Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole
- Daniel M Musher, MD
Daniel M Musher, MD
- Professor of Medicine, Professor of Molecular Virology and Microbiology
- Baylor College of Medicine
Streptococcus pneumoniae (pneumococcus) is the most commonly identified bacterial cause of pneumonia and acute sinusitis and, along with Haemophilus influenzae, is one of the two most common causes of otitis media and acute exacerbations of chronic bronchitis. The fluoroquinolones (often called quinolones) have been used widely to treat adults with these conditions. In 2016, the US Food and Drug Administration (FDA) stated that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits for patients with acute sinusitis (as well as acute bronchitis and uncomplicated urinary tract infections) who have other treatment options . This safety alert is likely to reduce the indiscriminate use of the fluoroquinolones, thereby preserving the susceptibility of pneumococci. (See "Fluoroquinolones", section on 'Restriction of use for uncomplicated infections'.)
Doxycycline is used for the treatment of acute bacterial sinusitis (as an alternative agent for patient with penicillin allergy) , acute exacerbation of chronic bronchitis , and pneumonia in adult outpatients . Trimethoprim-sulfamethoxazole (TMP-SMX) was commonly used to treat these conditions from the mid-1970s to the mid-1990s, but this combination drug has largely fallen out of favor because of the high rate of pneumococcal resistance.
Pneumococci were uniformly susceptible to all antibiotics used to treat bacterial infections of the respiratory tract until outbreaks of infection due to antibiotic-resistant pneumococci occurred in South Africa in the late 1970s [5,6]. Although the responsible organisms were called penicillin-resistant pneumococci, they had acquired genetic material that encoded broad resistance both to penicillin and to other commonly used antibiotics. In the ensuing decades, pneumococcal resistance has arisen in a number of clinically relevant classes of antibiotics.
The mechanisms of action and resistance and clinical data on the outcome of therapy in respiratory tract infections will be reviewed here for the fluoroquinolones, doxycycline, and TMP-SMX. Resistance to the other classes of drugs is discussed separately. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" and "Resistance of Streptococcus pneumoniae to the macrolides, azalides, lincosamides, and ketolides".)
The fluoroquinolones consist of a family of related compounds, including ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin. Use of these drugs to treat respiratory infection represented a major therapeutic advance. At the time of their introduction, these drugs were uniformly active against S. pneumoniae as well as Haemophilus, Moraxella, Legionella, Mycoplasma, and Chlamydia spp. Except for very low rates of resistance of pneumococci and rare reports of resistance among Haemophilus, they remain so to the present. (See "Fluoroquinolones".)
- FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm (Accessed on May 26, 2016).
- Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg 2015; 152:S1.
- Dever LL, Shashikumar K, Johanson WG Jr. Antibiotics in the treatment of acute exacerbations of chronic bronchitis. Expert Opin Investig Drugs 2002; 11:911.
- Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27.
- Appelbaum PC, Bhamjee A, Scragg JN, et al. Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977; 2:995.
- Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978; 299:735.
- Fukuda H, Hiramatsu K. Primary targets of fluoroquinolones in Streptococcus pneumoniae. Antimicrob Agents Chemother 1999; 43:410.
- Pestova E, Millichap JJ, Siddiqui F, et al. Non-PmrA-mediated multidrug resistance in Streptococcus pneumoniae. J Antimicrob Chemother 2002; 49:553.
- Smith HJ, Nichol KA, Hoban DJ, Zhanel GG. Dual activity of fluoroquinolones against Streptococcus pneumoniae: the facts behind the claims. J Antimicrob Chemother 2002; 49:893.
- Brueggemann AB, Coffman SL, Rhomberg P, et al. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Antimicrob Agents Chemother 2002; 46:680.
- Jorgensen JH, Weigel LM, Swenson JM, et al. Activities of clinafloxacin, gatifloxacin, gemifloxacin, and trovafloxacin against recent clinical isolates of levofloxacin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 2000; 44:2962.
- Pletz MW, Shergill AP, McGee L, et al. Prevalence of first-step mutants among levofloxacin-susceptible invasive isolates of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 2006; 50:1561.
- Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents 2010; 36:197.
- Jacobs MR, Good CE, Windau AR, et al. Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 2010; 54:2716.
- Patel SN, McGeer A, Melano R, et al. Susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Antimicrob Agents Chemother 2011; 55:3703.
- Thornsberry C, Brown NP, Draghi DC, et al. Antimicrobial activity among multidrug-resistant Streptococcus pneumoniae isolated in the United States, 2001-2005. Postgrad Med 2008; 120:32.
- Kupronis BA, Richards CL, Whitney CG, Active Bacterial Core Surveillance Team. Invasive pneumococcal disease in older adults residing in long-term care facilities and in the community. J Am Geriatr Soc 2003; 51:1520.
- Pletz MW, van der Linden M, von Baum H, et al. Low prevalence of fluoroquinolone resistant strains and resistance precursor strains in Streptococcus pneumoniae from patients with community-acquired pneumonia despite high fluoroquinolone usage. Int J Med Microbiol 2011; 301:53.
- Scheld WM. Maintaining fluoroquinolone class efficacy: review of influencing factors. Emerg Infect Dis 2003; 9:1.
- Pankuch GA, Bozdogan B, Nagai K, et al. Incidence, epidemiology, and characteristics of quinolone-nonsusceptible Streptococcus pneumoniae in Croatia. Antimicrob Agents Chemother 2002; 46:2671.
- Ho PL, Yung RW, Tsang DN, et al. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J Antimicrob Chemother 2001; 48:659.
- Wang H, Chen M, Xu Y, et al. Antimicrobial susceptibility of bacterial pathogens associated with community-acquired respiratory tract infections in Asia: report from the Community-Acquired Respiratory Tract Infection Pathogen Surveillance (CARTIPS) study, 2009-2010. Int J Antimicrob Agents 2011; 38:376.
- Ho PL, Tse WS, Tsang KW, et al. Risk factors for acquisition of levofloxacin-resistant Streptococcus pneumoniae: a case-control study. Clin Infect Dis 2001; 32:701.
- Chodosh S, McCarty J, Farkas S, et al. Randomized, double-blind study of ciprofloxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group. Clin Infect Dis 1998; 27:722.
- Shah PM, Maesen FP, Dolmann A, et al. Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study. J Antimicrob Chemother 1999; 43:529.
- Masterton RG, Burley CJ. Randomized, double-blind study comparing 5- and 7-day regimens of oral levofloxacin in patients with acute exacerbation of chronic bronchitis. Int J Antimicrob Agents 2001; 18:503.
- Schaberg T, Ballin I, Huchon G, et al. A multinational, multicentre, non-blinded, randomized study of moxifloxacin oral tablets compared with co-amoxiclav oral tablets in the treatment of acute exacerbation of chronic bronchitis. J Int Med Res 2001; 29:314.
- File TM Jr, Segreti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41:1965.
- Fogarty C, Grossman C, Williams J, et al. Efficacy and safety of moxifloxacin versus clarithromycin for community-acquired pneumonia. Infect Med 1999; 16:748.
- Jones RN, Andes DR, Mandell LA, et al. Gatifloxacin used for therapy of outpatient community-acquired pneumonia caused by Streptococcus pneumoniae. Diagn Microbiol Infect Dis 2002; 44:93.
- Nicholson SC, Wilson WR, Naughton BJ, et al. Efficacy and safety of gatifloxacin in elderly outpatients with community-acquired pneumonia. Diagn Microbiol Infect Dis 2002; 44:117.
- Lode H, File TM Jr, Mandell L, et al. Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability. Clin Ther 2002; 24:1915.
- Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002; 346:747.
- Kays MB, Smith DW, Wack ME, Denys GA. Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacotherapy 2002; 22:395.
- Anderson KB, Tan JS, File TM Jr, et al. Emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia. Clin Infect Dis 2003; 37:376.
- Hoban DJ, Bouchillon SK, Johnson BM, et al. In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004). Diagn Microbiol Infect Dis 2005; 52:215.
- Jones RN, Wilson ML, Weinstein MP, et al. Contemporary potencies of minocycline and tetracycline HCL tested against Gram-positive pathogens: SENTRY Program results using CLSI and EUCAST breakpoint criteria. Diagn Microbiol Infect Dis 2013; 75:402.
- Nelson ML, Levy SB. Reversal of tetracycline resistance mediated by different bacterial tetracycline resistance determinants by an inhibitor of the Tet(B) antiport protein. Antimicrob Agents Chemother 1999; 43:1719.
- Steigbigel NH, Reed CW, Finland M. Susceptibility of common pathogenic bacteria to seven tetracycline antibiotics in vitro. Am J Med Sci 1968; 255:179.
- SCHAEDLER RW, CHOPPIN PW, ZABRISKIE JB. PNEUMONIA CAUSED BY TETRACYCLINE-RESISTANTPNEUMOCOCCI. N Engl J Med 1964; 270:127.
- Holt R, Evans TN, Newman RL. Tetracycline-resistant pneumococci. Lancet 1969; 2:545.
- Kahlmeter G, Kamme C. Tetracycline-resistant group A streptococci and pneumococci. Scand J Infect Dis 1972; 4:193.
- Tetracycline resistance in pneumococci and group A streptococci. Report of an ad-hoc study group on antibiotic resistance. Br Med J 1977; 1:131.
- Zhanel GG, Palatnick L, Nichol KA, et al. Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003; 47:1867.
- Musher D, unpublished.
- Kucers A, Bennett NM. The use of antibiotics: a comprehensive review with clinical emphasis, William Heinemann Medical Books Ltd, London 1979.
- Ailani RK, Agastya G, Ailani RK, et al. Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia. Arch Intern Med 1999; 159:266.
- Punakivi L, Keistinen T, Backman R, et al. Oral ofloxacin once daily and doxycycline in the treatment of acute exacerbations of chronic bronchitis. Scand J Infect Dis Suppl 1990; 68:41.
- Hitchings GH. Mechanism of action of trimethoprim-sulfamethoxazole. I. J Infect Dis 1973; 128:Suppl:433.
- Burchall JJ. Mechanism of action of trimethoprim-sulfamethoxazole. II. J Infect Dis 1973; 128:Suppl: 437.
- Simberkoff MS, Lukaszewski M, Cross A, et al. Antibiotic-resistant isolates of Streptococcus pneumoniae from clinical specimens: a cluster of serotype 19A organisms in Brooklyn, New York. J Infect Dis 1986; 153:78.
- Henderson FW, Gilligan PH, Wait K, Goff DA. Nasopharyngeal carriage of antibiotic-resistant pneumococci by children in group day care. J Infect Dis 1988; 157:256.
- Reeves RR, Musher DM. Antibiotic-resistant pneumococcus in a hemophiliac with AIDS. Hosp Pract 1991; 26:81.
- Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis 2005; 41:139.
- Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000. Clin Infect Dis 2002; 34 Suppl 1:S4.
- Vanderkooi OG, Low DE, Green K, et al. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis 2005; 40:1288.
- Chodosh S, Eichel B, Ellis C, et al. Trimethoprim-sulfamethoxazole compared with ampicillin in acute infectious exacerbations of chronic bronchitis: a double-blind, crossover study. J Infect Dis 1973; 128:Suppl:710.
- Quick CA, Wagner D. Trimethoprim-sulfamethoxazole in the treatment of infections of the ears, nose, and throat. J Infect Dis 1973; 128:Suppl:696.
- Howie VM, Dillard R, Lawrence B. In vivo sensitivity test in otitis media: efficacy of antibiotics. Pediatrics 1985; 75:8.
- Shurin PA, Pelton SI, Donner A, et al. Trimethoprim-sulfamethoxazole compared with ampicillin in the treatment of acute otitis media. J Pediatr 1980; 96:1081.
- Mechanisms of action and resistance
- Prevalence of resistance
- Clinical efficacy
- - Acute exacerbation of chronic bronchitis
- - Pneumonia
- Mechanisms of action and resistance
- Prevalence of resistance
- Clinical efficacy
- Mechanisms of action and resistance
- Activity and prevalence of resistance
- Clinical efficacy
- - Lower respiratory infection
- - Upper respiratory infection