Clavulanic acid

Abstract

Pharmacologic parameters have been defined to predict efficacy in antimicrobial selection for the treatment of uncomplicated skin and skin structure infections (uSSSIs). Pharmacokinetics (PK) and pharmacodynamics (PD) are the bases for describing the in vivo behavior of antimicrobial agents. T>MIC is the duration of time that a pathogen is exposed to concentrations of antimicrobial agents that exceed the MIC of that particular organism. For antimicrobials with time-dependent activity (eg, penicillin and cephalosporins), the T>MIC needed to eradicate bacteria is generally 40% to 50% of the dosing interval. The most frequently prescribed oral antimicrobials for uSSSI are oral cephalosporins, amoxicillin/clavulanic acid, macrolides, anti-staphylococcal penicillins, and fluoroquinolones. The selected oral agent should display a broad spectrum of antimicrobial coverage, be able to be dosed once, or at most twice, a day, and show high levels of target attainment ([greater than or equal to]90%) for eradicating the key pathogens associated with uSSSI. The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the community setting (CA-MRSA) is especially troublesome in that oral cephalosporins (and all other [beta]-lactam agents) are contraindicated, requiring alternative therapeutic approaches. While a common cause of cutaneous disease, including abscess formation, CA-MRSA has caused life-threatening necrotizing fasciitis and pneumonia. Treatment of abscesses produced by this pathogen consists of incision and drainage followed by an appropriate oral antimicrobial, based upon knowledge on the local resistance prevalence rates or as directed by culture and susceptibility testing.

Introduction

When penicillin was introduced in 1942, dosage schedules of antibiotics were based upon animal infection models and empirical results obtained on patients. It was not until 1950 that Eagle and colleagues (1) established the basis for pharmacologic indices now used to compare activities of different antimicrobial agents and develop optimal dosing regimens. (2)

Eagle and colleagues noticed that in animals that had been given penicillin, killing of pathogens stopped when the serum concentration of penicillin dropped to levels below the minimum inhibitory concentration (MIC). They also noted that penicillin's therapeutic effects (on a specific dosage schedule) were related to how long the drug concentration remained above the bactericidal level, and that cure rates of animals did not increase with penicillin concentrations above this "effective" level. In other words, increasing the penicillin concentration above the therapeutic level did not produce greater efficacy. These observations laid the foundation for the understanding that T>MIC, the cumulative percentage of time over the dosing interval that the drug concentration exceeded MIC of the pathogen, is the key target parameter. (2-4)

For antimicrobials with time-dependent activity (eg, penicillin and cephalosporins), the T>MIC needed to eradicate bacteria is generally 40% to 50% of the dosing interval. (5,6) For example, the relationship between efficacy and T>MIC has been evaluated in patients with acute otitis media caused by Hemophilus influenzae and Streptococcus pneumoniae. Cure rates of 80% to 85% were regularly achieved when T>MIC values for [beta]-lactams were 40% to 50% of the dosing interval for [beta]-lactams. (7,8)

The MIC is defined as the lowest concentration of antimicrobial agent that inhibits the growth of pathogen. (9) It is an in vitro measurement of which antimicrobials display the greatest activity against a target pathogen. The MI[C.sub.50] is the lowest concentration of drug that inhibits growth of one-half of isolates tested, whereas the MI[C.sub.90] is the lowest concentration that inhibits 90% of isolates tested. (4) MIC has limited usefulness because it is an in vitro test. Less frequently used and applied to more serious or intractable deep-seated infections, the minimum bactericidal concentration (MBC) is an in vitro test that is defined as the lowest drug concentration reducing the viable bacterial count by 99.9% or more over 24 hours compared to the initial inoculum.

To obtain clinically useful information, additional pharmacologic indices have been defined to describe antimicrobial efficacy. Pharmacokinetics (PK) and pharmacodynamics (PD) are the bases for describing the in vivo drug behavior. PK refers to the absorption, distribution, and elimination of antimicrobial agents; it describes the concentration-time profile of drugs in the patient. The peak serum concentration ([C.sub.max]) of a drug is a PK parameter. PD describes the relationship between antimicrobial effect (MIC) and the drug concentrations (PK parameters). (6) The product of drug concentration and time of exposure to the drug over the dosing interval is expressed as the AUC (area under the curve). [C.sub.max]/MIC and AUC/MIC are useful indices for determining efficacy of concentration-dependent (as opposed to time-dependent) antimicrobial agents (eg, macrolides and fluoroquinolones). Target T>MIC or AUC/MIC values necessary for optimal therapy differ by pathogen species (shorter for Gram-positive organisms and longer for Gram-negative organisms).

The purposes of this overview are to (1) show how PK/PD indices are used to select appropriate antimicrobials and dosing regimens that will optimize outcomes of patients with uncomplicated skin and skin structure infections (uSSSIs) and (2) present an update on the recent emergence of infections produced by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).

Treatment of uSSSI

The pathogens most commonly associated with uSSSIs are Gram-positive pathogens such as S. aureus, coagulasenegative staphylococci (S. epidermidis), Streptococcus pyogenes (Group A), Streptococcus agalactiae (Group B), other [beta]-hemolytic streptococci (Groups C, F, G), and enteric bacilli such as Escherichia coli and Klebsiella species. The most frequently prescribed oral antimicrobials for uSSSI are oral cephalosporins, amoxicillin/clavulanic acid, macrolides, antistaphylococcal penicillins, and fluoroquinolones. When selecting an antimicrobial agent, physicians should consider PK, PD, antimicrobial spectrum and potency, resistance patterns, drug safety profile, and probability of patient compliance. Compliance is heavily influenced by factors such as drug tolerability and dosing schedule.

Pharmacokinetic/Pharmacodynamic (PK/PD) Considerations

The relationship between T>MIC and organism eradication is shown in Figure 1. Static inhibition occurs at shorter T>MIC (eg, 20% of the dosing interval) compared to maximal killing which usually requires approximately 50% of the dosing interval. For cephalosporins used in the outpatient setting, T>MIC values ranging from 20% to 30% are associated with optimal outcomes in the treatment of uSSSIs because of the preponderance of Gram-positive isolates and the unnecessary requirements for maximal, bactericidal actions.

Categorical breakpoints (susceptible, intermediate, and resistant) are used when testing bacterial isolates to characterize the activity of antimicrobial agents that may be considered for use against a demonstrated or presumed infecting pathogen. These in vitro criteria have been promulgated by professional organizations including the US Food and Drug Administration, the Clinical Laboratory Standards Institute (CLSI; formerly the National Committee on Clinical Laboratory Standards), and various European national standards organizations such as the European Society of Clinical Microbiology and Infectious Diseases (EUCAST). For a given antimicrobial agent, a pathogen is deemed susceptible when the MIC is at or below a designated breakpoint concentration and resistant when the MIC is above another breakpoint for the designated antimicrobial agent and bacterial species. (9)

Breakpoints based upon characteristics of PK and PD (PK/PD breakpoints) can be used to reliably predict antimicrobial efficacy by integrating pharmacologic and microbiologic data. Use of such PK/PD breakpoints can, for example, predict efficacy of an agent such as amoxicillin/clavulanate against enteric bacilli, S. aureus, and S. pyogenes with usual twice-daily dosing (Figure 2). Amoxicillin/clavulanate will predictably display activity against S. pyogenes because the MI[C.sub.90] (0.06 [micro]g/mL) for this species is below the PK/PD breakpoint of 2 [micro]g/mL where 90% of infections would respond to the usually prescribed dose. Coverage of S. aureus is less optimal (for methicillin-susceptible strains only) because the MI[C.sub.90] of this pathogen is higher and the antimicrobial is present at concentrations above the PK/PD breakpoint for a smaller, suboptimal percentage of the dosing interval. Enteric bacilli are poorly covered because the peak drug concentration does not reach the MI[C.sub.90] for these organisms.

[FIGURE 1 OMITTED]

Comparison of the PK/PD relationships for two dosing regimens of cefdinir (an oral suspension) in children demonstrates consistently high levels of target attainment (T>MIC at 20% to 30%; Figure 3). More than 90% of key pathogen isolates associated with uSSSI can be expected to respond to cefdinir.

Bacterial Resistance Among SSSI Pathogens

Community-acquired uSSSIs are rarely cultured by primary care physicians. Even when they are, orally administered antimicrobials--cephalosporins, new macrolides, and fluoroquinolones--are seldom tested in vitro against SSSI-associated pathogens. As a result, physicians are unaware of prevailing resistance rates and may prescribe inappropriate empiric antimicrobial therapy that further selects for bacterial resistance. If available, local susceptibility data from strains of uSSSI are helpful in selecting agents for empiric therapy. As resistance rates change over time, utilization of culture and susceptibility testing should be routinely performed.

Two emerging resistance problems are currently altering prescribing habits for uSSSI. Resistance to macrolides (erythromycin, azithromycin, clarithromycin) among [beta]-hemolytic (10% to 30%) or viridans group streptococci (8%) is achieving a threshold whereby adequate coverage can no longer be reliably predicted. Likewise, the emergence of CA-MRSA, which can also display resistance to macrolides and other commonly prescribed drug classes such as the fluoroquinolones, is of even greater clinical concern. (10)

[FIGURE 2 OMITTED]

Characterization and Treatment of CA-MRSA

While the occurrence of MRSA in the hospital environment has been known for decades, the emergence of CA-MRSA is a recent phenomenon that is now being documented worldwide. (11) Risk factors include intravenous drug use, previous use of antimicrobials, diabetes, chronic skin disease, and malignancy. Persons without these risk factors are, however, found to be commonly infected. Outbreaks have occurred in a variety of settings in which individuals are in close physical contact--universities, schools, daycare centers, cruise ships, athletic groups, and prisons. (12) A careful patient history to exclude previous health care contacts helps to differentiate between community-associated and hospital-acquired MRSA (which tend to be more multidrug-resistant).

The genetic backgrounds of CA-MRSA strains from different parts of the world can be unique to their respective regions. (13) Genetic features common to CA-MRSA include the PantonValentine leukocidin (PVL) gene, the staphylococcal-cassette-chromosome mec type IVa (SCCmecIVa) gene, plus distinct components of local endemic/epidemic clones. (14) PVL is a cytotoxin that destroys leucocytes and causes tissue necrosis; this cytotoxin has been detected in a small percentage (<5%) of S. aureus strains overall, but is predominant in some CA-MRSA clones, especially those that produce infections with poor outcomes. (15)

[FIGURE 3 OMITTED]

CA-MRSA is usually associated with cutaneous infections--furuncles (40%), carbuncles (28%), abscess (14%), and folliculitis (5%). (16) These organisms are often resistant in vitro to both macrolide and [beta]-lactam agents, but not other antimicrobial classes. (17,18) These clones are recognized, however, to also produce life-threatening fasciitis and necrotizing pneumonia. (19,20) Treatment of cutaneous CA-MRSA abscess-related disease consists primarily of incision and drainage followed by administration of oral antimicrobials.

An example of one such outbreak was reported in 2005, where skin abscesses caused by CA-MRSA were observed among members of a professional football team and determined to have spread to members of an opposing team during competitive play. (17) Eight cutaneous infections--all developed at turf-abrasions sites--were found among five of the 58 players (9%). S. aureus isolates were found to contain the genes for PVL and SCCmecIVa resistance, and were found to be clonal type USA300-0114 (a wide-spread clone) when analyzed by pulsed-field gel electrophoresis (PFGE). Infections resolved after abscesses were drained and players were given oral antimicrobial therapy. Unlike MRSA strains found in health care settings, this community-associated clone, and others like it, caused skin infection in healthy individuals, was susceptible to most commonly used agents other than [beta]-lactams and macrolides, and displayed typical genotypic characteristics.

Conclusions

Advancements in our understanding of PK/PD parameters now permit physicians to better predict efficacy of antimicrobial agents when treating the usual pathogens associated with uSSSIs. For oral cephalosporins used in the outpatient setting, T>MIC values ranging from 20% to 30% are associated with optimal outcomes in the treatment of uSSSIs because of the preponderance of Gram-positive isolates and the unnecessary requirements for maximal bactericidal PD action. However, emergence of resistance to many of the commonly utilized classes of agents ([beta]-lactams, macrolides, and fluoroquinolones) is changing our perception of empiric therapeutic approaches. The recommendation has recently been made to consider MRSA as a potential pathogen wherever S. aureus infections occur in the community setting, (21) necessitating the need for routine incorporation of culture and susceptibility testing into the initial outpatient visit. Because CA-MRSA are to be considered resistant to [beta]-lactams and usually macrolides, incision and drainage followed by appropriate oral antimicrobic therapy (as directed by in vitro testing) can be expected to resolve most uncomplicated cutaneous infections.

Disclosure: Drs. Fritsche and Jones are consultants to Abbott Laboratories.

References

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Address for Correspondence

Thomas R. Fritsche MD PhD

JMI Laboratories

345 Beaver Kreek Ctr

North Liberty, IA 52317

Phone: 319-665-3370

Fax: 319-665-3371

e-mail: thomas-fritsche@jmilabs.com

Thomas R. Fritsche MD PhD, Ronald N. Jones, MD

JMI Laboratories, North Liberty, IA

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