Penicillin for community-acquired pneumonia?

Few clinicians would identify penicillin at the top of their list of agents for treat- ment of community-acquired pneumonia in 2009. However, when reviewing the available clinical data for use of penicillin to treat Streptococcus pneumoniae infections, I was surprised by how attractive this agent looked in light of a review of published case reports and available susceptibility profiles. While there have been comprehensive discussions on this topic published recently, I had underappreciated the potential role of this agent until I took a slightly closer look at the data.

Until approximately 15 years ago, penicillin was suggested as the agent of choice for treatment of pneumonia. However, this recommendation changed to favor macrolides, cephalosporins and fluoroquinolones in the setting of increased penicillin resistance. At that time, a minimum inhibitory concentration breakpoint of 2 mcg/mL was used to classify S. pneumoniae isolates resistant to penicillin. The clinical correlation of this breakpoint, however, was derived from patients with meningitis. Due to limited drug penetration to the cerebral spinal fluid, such a low breakpoint was warranted. However this is too conservative for pulmonary infections when testing drugs that readily penetrate into lung tissue. This problem was addressed with the cephalosporin class and resulted in modified breakpoints for non-central nervous system disease in 2002. However, the Clinical and Laboratory Standards Institute did not change S. pneumoniae breakpoints for penicillin until January 2008. The new breakpoints identify 8 mcg/mL as the threshold above which isolates are reported resistant.

The effect of this change in breakpoints greatly alters the landscape of penicillin resistant S. pneumoniae, which was the driving force behind the switch from universal penicillin use for treating pneumococcal pneumonia. The Centers for Disease Control coordinates a population-based laboratory surveillance program for invasive bacterial disease, called Active Bacterial Core Surveillance (ABCs). Data obtained through the program for S. pneumoniae from 2006 and 2007 showed a penicillin resistance rate of just over 10% for the two years with an additional 15% of isolates being only intermediately susceptible to penicillin for patients with invasive disease. The majority of these isolates (66%) were obtained from cases of pneumonia with concomitant bacteremia. When the new 2008 Clinical and Laboratory Standards Institute breakpoints were applied to the same set of isolates, resistance to penicillin dropped to 1.2% and intermediate susceptibility fell to only 5.6% of cases.

Clinical implications

Perhaps a more relevant question is whether or not penicillin-resistance to S. pneumoniae has clinical implications at all. In a 2006 review in Clinical Infectious Diseases, Lance R. Peterson, MD, from Northwestern University reviewed the evidence of beta-lactam therapy failures in patients with penicillin-resistant S. pneumoniae pneumonia. The review highlights three main points regarding penicillin treatment failures: 1) Studies fail to correlate negative outcomes for patients with penicillin-resistant S. pneumoniae infection with specific antibiotic treatment; 2) Prospective clinical trials have not shown differences in treatment outcome with penicillin in the setting of penicillin-resistance; and 3) There is only a single case report where a firm conclusion of penicillin failure in the setting of documented drug resistance can be made. In this case, the minimum inhibitory concentration of the infecting organism was 8 mcg/mL. Perhaps the shift away from penicillin may have been premature.

At the time that penicillin was removed as the agent of choice for the treatment of community-acquired pneumococcal pneumonia, there were several new and emerging treatment options for this infection. The macrolides including azithromycin had become available and the respiratory fluoroquinolones were on the horizon. These new agents were attractive for managing disease and, at the time, not associated with high-levels of drug resistance. However, that is no longer the case. In the same data set obtained through the ABCs program, erythromycin resistance in S. pneumoniae was between 21% and 22% for 2006-2007, and tetracycline resistance had risen to more than 10% in the same time period. Quinolone resistance among S. pneumoniae has remained low (less than 1% in 2006-2007).

Current guidelines

Current guidelines released by the Infectious Diseases Society of America support the use of either a respiratory fluoroquinolone as monotherapy or beta-lactams in combination with a macrolide for outpatient treatment of community-acquired pneumonia in the setting of comorbidities or inpatient management for patients not requiring care in the intensive care unit.

For outpatient therapy, amoxicillin is listed as the beta-lactam of choice and ampicillin is among options for hospitalized patients, providing that they are dosed correctly.

The issue of dose is an important component of any recommendation including the penicillins for pneumococcal disease. To treat organisms with an minimum inhibitory concentration = 8 mcg/mL, daily doses of antibiotics should exceed 18 million units for penicillin, 8 g for ampicillin and 4 g for amoxicillin, all in divided doses and correctly adjusted for renal function.

Based on these current IDSA recommendations, many practitioners and institutional protocols rely on a combined approach of either respiratory fluoroquinolones or a cephalosporin plus a macrolide for their patients with community-acquired pneumonia. However, each of these approaches is associated with the potential for negative consequences including C. difficile infection with the fluoroquinolones and VRE selection with broad-spectrum cephalosporins. Additionally, both of these drug classes have been associated with clinical failures attributed to antibiotic resistance.

CMS criteria

It is important to point out that use of penicillins (penicillin, ampicillin and amoxicillin without clavulanic acid) do not currently meet CMS criteria for performance measure PN-6-b, initial antibiotic selection for community-acquired pneumonia in hospitalized patients. Therefore, the impact of these data on initial drug selection in the inpatient setting will remain minimal. Although, it may broaden treatment options for step-down therapy in patients initially receiving a beta-lactam containing antibiotic regimen and expand drug options for practitioners in the community setting.

It is possible that pending further review, penicillin may be returned as a beta-lactam option to the national guidelines for treatment of community-acquired pneumonia and, appropriately, regulatory agencies would follow suit. However, the decision to remove penicillin from the treatment guidelines also took into consideration the possibility of future emerging resistance. Perhaps one reason that penicillin resistance rates had stabilized prior to the change in breakpoints can be attributed to the decreased use of the class for this infection. This factor would also need to be carefully weighed before returning penicillin to the guidelines.

As the 2008-2009 pneumonia season draws to a close, this is the time that many institutions and clinicians reflect on treatment protocols and form plans for management for the coming year. In addition, at the time of this writing, the potential of a swine flu pandemic is looming. Current IDSA guidelines recommend that in cases of influenza pandemic, patients receive oseltamivir in combination with an agent active against S. pneumoniae as a moderate level recommendation. Perhaps, the role of penicillin deserves consideration in these treatment algorithms.

Elizabeth Dodds Ashley, PharmD, MHS, is an Associate in Research/Clinical Pharmacy at the Duke University Medical Center Division of Infectious Diseases.

For more information:

• Peterson LR. Penicillins for treatment of pneumococcal pneumonia: Does in vitro resistance really matter? Clin Infect Dis. 2006;42:224-33.
• Chiou C. Does penicillin remain the drug of choice for pneumococcal pneumonia in view of emerging in vitro resistance? Clin Infect Dis. 2006;42:234-7.
• www.cdc.gov/ncidod/dbmd/abcs/index.htm