Treatment options for resistant pneumococcal infections

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1 Treatment options for resistant pneumococcal infections Clirz hlicrobiol Inject 1999; 5: 4S3-4Sll Romaiz Pallarcs, Olga Capdevila arid Zwimaczrlada Grazi Infectious Diseases Service, Hospital Bellvitge and University of Barcelona, Barcelona, Spain INTRODUCTION In spite of major advances in medical care, infections caused by Streptococcus pneurnorziae continue to be frequent all over the world and are associated with significant morbidity or mortality [l-51. Thus, S. pneurnoniae has remained a major cause of community-acquired pneumonia, acute otitis media and sinusitis, exacerbation of chronic bronchitis, and acute bacterial meningitis [1,3]. The mortality rate in adult patients suffering from severe pneumococcal pneumonia or meningitis may be as high as 30% [1,6]. Over recent years we have seen significant changes in the epidemiology of pneumococcal infections, such as: first, the emergence of S. pneurnoniae strains resistant to penicillin and other antimicrobials [7-131, which has complicated the treatment of such infections; second, the increasing prevalence of pneumococcal infections in specific groups of patients such as those with HIV infection and other immunosuppressive conditions [ ; and third, the advanced age of the population, since elderly people are at higher risk for pneumococcal infections [l]. Several options appear to be available to respond to this situation. First, a more appropriate and rational use of antibiotics may significantly reduce the resistance rates [17,18]. Second, the availability of the new antimicrobial agents (e.g. new quinolones) may improve the treatment options for pneumococcal infections [19-22]. Third, future vaccine developments may help in prevention strategies [23,24]. Corresponding author and reprint requests: Roman Pallares, Infectious Diseases Service, Hospital Bellvitge, L'Hospitalet, Barcelona, Spain Tel: Fax: rpg@comb.es On the basis of new discoveries in the field of immune response to pneumococcal infection and carriage, we may anticipate that the implementation of preventive strategies such as pneumococcal vaccination programs (251 (using the polysaccharide pneumococcal vaccines and/or conjugate pneumococcal vaccines and/ or protein pneumococcal vaccines) may diminish infection rates and, in the most optimistic scenario, may even 'eradicate' the pneumococcus from the nasopharynx, and, consequently prevent pneumococcal infections altogether. In this review, we shall try to provide an update on the most significant current findings of antibiotic resistance in S. pneumoniae as they bear on the treatment options of pneumococcal infections. Our remarks will be restricted to the treatment of pneumonia and meningitis, primarily in adult patients. ANTIBIOTIC RESISTANCE Over the last four decades, many strains of S. pneumoniae have become resistant to various classes of antibiotics, the only exception being vancomycin [ Resistance to tetracycline, penicillin and erythromycin, singly or in combination, appeared in S. pneurnoniue in the 1960s, and resistance to chloramphenicol and cotrimoxazole in the 1970s. Of special concern was the first description of multiresistant strains (including high-level resistance to penicillin), which were initially reported in the 1970s in South Africa [26,27]. During the 1980s and the 1990s, the pneumococcus has become resistant to cephalosporins and quinolones [13,20,22], and there has been a spread of penicillinresistant and multiresistant pneumococci all over the world [8,11,20]. Currently, the prevalence and patterns of antibiotic resistance in S. pneumoniae vary widely from one country to another, and children with otitis media tend to harbor strains with higher levels of resistance Rates of resistance to penicillin have increased in countries such as the USA [34], Canada [29], Korea [38], France [40], Hungary [28] and Spain [13](Table 4s3

2 ~~ ~~~~ 4s4 Clinical Microbiology and Infection, Volume 5 Supplement 4 l), but have remained at very low levels in Germany [41], Belgium [42], England and Wales [43]. It is important to know that when S. pneumoniae shows an increased MIC for penicillin G, it also shows increased MICs for other j3-lactams, although to hfferent degrees [ Thus, when compared with the MICs of penicdhn G, the MICs of amoxycillin and also the MICs of cephalosporins such as cefotaxime, ceftriaxone, cefpirome and cefepime are usually 1-2 dilutions smaller. The MICs of carbapenem such as imipenem or meropenem are stdl lower by 1-2 dilutions when compared to the MIC of cefotaxime. On the other hand, other cephalosporins such as ceftazidime, cefaclor and cefixime have very poor in vitro activity against penicillin-resistant strains [44]. Moreover, penicillin-resistant strains are likely to be multiresistant: they often show resistance to other antibiotics such as macrolides, tetracycline, chloramphenicol and co-trimoxazole [12,13]. To date, there are no reports of pneumococcal strains resistant to vancomycin or teicoplanin, and only a few strains have been reported to be resistant to rifampin [12]. The distribution of the serogroups/serotypes of S. pneumoniae may vary widely according to the age of the population and the geographic area [13], which may have important implications for vaccine development and vaccination strategies. However, the most frequent serogroups/serotypes classically associated with penicillin resistance and often showing multiresistance are the following: 23, 19, 14, 9 and 6. Some reports have shown that prior p-lactam antibiotic therapy may be an identifiable risk factor for the carriage stage or infection caused by penicillinresistant pneumococcal strains [17,18,47,48]. Moreover, a recent study has shown that a low daily dose and a long duration of treatment with a B-lactam antibiotic increases the risk for carriage of penicillin-resistant pneumococci [18]. One may speculate that this selective pressure exerted by the enormous (and often inappropriate) antibiotic consumption has played an important role in the rapid emergence and global spread of antibiotic-resistant pneumococci [ NEW POTENTIAL AGENTS FOR TREATING PNEUMOCOCCAL INFECTIONS The emergence of multiresistant pneumococci has stimulated research into new antimicrobial drugs, including new-generation quinolones and other compounds. Thus, although old quinolones, such as ciprofloxacin and ofloxacin, have little activity against S. pneumoniae, some of the newest agents, such as trovafloxacin, clinafloxacin, sparfloxacin and grepafloxacin, are very active compounds against both penicillinresistant and -susceptible strains [20,22,52,53]. In addition, these new quinolones have very good activity against almost all other common bacterial respiratory pathogens and may play an important role in the therapy of adult patients with severe communityacquired pneumonia [ 191. However, extensive and inappropriate use of these quinolones may also be associated with rapid emergence of resistance. Thus, nowadays, there are a few Table 1 Antibiotic resistance in Streptococcus pneumoniae MIC (mg/l) % resistance MIC9o Penicdin Intermediate High resistance Cefotaxime Intermediate High resistance Co-trimoxazole Tetracycline Chloramphenicol Erythromycin Vancomycin Ciprofloxacin Ofloxacin Spadoxacin Trovalloxacin >= o >=2.0 >=1.0 1.o > =2 > =4/76 > =4 >=8 >=1 >1 > =4 > =8 >=2 > = /76 > > Four hundred and seventy-six pneumococcal strains consecutively isolated from adult patients in Bellvitge Hospital, Barcelona (Spain) during the period The isolates were from blood (n=75), upper respiratory tract (n=359), lower respiratory tract (n= 18), cerebrospinal fluid (n=7), and other origins (n=17). Data taken from Linares et al [22]. MIC breakpoints accordmg to NCCLS [81].

3 Pallares et al: Treatment options for resistant pneumococcal infections 4s5 pneumococcal strains which are resistant to these agents (Table 1). The mechanisms of quinolone resistance in S. prieumoniae usually involve mutations in the parc gene of topoisomerase IV, which produces low-level resistance, but when it is associated with mutations in the gyra gene, then the pneumococcus may acquire high-level resistance [21,22]. It is also important to know that some of these new quinolones have been associated with adverse effects [21]. There are several other drugs that are under investigation for the treatment of pneumococcal infections. Streptogramins, such as the combination of quinupristin and dalfoprisitin (Synercid), are very active compounds against penicillin- and erythromycinresistant strains [54]. Other compounds which appear promising for the treatment of multiresistant pneumococcal infections are tricyclic p-lactams such as safetrinem, new glycopeptides, oxazolidinones, and rifabutin [54,55]. CLINICAL AND THERAPEUTIC IMPLICATIONS OF RESISTANCE In order to be clinically relevant, the in vitro definition of resistance should be associated with poor clinical outcomes. Thus the definition of breakpoints for each antimicrobial and for each microorganism is an important and difficult decision that should be made by expert committees such as the National Committee for Clinical Laboratory Standards (NCCLS). Table 2 Treatment of adult pneumococcal pneumonia Initial therapy Mild/moderate pneumonia Primary: oral amoxycillin 1 g/8 h Alternative: oral amoxycillin-clavnlanate 1 g/8 h or oral cefuroxime 750 mg/8-12 h or oral macrolide (e.g. erythromycin, clarithromycin) or IM penicillin procaine 1.2 mu/12 h Severe pneumonia Primary: i.v. ceftriaxone 1-2 g/24 h or IV cefotaxime 1-2 g/8 h or IV amoxycillin-clavulanate 2 g/8 h (2) IV erythromycin 1 g/6 h Alternative: IV cefpirome 1-2 g/12 h or IV cefepime 1-2 g/8-12 h or IV imipenem 500 mg/6 h or JV meropenem 1 g/8 h or IV vancomycin 1 g/12 h or a new quinolone (e.g. trovafloxacin or sparfloxacin) Modifications based on susceptibility studies Strains susceptible to penicillin (MICs < =0.06 mg/l) IV penicillin G 1 inu/4 h or IV ampicillin 1 g/6 h Penicillin MICs mg/l IV penicillin G 2 mu/4 h or IV ampicillin 2 g/6 h Penicillin MICs > =4.0 mg/l Based on clinical response to initial therapy and antibiotic susceptibility Dosage recommendations are approximate values for an adult patient of 6&70 kg. Table 3 Treatment of adult pneumococcal meningitis Initial therapy Primary: IV cefotaxime mg/kg per day (5-6 g/6 h) (maximum 24 g/day) (5) IV vancomycin 30 mg/kg per day (1 g/12 h) Alternative: IV vancomycin (+) IV rifampin 900 mg/24 h or IV cefotaxime (+) IV rifampin Modification when susceptibility studies are known Strains susceptible to penicillin IV penicillin G 3-4 mu/4 h Strains non-susceptible (penicillin MICs > =0.12 mg/l): Strains susceptible to cefotaxime IV cefotaxime 200 mg/kg per day (3-4 g/6 h) or IV ceftriaxone 50 mg/kg per day (4 g/24 h) Strains non-susceptible (cefotaxime MICs > = 1.O mg/l) IV cefotaxime nig/kg per day (5-6 g/6 h) (maximum 24 g/day) (2) IV vancomycin 30 mg/kg per day (1 g/12 h) or other alternative based on susceptibility studies (e.g. vancomycin (+) rifampin or meropenem or a new quinolone) Dosage recommendations are approximate values for an adult patient of kg.

4 4S6 Clinical Microbiology and Infection, Volume 5 Supplement 4 An important parameter to be considered is the therapeutic index, which is defined as the ratio of drug concentration achievable at the site of infection and the drug concentration that inhibits growth (MIC). In the case of meningitis, the relevant parameter is actually the drug concentration that lulls the bacteria (minimal bactericidal concentration, MBC), and it has been suggested that for penicillin and most other p- lactams the therapeutic index should be 10-fold or higher. Moreover, the bactericidal activity and efficacy of p-lactam antibiotics are dependent on the time for which their concentrations exceed the MIC (time > MIC), which should be at least 40-50% of the dosing interval [56]. In contrast, the efficacy of other drugs such as aminoglycosides and quinolones depends on high peak concentration and their prolonged postantibiotic effect There is convincing evidence that the emergence of pneumococcal strains with decreased susceptibility to penicillin (even those with intermediate resistance) has had a real impact on the outcome of meningitis. The levels of penicillin achieved in the cerebrospinal fluid (CSF) are close to or even lower than the MICs of intermediately penicillin-resistant strains, and this explains the number of pediatric and adult patients with meningitis who fail on penicfin therapy [54,58,62,63]. When the infection is located outside the central nervous system, such as in the case of pneumonia or bacteremia, resistance to penicillin is not associated with poor outcomes such as failure to respond to therapy or higher mortality rate [6, This can be explained by the fact that the levels of penicillin (or related p-lactams such as amoxycillin or ampicillin) achievable in serum and pulmonary tissues are several times higher than the MICs for the most common currently infecting pneumococcal strains [56]. Thus the breakpoints of penicillin for nonmeningeal strains are probably too conservative because patients with pneumococcal pneumonia having strains with a penicillin MIC <=2 mg/l respond well to penicillin therapy [6]. For the same reasons, breakpoints of cefotaxime (or ceftriaxone) for non-meningeal strains are probably also inappropriate, since, to our knowledge, no clinical failures have been reported in the case of pneumonia with an MIC of cefotaxime < =2 mg/l [6,69]. However, it is important to know that there are several other cephalosporins such as cefaclor, cefixime or ceftazidime with very poor in vitro activity against penicillin-resistant pneumococci [44], and these drugs should not be used for treating pneumococcal infections, because clinical failures have occurred [69]. In addition, resistance to non-p-lactam antibiotics has often been associated with clinical failures, and there are several reports on the failure of erythromycin, tetracycline, co-trimoxazole and ciprofloxacin in the treatment of pneumococcal pneumonia caused by resistant strains [ PNEUMONIA Patients with clinical pneumonia should be treated empirically, since laboratory testing requires at least h before the results are known. Moreover, despite extensive diagnostic testing and a presumptive clinical diagnosis, a causative agent is identified in only about 50% of all cases of pneumonia. In the current era of antibiotic resistance, at least 10 major considerations should be borne in mind when selecting initial empirical therapy for a patient with a presumptive pneumococcal pneumonia [69]. It will be important to: (1) know the local prevalence of drugresistant pneumococci; (2) evaluate whether the patient is at higher risk for colonization-infection due to drugresistant strains, as, for example, young age, day-care attendance, recent antimicrobial therapy, recent hospitalization and living in closed institutions such as nursing homes or prisons [69,72,73]; (3) think about the possibility of other common respiratory pathogens, and treat them empirically in severe pneumonia cases; (4) evaluate factors such as age, underlying conditions and severity of illness which may influence the etiology and prognosis of pneumonia; (5) rule out the possibility of concomitant pneumococcal meningitis, since the treatment options are substantially different; (6) evaluate whether the patient can benefit from hospitalization and supportive measures such as oxygen; (7) ask about the history of drug allergy; (8) think about the most appropriate dosage and route of the drug administration; (9) know the potential toxicity of the drug; and (10) consider economic costs. Therapy of presumptive pneumococcal pneumonia should be initially chosen in each patient according to the severity of the infection. Thus, we define mild/moderate pneumonia as cases in which patients fulfill the criteria of low risk [74] and may be treated as outpatients. Severe pneumonia is defined as cases in patients who are over 50 years, and who exhibit co-morbid conditions or other factors associated with increased mortality [3,4,6], and who need to be treated in hospital. Table 2 shows the suggested treatment for adult pneumococcal pneumonia. Mildhoderate pneumonia (outpatient) On the basis of the current levels of resistance, high dosage of oral amoxycillin (50 mg/kg per day) may be the therapy of choice for patients in whom the pneumococcal etiology is strongly suggested by clinical

5 Pallares et al: Treatment options for resistant pneumococcal infections 4s7 and radiological findings and, if possible, by sputum examination. However, an alternative drug may be required in some patients. Thus, oral amoxycillin-clavulanic acid (1 g/8 h) could be preferred in patients with chronic bronchitis in whom Haemophiltls infllrenzae may also be a common bacterial pathogen and is often B-lactamase positive. In patients with penicillin allergy, other drugs such as oral cefuroxime 750 mg/8-12 h (penicillinallergic patients may have cross-allergy with cephalosporins) or a macrolide such as erythromycin 500 mg/ 6 h or clarithromycin 500 mg/13 h should be considered. When the oral route is not tolerated, intramuscular procaine penicillin 1.3 mu/ 12 h may be chosen. If there is a consistent doubt between diagnosis of pneumococcal and atypical pneumonia, one may decide to prescribe a macrolide. However, one should remember that high rates of erythromycin resistance in S. prieurnoriise were reported in some countries, and that strains with erythromycin resistance also show cross-resistance to the new macrolides [66,69]. Today, the new quinolones such as trovafloxacin or sparfloxacin, which have good activity against pneumococci and atypical pathogens [19], should not be widely used in the treatment of mild/moderate pneumonia cases and probably should be reserved for severe pneumonia cases. Although co-trimoxazole has been used for the treatment of pneumonia in places in which pneumococci show low resistance rates [75], in our opinion this drug should not be widely recommended for treating pneumonia, because of the high prevalence of resistant strains (Table 1). Severe pneumonia (inpatient) As mentioned above, patients who have severe pneumonia should be hospitalized, and most of them will require parented antibiotics and other supportive measures. The initial empirical antibiotic therapy for severe pneumonia should include coverage of S. pnetlmoniae, the most common bacterium causing severe community-acquired pneumonia, and other common respiratory pathogens [3,4]. Thus, intravenous ceftriaxone 1-3 g/24 h, cefotaxime 1-3 g/8 h or amoxycillin-clavulanate 2 g/8 h could be the treatment of choice, and erythromycin 1 g/6 h should be added when Lqqionella or an atypical pathogen cannot reasonably be ruled out. Alternative drugs may include a new cephalosporin such as cefpirome or cefepime, a carbapenem such as imipenem or meropenem, a glycopeptide such as vancomycin or teicoplanin, or a new quinolone such as trovafloxacin or sparfloxacin. We think that carbapenems and glycopeptides (e.g. vancomycin) should not be widely used for the initial empirical therapy of community-acquired pneumonia. However, in specific groups of patients, such as those with cancer and AIDS in whom other fastidious organisms may be involved, the initial therapy of choice for severe pneumonia should be a drug such as cefpirome, cefepime or a carbapenem, which also have activity against Psetldomonas aeriilqitzosa. Other cephalosporins, such as cefiazidime, have little activity against penicillin-resistant pneumococci [44]. The use of some of the new quinolones such as trovafloxacin or sparfloxacin may play an important role as the initial empirical therapy in severe pneumonia cases in the near future, since they have very good activity against pneumococci and other common respiratory pathogens [19]. When the laboratory results are known, initial empirical antibiotic therapy should be switched to the narrowest-spectrum antibiotic according to the results of the susceptibility studies and the clinical response. Thus, standard dosage of penicillin G is the treatment of choice for susceptible pneumococci (MIC < =U.06 mg/l). In addition, patients infected with pneumococci with MICs for penicillin G of mg/l may respond to intravenous penicillin G or ampicillin therapy, although it would be prudent to suggest high dosage (e.g U/kg per day of penicillin G) in order to reach higher serum and pulmonary levels. However, it is not known whether patients infected with pneumococci with MICs for penicillin G of 1 mg/l or higher may be appropriately treated with penicillin, and continuation therapy should be based on the response to initial empirical therapy and the susceptibility to other drugs. Finally, some experimental studies in animals have suggested that the combination of amoxycillin and gentamicin or amoxycillin and fosfomycin may have synergistic effects against penicillin-resistant pneuniococcal pneumonia [76,77], although, to our knowledge, there are no reported clinical data with these combinations. MENINGITIS Patients with pneumococcal meningitis caused by strains with any degree of resistance (intermediate or high-level resistance) to penicillin do not respond to therapy with penicillin or ampicillin [66]. This is because intravenous penicillin achieves insufficient CSF levels to kill these pneumococcal strains [57]. Moreover, there have been several reports of cefotaxime or cefiriaxone failure in pneumococcal

6 4S8 Clinical Microbiology and Infection, Volume 5 Supplement 4 meningitis caused by cefotaxime-resistant strains [54, 631 in which most of the patients were treated with standard dosage (approximately 200 mg/kg per day). However, cefotaxime administered at higher dosage (approximately mg/kg per day, with a maximum of 24 g/day) may be effective at least for those with intermediate resistance [62]. In pedatric patients, the administration of high-dose cefotaxime may not always lead to suficient bactericidal activity in the CSF against strains with decreased susceptibility to cefotaxime [78]. Of special concern is the recent description of some pneumococcal strains with highlevel resistance to cefotaxime [79]. The administration of vancomycin at a dosage of 30mg/kg per day (the maximum dosage advised for adult patients) may not be appropriate for pneumococcal meningitis, since clinical failures have been reported [60]. These failures could be due to the highly variable concentrations of vancomycin achieved in the CSF, particularly when it is administered in association with dexamethasone [60]. In children, vancomycin can be given at higher dosage (60 mg/kg per day) and, to our knowledge, no clinical failure has been reported in pediatric pneumococcal meningitis treated with this drug. Chloramphenicol was considered to be an alternative for penicillin-resistant pneumococcal meningitis. However, it has been shown that several penicillinresistant pneumococci are also resistant to chloramphenicol [12]. In addition, unsatisfactory results with chloramphenicol were observed in chloramphenicolsusceptible and penicillin-resistant pneumococcal meningitis [80]. These failures were related to poor bactericidal activity of chloramphenicol (increased MBCs) in penicillin-resistant strains when compared with penicillin-susceptible strains [80]. Antibiotic therapy for patients with pneumococcal meningitis must not be penicillin until the strain is known to be fully susceptible. Most of the recommended regimens are mainly based on susceptibility to cephalosporins. Results from experimental meningitis studies may help us to find better alternatives for the treatment of resistant pneumococcal meningitis. Table 3 shows the suggested treatment for adult pneumococcal meningitis. Initial empirical therapy The initial empirical therapy for adult patients with pneumococcal meningitis (a purulent meningitis and a CSF Gram stain showing typical Gram-positive diplococci) should be a regimen including highdose cefotaxime ( mg/kg per day, maximum 24 g/day) with or without vancomycin (30 mg/kg per day) [62,66]. We think that it would be prudent to suggest the combination of high-dose cefotaxime and vancomycin in places in which high-level cefotaxime resistance (MICs >=2 mg/l) has been observed. This combination is supported by the results of some experimental meningitis studies in which the combination of cephalosporin plus vancomycin was synergistic and more effective than either drug alone [63]. However, it is important to know that vancomycin (at the recommended dosage for adults) may achieve insufficient CSF levels [60], and, therefore, combination with high-dose cefotaxime may be necessary. Vancomycin should be discontinued when laboratory results are known and the pneumococcal strain is susceptible to penicilhn or cephalosporins. Alternative regimens for initial empirical therapy include the combination of vancomycin and rifampin (900 mg/24 h), or the combination of cefotaxime and rifampin [66]. Rifampin should not be used as monotherapy, because of the rapid development of resistance. Therapy for known pneumococcal meningitis When laboratory results are known, any modification of the initial therapy should be based on antibiotic susceptibility and clinical status of the patient or the results of a control lumbar puncture. Most authorities recommend a second lumbar puncture in all patients with antibiotic-resistant pneumococcal meningitis. Thus, standard dosage of intravenous penicillin G remains the therapy of choice for patients having susceptible strains, and alternative drugs are only necessary in allergic patients (e.g. ceftriaxone or chloramphenicol or vancomycin plus rifampin). In contrast, penicillin G must not be administered to patients having strains with penicillin MICs >= 0.12 mg/l. In such patients, the antibiotic therapy should be selected according to susceptibility to cephalosporins. Thus, standard dosage of intravenous cefotaxime (200 mg/kg per day) or ceftriaxone (50 mg/kg per day, maximum 4 g/day) may be given to patients with strains susceptible to these cephalosporins [66]. For patients with strains showing intermediate resistance to cefotaxime, therapy with high-dose cefotaxime may be appropriate, and for patients with strains showing MICs of cefotaxime > =2 mg/l it would be prudent to continue the initial therapy (e.g. high-dose cefotaxime plus vancomycin) if the clinical evolution and the results of a control lumbar puncture are favorable. Any alternative therapy for cephalosporin-resistant pneumococcal meningitis is complicated and should be based on the results of susceptibility tests. Some available alternatives may be the combination of vanco-

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