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* From the Pulmonary Section, Bronx Veterans Affairs Medical Center, Bronx, NY.
Correspondence to: Robert E. Siegel, MD, FCCP, Associate Chief, Pulmonary Section, Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468; e-mail: siegel.robert{at}bronx.va.gov
Key Words: antibiotic • community-acquired pneumonia • penicillin resistance • Streptococcus pneumoniae
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Introduction |
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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
reported3
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 ... ."4
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.5
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.6
Tissue levels of ß-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 ß-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 vitro
resistance 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 x time levels remain above
MIC.7
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.8 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.9 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 al10 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.11 12 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 studies13 with 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.14
The importance of these clinical observations is multifold. First, the
continued successful treatment of patients with CAP caused by PRSP and
MDRSP with the ß-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 pneumoniae
due 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.15
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, 8
µg/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 ß-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 with
ß-lactams (because of poor CNS antibiotic
penetration),16
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 recent
ß-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 us11 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.17 18 Therefore, 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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Footnotes |
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Received for publication December 15, 1998. Accepted for publication March 2, 1999.
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References |
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TOPIntroductionReferences |
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 G. A. Drummond and D. R. Jenkins Treatment protocols for community-acquired pneumonia: evidence-based must replace consensus-based J. Antimicrob. Chemother., October 1, 2000; 46(4): 640 - 641. [Full Text] [PDF]
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