam, and tazobactam, are also available in combination with ampicillin, ceftazidime, ceftolozane, and piperacillin. The role of the beta-lactamase inhibitor is to prevent the breakdown of the beta-lactam by organisms that produce the enzyme, thereby enhancing antibacterial activity. These combinations are suitable alternatives for infections caused by beta-lactamase-producing organisms such as S. aureus, Haemophilus influenzae, and Bacteroides fragilis.
The beta-lactam/beta-lactamase inhibitors diffuse into most body tissues, with the exception of the brain and CSF. The half-life of both components in each combination is approximately 1 hour. Because these drugs are eliminated by glomerular filtration, renal dysfunction necessitates dosage changes (Table 8.4). The compounds are removed by hemodialysis and peritoneal dialysis.
Mechanism of Action and Spectrum of Activity
The beta-lactam components of the combinations are cell wall-active agents. They interfere with bacterial cell wall synthesis by binding to and inactivating PBPs. The beta-lactamase inhibitors irreversibly bind to most beta-lactamase enzymes, protecting the beta-lactam from degradation and improving their antibacterial activity. The beta-lactamase inhibitors alone lack significant antibacterial activity. The spectrum of activity is similar to the penicillin derivative, with broader coverage against beta-lactamase-producing organisms.
Clinical Uses
Based on their broad spectrum of activity, the beta-lactam/beta-lactamase inhibitors are frequently used in treating polymicrobial infections. They are used extensively to treat intraabdominal and gynecologic infections, and skin and soft tissue infections, including human and animal bites, as well as foot infections in diabetic patients. Respiratory tract infections, including aspiration pneumonia, sinusitis, and lung abscesses, have been successfully treated with these combinations.
Adverse Events
The addition of the beta-lactamase inhibitor to the penicillins has not resulted in any new or major adverse events. The major effects associated with the beta-lactam/beta-lactamase inhibitor combinations are hypersensitivity reactions and GI side effects such as nausea and diarrhea associated with oral administration. Elevated aminotransferase levels have been documented for all agents.
Drug Interactions
The combinations are physically incompatible with parenteral aminoglycosides. Each of the penicillins in the combinations has been associated with the inactivation of aminoglycosides in vitro. The clinical significance of this interaction is unknown.
CEPHALOSPORINS
The cephalosporins, a beta-lactam group, are structurally similar to the penicillins. Substitutions on the parent compound, 7-aminocephalosporanic acid, produce compounds with different pharmacokinetic properties and spectra of activity. The cephalosporins are divided into “generations” based on their antimicrobial spectrum of activity. The progression from first to fourth generation in general reflects an increase in gram-negative coverage and a loss of gram-positive activity.
Note: Dosage adjustment necessary for all agents in patients with renal impairment except ceftriaxone.
* Dosage adjustment necessary in patients with liver dysfunction.
Pharmacokinetics and Pharmacodynamics
The cephalosporins are well absorbed from the GI tract. In some cases, food enhances absorption. They penetrate well into tissues and body fluids and achieve high concentrations in the urinary tract. Noncephamycin second-generation agents and all third- and fourth-generation agents penetrate the CSF and play a role in treating bacterial meningitis. Most of the oral and parenteral cephalosporins are excreted by the kidney, with the exception of ceftriaxone (Rocephin) and cefoperazone (not available in the United States), which are eliminated by the liver. The cephalosporins exhibit a time-dependent bactericidal effect and a prolonged PAE against staphylococci. Table 8.5 provides dosing information.
Only gold members can continue reading. Log In or Register to continue
