Increasing Pneumococcal Fluoroquinolone Resistance

[Guest guest]

More Bad News: Increasing Pneumococcal Fluoroquinolone Resistance

Stratton, MD Disclosures

San Diego, Saturday, September 28, 2002 -- The second day of ICAAC again

brought bad news about resistance for the practicing clinician. This bad

news concerns Streptococcus pneumoniae, one of the most common pathogens

causing community-acquired pneumonia, and heralds the possible demise of

fluoroquinolones as effective agents for this microorganism. Today,

Jane Ferraro, PhD,[1] in a slide session on Surveillance and Early

Detection of Resistance (Abstract C2-650), reported the prevalence of

fluoroquinolone resistance among S pneumoniae isolated in the United

States during the winter of 2000-2001. This report caught everyone's

attention and raises considerable concern over the future of these

agents for the therapy of pneumococcal pneumonia. This is a far cry from

just a year ago, when many were debating the clinical significance of

drug resistance in S pneumoniae.[2,3] What has happened in the past year

that has made such a difference? A brief review of the therapy of

pneumococcal pneumonia is in order.

S pneumoniae is the most common cause of community-acquired pneumonia

and has a case-fatality rate of 15% to 25% with invasive (ie,

bacteremic) disease.[4,5] A beta-lactam agent such as a penicillin or a

cephalosporin has long been the drug of choice for treating pneumococcal

pneumonia unless the patient was allergic to penicillin, in which case a

macrolide was substituted.[6] Unfortunately, this important respiratory

pathogen has been becoming increasingly resistant to both beta-lactam

agents and macrolides.[7] As mentioned earlier, the community-based

physician has been less concerned with this emergence of pneumococcal

resistance simply because they had not seen the clinical evidence for

such resistance, which is the failure of empirical antimicrobial therapy

for community-acquired infections. Although treatment failures due to

penicillin or cephalosporin resistance have been reported for

pneumococcal meningitis,[8,9] the failure of these agents in

pneumococcal pneumonia has not been noted.[10-13]

Despite the lack of evidence for penicillin/cephalosporin failure in

pneumococcal pneumonia, the reports of penicillin resistance in S

pneumoniae have resulted in the increased use of fluoroquinolones for

the empiric therapy of community-acquired pneumonia.[14] The use of

fluoroquinolones has been especially high for the outpatient therapy of

respiratory tract infections.[15] Indeed, the so-called " respiratory

tract " fluoroquinolones such as levofloxacin, gatifloxacin, and

moxifloxacin have been developed especially for the treatment of

pneumococcal respiratory infections.[16]

Based on previous experience, increased use of fluoroquinolones for the

therapy of respiratory tract infections would be predicted to result in

increased resistance. This has been reported in Canada,[17] but has

appeared to be less of a problem in the United States.[18] However, in

the past year the story of fluoroquinolone resistance and the

pneumococcus began to change. First and foremost, there have been

several case reports of therapeutic failures with levofloxacin therapy

of pneumococcal pneumonia.[19,20] This suggests that fluoroquinolone

resistance may be a clinical problem in the near future. Thus, when Dr.

Ferraro presented new information on the emergence of fluoroquinolone

resistance in pneumococcal isolates in the United States, all were ready

to listen.

Ferraro and colleagues reported increased fluoroquinolone resistance

(levofloxacin minimum inhibitory concentration [MIC] >/= 8 mcg/mL) in

0.8% of pneumococcal isolates overall, with Massachusetts (4.8%) and

Colorado (4.6%) having somewhat higher rates. Salem, Massachusetts, had

a rate of 21.8%. The molecular mechanism of this resistance is double

mutations in the parC and gyrA genes. High-level fluoroquinolone

resistance, with MICs > 8 mcg/mL for pneumococci, should it continue to

increase in the United States, could make the use of fluoroquinolones

for pneumococcal pneumonia problematic, to say the least.

At this point, the infectious diseases practitioner may ask what should

be the optimal therapy of pneumococcal pneumonia in the hospitalized

patient. This question was answered, in part, by 2 other reports

today[21,22] and one published study.[23] All suggest that the

combination of a beta-lactam agent with a macrolide significantly

reduces the mortality rate of bacteremic pneumococcal pneumonia compared

with monotherapy (including fluoroquinolones). Thus, for the

hospitalized patient with pneumococcal pneumonia, initial therapy with a

newer cephalosporin (ie, cefotaxime 1 g every 8 hours or ceftriaxone 1 g

every 12 hours) and intravenous azithromycin 500 mg once daily appears

to be optimal.

References

Ferraro MJ, Brown S, Harding I. Prevalence of fluoroquinolone resistance

amongst Streptococcus pneumoniae isolated in the United States during

the winter of 2000-01. Abstract C2-650. Program and abstracts of the

42nd Interscience Conference on Antimicrobial Agents and Chemotherapy;

September 27-30, 2002; San Diego, California. Abstract C2-650.

Bauer T, Ewig S, Marcos MA, Schultze-Werninghaus, A.

Streptococcus pneumoniae in community-acquired pneumonia. How important

is drug resistance? Med Clin North Am. 2001;85:1367-1379. Abstract

Doern GV. Antimicrobial resistance with Streptococcus pneumoniae: much

ado about nothing? Semin Respir Infect. 2001;16:177-184. Abstract

Musher DM, andraki I, Graviss EA, et al. Bacteremic and

non-bacteremic pneumococcal pneumonia. A prospective study. Medicine.

2000;79:210-221. Abstract

Austrian R, Gold J. Pneumococcal bacteremia with special reference to

bacteremic pneumococcal pneumonia. Ann Intern Med. 1964;60:759-776.

Musher D. Infections caused by Streptococcus pneumoniae: clinical

spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis.

1992;14:801-809. Abstract

Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of

multidrug-resistant Streptococcus pneumoniae in the United States. N

Engl J Med. 2000;343:1917-1924. Abstract

Sloas MM, Barrett FF, Chesney PJ, et al. Cephalosporin treatment failure

in penicillin- and cephalosporin-resistant Streptococcus pneumoniae

meningitis. Pediatr Infect Dis J. 1992;11:662-666. Abstract

Catalan MJ, Fernandez JM, Vazquez A, et al. Failure of cefotaxime in the

treatment of meningitis due to relatively resistant Streptococcus

pneumoniae. Clin Infect Dis. 1994;18:766-769. Abstract

Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and

cephalosporin and mortality from severe pneumococcal pneumonia in

Barcelona, Spain. N Engl J Med. 1995;333:474-480. Abstract

Ewig S, Ruiz M, A, et al. Pneumonia acquired in the community

through drug-resistant Streptococcus pneumoniae. Am J Respir Crit Care

Med. 1999;159:1835-1842. Abstract

Moroney JF, Fiore AE, on LH, et al. Clinical outcomes of

bacteremic pneumococcal pneumonia in the era of antibiotic resistance.

Clin Infect Dis. 2001;33:797-805. Abstract

Pallares R, Capdevila O, Linares J, et al. The effect of cephalosporin

resistance on mortality in adult patients with nonmenigeal systemic

pneumococcal infections. Am J Med. 2002;113:120-126. Abstract

Heffelfinger JD, Dowell SF, nsen JH, et al. Management of

community-acquired pneumonia in the era of pneumococcal resistance. Arch

Intern Med. 2000;160:1399-1408. Abstract

File TM Jr. Apprpriate use of antimicrobials for drug-resistant

pneumonia: focus on the significance of beta-lactam-resistance

Streptococcus pneumoniae. Clin Infect Dis. 2002;34(suppl 1):S17-S26.

nsen JH, Weigel LM, Ferraro MJ, Swenson JM, Tenover FC. Activities

of newer fluoroquinolones against Streptococcus pneumoniae clinical

isolates including those with mutations in the parC, gyrA, and parE

loci. Antimicrob Agents Chemother. 1999;43:329-334. Abstract

Chen DK, McGeer A, de Azavedo JC, Low DE, and the Canadian Bacterial

Surveillance Network. Decreased susceptibility of Streptococcus

pneumoniae to fluoroquinoloones in Canada. N Engl J Med.

1999;341:233-239. Abstract

Brueggemann AB, Coffman SL, Rhomberg P, et al. Flouroquinolone

resistance in Streptococcus pneumoniae in United States since 1994-1995.

Antimicrob Agents Chemother. 2002;46:680-688. Abstract

son R, Cavalcanti R, Brunton J, et al. Resistance to levofloxacin

and failure of treatment of pneumococcal pneumonia. N Engl J Med.

2002;346:747-750. Abstract

Kays MB, DW , Wack ME, Denys GA. Levofloxacin treatment failure in

a patient with fluoroquinolonresistant Streptococcus pneumoniae.

Pharmacotherapy. 2002;22:395-399. Abstract

Weiss K, Cortes L, Beaupre A, et al. Clinical characteristics, initial

presentation and impact of treatment on mortality in bacteremic

Streptococcus pneumoniae pneumoniae. Program and abstracts of the 42nd

Interscience Conference on Antimicrobial Agents and Chemotherapy;

September 27-30, 2002; San Diego, California. Abstract L-987.

ez JA, Horcajada JP, Almela M, et al. Effect of initial treatment

with a beta-lactam plus a macrolide compared with a beta-lactam alone on

bacteremic pneumococcal pneumonia mortality. Program and abstracts of

the 42nd Interscience Conference on Antimicrobial Agents and

Chemotherapy; September 27-30, 2002; San Diego, California. Abstract

L-988.

Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for

severe bacteremic pneumococcal pneumonia. Arch Intern Med.

2001;161:1837-1842. Abstract

Becki

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