The Significance of Serum vs Tissue Levels of Antibiotics in the Treatment of Penicillin-Resistant Streptococcus pneumoniae and Community-Acquired Pneumonia
1999; Elsevier BV; Volume: 116; Issue: 2 Linguagem: Inglês
10.1378/chest.116.2.535
ISSN1931-3543
Autores Tópico(s)Antibiotic Use and Resistance
ResumoWhen treating serious infections, the emphasis has traditionally been placed on establishing and sustaining serum antimicrobial levels above the minimal inhibitory concentration (MIC) for likely infecting pathogens, in order to eradicate the infection. This is particularly true withβ -lactam and macrolide antibiotics, which kill on the basis of time-dependent kinetics, or on time-serum levels that are maintained above the MIC. These antibiotics do not exhibit concentration-dependent killing or sustained killing when serum levels fall below the MIC, as seen with aminoglycosides and fluoroquinolones. The issue of maintaining high serum levels is crucial in intravascular infections, such as endocarditis, or in infections in tissues in which antibiotic penetration is poor, such as meningitis. The lung is a highly vascular organ in which many antibiotics concentrate above serum levels. Antibiotics follow a concentration gradient from serum to extracellular fluid to intracellular site. Macrolides, in particular, as well as fluoroquinolone antibiotics accumulate in lung tissue, in macrophages, and in neutrophils at levels above those in the serum.1Bergogne-Bérézin E Vallée E Pharmacokinetics of antibiotics in respiratory tissues and fluids.in: Pennington JE Respiratory infections: diagnosis and management. 3rd ed. Raven Press, New York, NY1994: 715-740Google Scholar For intracellular pathogens, such as Legionella, intracellular antibiotic concentrations may be the most important determinant of outcome. For extracellular pathogens, such as pneumococci, the most crucial sites for antibiotic accumulation may be the extracellular fluid and the alveolar-lining fluid. Studies that utilize bronchial mucosal biopsies or animal infection models demonstrate that β-lactam antibiotics accumulate in lung tissue at levels that are close to or slightly below serum levels. However, models of inflammation and infection have not been adequately studied to determine the antibiotic penetration into the site of infection.1Bergogne-Bérézin E Vallée E Pharmacokinetics of antibiotics in respiratory tissues and fluids.in: Pennington JE Respiratory infections: diagnosis and management. 3rd ed. Raven Press, New York, NY1994: 715-740Google Scholar In addition, the clearance of antibiotics from the alveolar-lining fluid has also not been studied sufficiently to determine the effect of infection on local drug levels.2Honeybourne D Antibiotic penetration into lung tissues.Thorax. 1994; 49: 104-106Crossref PubMed Scopus (63) Google ScholarClinical results in pneumonia may depend more on tissue penetration and accumulation in the infected lung than on serum levels. This might explain two recent observations in the treatment of pneumonia: (1) the lack of clinically observed treatment failures with β-lactam or macrolide antibiotic therapy despite an epidemic of penicillin-resistant Streptococcus pneumoniae (PRSP) and multidrug-resistant Streptococcus pneumoniae (MDRSP); and (2) the success of ultrashort IV antibiotic treatment regimens, with rapid oral switch, for hospitalized patients with moderately severe community-acquired pneumonia (CAP). A surprising clinical observation in recent years has been that studies reveal increasing levels of PRSP and MDRSP without clinical reports of widespread pneumonia treatment failures. Studies show that S pneumoniae is the most common cause of pneumonia in the United States, and recent surveys reveal isolates with an intermediate penicillin resistance in 27.8% of patients and a high-grade penicillin resistance (MIC ≥ 2 μg/mL) in 16.0% of patients in the United States. In addition, 11.7 to 14.3% of isolates are reported3Doern GV Pfaller MA Kuger K et al.Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.Clin Infect Dis. 1998; 27: 764-770Crossref PubMed Scopus (415) Google Scholar to be macrolide resistant. Despite these in vitro data, the recent Guidelines for Treatment of Community-Acquired Pneumonia, as published by the Infectious Disease Society of America, states that “Members of the Panel are not aware of clinical failures of penicillin treatment for pneumococcal pneumonia that have been ascribed to in-vitro resistance … .”4Bartlett JG Breiman RF Mandell LA et al.Community-acquired pneumonia in adults: guidelines for management; The Infectious Diseases Society of America.Clin Infect Dis. 1998; 28: 811-838Crossref Scopus (869) Google Scholar In a 10-year study of pneumonia in Barcelona, no increase in the pneumonia death rate was seen in patients who were infected with PRSP who were treated with penicillin or ampicillin.5Pallares R Liñares J Vadillo M et al.Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.N Engl J Med. 1995; 333: 474-480Crossref PubMed Scopus (751) Google Scholar This may reflect the fact that many of the organisms that are reported as resistant may be susceptible to higher, clinically achievable levels in the infected tissue.6Ellner PD Neu HC The inhibitory quotient.JAMA. 1981; 246: 1575-1578Crossref PubMed Scopus (131) Google ScholarTissue levels of β-lactam antibiotics may be well above the resistance-breakpoint levels established by the National Committee for Clinical Laboratory Standards; for the macrolides, tissue levels may be severalfold above serum levels and MICs of highly resistant isolates. Those breakpoints were established for β-lactam antibiotics to determine efficacy in infections such as meningitis, where levels might barely reach the 2 μg/mL level established for high-grade penicillin resistance. These breakpoints are meant to be considered for infections in which borderline penetration makes these levels significant. They may have little relevance when lung infections are being treated and when levels at least 10 times these breakpoints are achieved in infected lung tissue. The dichotomy between in vitroresistance reports and clinical outcomes may be due to the fact that sustained tissue levels above the MIC are far more important determinants of clinical outcome than peak serum levels. When an antibiotic is chosen that functions on the basis of time-dependent killing, increasing the concentration of the drug beyond the MIC does not increase bacterial killing. Rather, the bacterial kill depends on the following: kill rate × time levels remain above MIC.7Drusano GL Pharmacology of anti-infective agents.in: Mandel GL Principles and practice of infectious disease. 4th ed. Churchill Livingstone, New York, NY1995: 225-233Google Scholar When the CAP clinical trials of the IV azalide azithromycin were begun, questions were raised whether there would be clinical failures in bacteremic patients with pneumonia. With azithromycin, a once-daily administered drug, serum levels fall rapidly, as levels in lung parenchyma and phagocytes rise severalfold. The results of those trials revealed that clinical outcomes were similar in bacteremic patients and in a control group treated with cefuroxime with or without erythromycin.8Plouffe JF. Safety of IV/oral azithromycin versus cefuroxime ± erythromycin in patients with community-acquired pneumonia. Paper presented at: 1998 American Society for Microbiology General Meeting; May 21, 1998; Atlanta, GAGoogle Scholar This result supports the concept that serum antibiotic levels may not be the most significant pharmacokinetic factor in the cure of patients with CAP, particularly when the infection has not spread beyond the lung and there are no existing barriers to adequate lung penetration, such as lung abscess or necrotizing pneumonia. Although it has been shown that patients with bacteremic pneumococcal pneumonia have a higher mortality than do nonbacteremic patients, much of the mortality results from systemic decompensation: ARDS, septic shock, and multiorgan dysfunction syndrome.9Watanakunakorn C Bailey TA Adult bacteremic pneumococcal pneumonia in a community teaching hospital, 1992–1996.Arch Intern Med. 1997; 157: 1965-1971Crossref PubMed Google Scholar Systemic decompensation may result from cytokine release in a small minority of patients, and the transient bacteremia seen in the majority of patients with CAP may be easily cleared with one or two doses of IV or oral antibiotics. The more important determinant of outcome may be sterilization of the infected lung, which is dependent on sustained antibiotic concentrations achieved in the lung. In one prospective study, hospitalized patients with CAP who had reached clinical stability were quickly switched from IV to oral antibiotic therapy. The mean IV duration was 3 days, and Ramirez et al10Ramirez JA Srinath L Ahkee S et al.Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia.Arch Intern Med. 1995; 155: 1273-1276Crossref PubMed Scopus (212) Google Scholar reported a cure rate of 99%. In two prospective, randomized, double-blind studies, we treated 66 hospitalized veterans (non-ICU) having significant medical comorbidity with 2 days of IV cefuroxime therapy that was followed by a switch to orally administered cefuroxime axetil. The combined cure rate was 89.4%, and this was similar to the control group cure rate of 89.2%. In the control group, 33 patients received between 5 and 10 days of IV cefuroxime.11Siegel RE Halpern NA Almenoff PL et al.A prospective randomized study of inpatient intravenous antibiotics for community-acquired pneumonia: the optimal duration of therapy.Chest. 1996; 105: 1109-1115Google Scholar12Siegel RE Alicia M Lee A et al.Comparison of seven versus ten days of antibiotic therapy for hospitalized patients with uncomplicated community-acquired pneumonia.Am J Ther. 1999; (in press)PubMed Google Scholar In those studies, there were seven patients with pneumococcal bacteremia (penicillin-sensitive) who were randomized to the 2-day IV group. All of the patients were cured except one patient who died within 24 h from septic shock while on IV therapy. In an interim analysis of an ongoing prospective study in which we treated 28 hospitalized patients with CAP with one dose of IV ceftriaxone followed 8 h later by a switch to oral cefuroxime axetil for 7 days, the cure rate was 91.7%; this outcome was similar to that reported in our previous studies13Siegel RE Alicea M Lee A et al.Inpatient treatment of community-acquired pneumonia with one dose of IV therapy prior to oral therapy [abstract].Am J Respir Crit Care Med. 1999; 159: A845Crossref PubMed Scopus (23) Google Scholarwith 2 to 10 days of IV therapy. In another study, investigators randomly assigned hospitalized patients with CAP to receive either the usual regimen of IV and oral antibiotics or oral ofloxacin alone. Despite oral treatment with a drug with relatively poor activity against Gram-positive organisms, clinically cured and improved patients were similar in both groups, again stressing that sustained tissue levels may be more important than serum MICs.14Sanders Jr, EW Morris JF Alessi P et al.Oral ofloxacin for the treatment of acute bacterial pneumonia: use of a nontraditional protocol to compare experimental therapy with “usual care” in a multicenter clinical trial.Am J Med. 1991; 91: 261-266Abstract Full Text PDF PubMed Scopus (47) Google Scholar The importance of these clinical observations is multifold. First, the continued successful treatment of patients with CAP caused by PRSP and MDRSP with the β-lactam and macrolide classes of antibiotics indicates that the recommendations for treatment of these patients should not be based solely on in vitro laboratory results, but should be based on the results of clinical trials. Many physicians are mistakenly interpreting the present data to indicate that pneumonia patients today must receive fluoroquinolone antibiotics or other classes of antibiotics that will treat this resistant organism to prevent antibiotic treatment failures. This practice trend will increase antibiotic cost and will predictably lead to the rapid development of fluoroquinolone resistance by S pneumoniaedue to the overuse of this antibiotic class. It has clearly been shown that overuse of one antibiotic class can rapidly increase selective pressure for the development of resistance. In Finland, clinical practice that included the excessive use of macrolide antibiotics led to a group A streptococcal (Streptococcus pyogenes) resistance to the macrolides, and sensitivities improved after the consumption of the macrolides was decreased.15Seppala H Klaukka T Vuopio-Varkila J et al.The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in Group A streptococci in Finland.N Engl J Med. 1997; 337: 441-446Crossref PubMed Scopus (1078) Google Scholar It is interesting that presently there is no antibiotic that has the US Food and Drug Administration-approved indication for treatment of the penicillin-resistant pneumococcus, due to a lack of clinical studies. In addition, the National Committee for Clinical Laboratory Standards has recently agreed tentatively to change the amoxicillin breakpoints for the determination of sensitivities to the following: sensitive,≤ 2 μg/mL; intermediate, 4 μg/mL; and resistant, ≥ 8μ g/mL. In doing so, they have determined that much of the data used by clinicians to change clinical practices may have been based on in vitro data that were not accurate. Increasing pneumococcal resistance is a worrisome trend, and it is likely to continue to expand. However, patients with CAP who respond clinically to β-lactam and macrolide antibiotics and in whom a resistant isolate is cultured should have treatment continued with these agents, unless there is metastatic spread of the infection beyond the lung or a tissue breakdown that might impede lung penetration. Because there have been deaths due to PRSP meningitis in patients being treated withβ -lactams (because of poor CNS antibiotic penetration),16John CC Treatment failure with use of a third-generation cephalosporin for penicillin-resistant pneumococcal meningitis: case report and review.Clin Infect Dis. 1994; 18: 188-193Crossref PubMed Scopus (191) Google Scholar physicians should be careful to use antibiotics to which PRSP is sensitive in cases in which a meningeal spread of the resistant organism is a possibility. These practices should continue until outcome studies of patients infected with PRSP and MDRSP are completed, or until clinical failures from this approach are demonstrated. In addition, for patients in whom there may be a reason to suspect PRSP (such as those who have received recentβ -lactam therapy, or those who are immunosuppressed), the physician might choose to use a new fluoroquinolone to prevent further development of resistance. Second, large clinical trials are needed to confirm that ultrashort courses of IV antibiotics prior to an oral switch are sufficient for most hospitalized patients with uncomplicated CAP, regardless of whether all of the signs of infection have fully responded to therapy. Clinical judgment is used by clinicians every day to treat outpatients who have CAP with oral therapy, even though these patients exhibit more severe signs of infection than does the hospitalized patient being evaluated for oral switch. Pilot studies have demonstrated the safety of an early transition to oral therapy, but the concept of switch therapy has not yet been fully accepted because large, multicenter clinical trials have not confirmed these results. A cost analysis that was performed by us11Siegel RE Halpern NA Almenoff PL et al.A prospective randomized study of inpatient intravenous antibiotics for community-acquired pneumonia: the optimal duration of therapy.Chest. 1996; 105: 1109-1115Google Scholar in an earlier trial suggested that $3 billion in health care expenditures could be saved if this paradigm of care was accepted. IV therapy in CAP is commonly used to keep serum levels of antibiotics elevated. However, when the decision is made to hospitalize a patient for the treatment of pneumonia, that decision is frequently made in order to observe the patient for possible clinical deterioration. It remains unproven that prolonged IV therapy offers these patients a treatment advantage, because antibiotic levels above the MICs of common pathogens can be sustained with oral therapy. Recent data from the Pneumonia Patient Outcomes Research Team study have demonstrated that patients prefer to be treated at home, and that their recovery, functional status, and return to work occur more quickly when they receive antimicrobial therapy at home.17Coley MC Li YH Medsger AR et al.Preferences for home vs hospital care among low-risk patients with community-acquired pneumonia.Arch Intern Med. 1996; 156: 1565-1571Crossref PubMed Google Scholar18Fine MJ Singer DE Marrie TJ et al.Medical outcomes of ambulatory and hospitalized low risk patients with community-acquired pneumonia [abstract].J Gen Intern Med. 1994; 9: 29PubMed Google ScholarTherefore, our goal should be to return these patients to their homes as soon as it is safe to do so. In summary, it appears that concern with serum levels of antibiotics and sensitivity testing based on achievable serum levels of antibiotics has led to clinical practices of care that are based on hypothesis and in vitro testing, rather than on proven results of well-controlled clinical trials. Clinical studies to answer some basic questions are needed: 1.Should antibiotic treatment choices be based on serum MICs, on achievable lung levels of antibiotics at the site of infection, or on clinical outcome studies?2.What is the optimal timing for the switch from IV to oral antibiotics for hospitalized patients with CAP? These answers are needed to guide the optimal treatment of this common infectious disease in an environment in which the infecting organisms, the antimicrobial alternatives, and the health-care environment are rapidly changing.
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