Impact of Antibiotic Resistance on Chemotherapy for Pneumococcal Infections

Over the past three decades, penicillin-resistant pneumococci have emerged worldwide. In addition, penicillinresistant strains have also decreased susceptibility to other /Mactams (including cephalosporins) and these strains are often resistant to other antibiotic groups, making the treatment options much more difficult. Nevertheless, the present in vitro definitions of resistance to penicillin and cephalosporins in pneumococci could not be appropriated for all types of pneumococcal infections. Thus, current levels of resistance to penicillin and cephalosporin seem to have little, if any, clinical relevance in nonmeningeal infections {e.g., pneumonia or bacteremia). On the contrary, numerous clinical failures have been reported in patients with pneumococcal meningitis caused by strains with MICs S 0.12 fig/ml, and penicillin should never be used in pneumococcal meningitis except when the strain is known to be fully susceptible to this drug. Today, therapy for pneumococcal meningitis should mainly be selected on the basis of susceptibility to cephalosporins, and most patients may currently be treated with high-dose cefotaxime (±) vancomycin, depending on the levels of resistance in the patient's geographic area. In this review, we present a practical approach, based on current levels of antibiotic resistance, for treating the most prevalent pneumococcal infections. However, it should be emphasized that the most appropriate antibiotic therapy for infections caused by resistant pneumococci remains controversial, and comparative, randomized studies are urgently needed to clarify the best antibiotic therapy for these infections.

pneumococcal strains have the ability to spread rapidly through- out the world.For example, the Spanish clone 23F and 6B have been disseminated to other countries in Europe and to other continents.69,82   The mechanism of resistance of pneumococci to penicillin is due to alterations of the penicillin binding proteins (PBPs) that have reduced their affinity for penicillin and related /3-lactams. 48,64,85,86Therefore, susceptibility to other /3-lactams is also affected and the minimal inhibitory concentrations (MICs) of these drugs rise in parallel with those of penicillin G, al- though with different degrees depending on the drug59, 67,76,83   (Table 1).Cefotaxime, ceftriaxone, cefpirome, and cefepime are the parenteral cephalosporins that yield the lowest MICs against penicillin-resistant strains.The MICs of carbapenems are smaller than those of cephalosporins.Thus, imipenem is highly active against penicillin-resistant strains, but meropenem is slightly less active in vitro than imipenem.Amongst oral ß- lactams, amoxicillin yields the lowest MICs against penicillinresistant pneumococci, and cefuroxime and cefpodoxime are the oral cephalosporins that yield the lowest MICs, although these are several times higher than those of amoxicillin.In ad- dition, penicillin-resistant strains are more likely to be resistant to other antibiotic groups such as erythromycin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole.17,54,61However, the newest quinolones (e.g., trovafloxacin, spar- floxacin, grepafloxacin) seem to be very active compounds against penicillin-resistant and -susceptible strains.The current in vitro definition of penicillin resistance by S. pneumoniae (National Committee for Clinical Laboratory Stan- dards, NCCLS 1995) is as follows: susceptible strains (MIC S 0.06 pg/ml of penicillin G), intermediate resistance (MIC 0.12-1.0pg/ml of penicillin G), and high-level resistance (MIC a: 2.0 pg/ml of penicillin G).However, the laboratory definition of resistance to penicillin was established before the clinical relevance of this level of resistance had been determined.In other words, the current in vitro definitions of peni- MIC-50/MIC-90 aData from the Microbiology Laboratory (1990)(1991)(1992)(1993)(1994)(1995), Bellvitge Hospital, Barcelona.•The ratio of trimethoprim-sulfamethoxazole is 1/19.
cillin resistance are open to question, particularly for those pneumococcal strains causing nonmeningeal infections.Although no prospective, randomized studies on the therapy of resistant pneumococcal infections have been carried out, the published data suggest that moderate penicillin-resistant pneumococci causing nonmeningeal infections such as pneumonia or bac- teremia have no therapeutic significance.11,31,33,55,74,75,80,84,91   This is because the serum concentrations achieved with penicillin or related ß-lactams are several times higher than the MICs of the strains.4On the other hand, however, pneumo- coccal meningitis poses a special therapeutic problem because of the levels of penicillin achieved in the cerebrospinal fluid (CSF) are inadequate to kill penicillin-resistant pneumococci including those with intermediate resistance,43 and several clin- ical failures have been reported.19,34,36,78   The management of pneumococcal infections caused by re- sistant strains has been debated in recent reviews,19'34,36,61'78 but several important questions remain to be answered.The most im- portant considerations in selecting empirical antibiotic therapy in patients with a suspected pneumococcal infection are the fol- lowing: prevalence and patterns of resistance in the patient's ge- ographic area; site of infection (e.g., meningitis); risk factors for penicillin-resistant strains (e.g., prior antibiotic use, young age, day-care attendance, prior hospitalization, nosocomial infec- tion)16,63,73,74; severity of illness and probability of death; route of drug administration; and potential toxicity and costs.
In this review, we will discuss the treatment of the most prevalent pneumococcal infections, focusing principally on adult patients.The regimens proposed herein are based on the current levels of resistance, but these recommendations may change in the near future.

THERAPY FOR PNEUMONIA
There are several reports dealing with the response to /3-lac- tam antibiotic therapy in penicillin-resistant pneumococcal pneumonia or bacteremia .11,31,33,55,74,75,80,84,91Friedland and Klugman33 carried out a prospective study of community-acquired pneumococcal infections in 207 South African children, most of them were treated with penicillin or ampicillin at a standard dosage.They found that the mortality rate was 14% in children with penicillin-resistant pneumococcal in- fections and 11% in children with penicillin-susceptible infection.
Tan and colleagues84 reported their experience during a 3- year period in Houston.All but 1 of 19 children with systemic infections caused by intermediate penicillin-resistant pneumo- cocci responded adequately to initial /3-lactam therapy (mostly amoxicillin or cefuroxime).
Friedland31 reported a series of 108 children with bacteremic pneumococcal infections, excluding meningitis.In children with pneumonia who were treated with ampicillin or an equivalent /3-lactam agent, 88% with penicillin-resistant infections and 93% with penicillin-susceptible infections had improved by day 7 of therapy.
Recently, we conducted a prospective nonintervention study with 504 adult patients with severe pneumococcal pneumonia; 29% of them were infected with penicillin-resistant strains. 75lthough the mortality rate was significantly higher in penicillin-resistant than in penicillin-susceptible cases (38% vs. 24%), after adjustment for other variables, the odds ratio for mortality in patients with penicillin-resistant strains was not sta- tistically significant.Moreover, when we compared the mor- tality rate in patients treated with penicillin or ampicillin, there were no statistically significant differences between patients in- fected with penicillin-resistant and those infected with penicillin-susceptible strains.Likewise, among patients treated with cefotaxime or ceftriaxone, the mortality rate was not significantly different in those infected with cephalosporin-resistant strains when compared with those infected with cephalosporinsusceptible strains.Our conclusion was that current levels of resistance to penicillin and cephalosporins are not associated with increased mortality in patients with severe pneumococcal pneumonia.Thus, these antibiotics can still be used as the ther- apy of choice for this disease.75 We suggest the following antibiotic therapy for communityacquired pneumococcal pneumonia (Table 2).

Initial empirical therapy
This refers to the treatment for a patient with a clinical picture and radiologie findings highly suggestive of pneumococ- cal pneumonia before the culture results are known.It should be emphasized that in patients with clinical suspicion of pneu- mococcal pneumonia, the diagnosis may be strongly reinforced by demonstrating polymorphonuclear leukocytes (PMNs) and Gram-positive cocci in pairs in the sputum.71However, some- times the clinical picture is not clear enough and the infection may be caused by other pathogens.This possibility should be taken into account in selecting empirical therapy, particularly when the patient has severe pneumonia.Empirical therapy for pneumococcal pneumonia should be classified according to the severity of the infection (Table 2).
Mild-to-moderate pneumonia.Mild-to-moderate pneumonia should be considered in a patient who is less than 65 years old and has no co-morbid conditions; in these cases, an outpatient treatment can be prescribed.
Amoxicillin may be the therapy of choice for patients with mild/moderate pneumonia in whom a characteristic clinical picture of pneumococcal pneumonia is present.However, amoxi- cillin-clavulanate may be preferred in some patients such as those with chronic obstructive pulmonary disease (COPD) in whom the causative organisms may be S. pneumoniae or other common pathogens such as Haemophilus influenzae (often ß- lactamase positive).
Alternative drugs such as cefuroxime, erythromycin, or penicillin procaine should be selected according to the history of allergy or when the oral route is not well tolerated.
In patients in whom, after a careful clinical evaluation, his/her physician has doubts about the diagnosis of pneumo- coccal pneumonia versus atypical pneumonia, a macrolide (e.g., erythromycin) should be given.However, it is important to know that if the causative organisms is a pneumococcus resis- tant to erythromycin the patient may not respond to this ther- apy.68 Severe pneumonia.Patients with severe community-acquired pneumonia should be hospitalized, and the criteria for severe pneumonia includes (one or more): age > 65 years; serious un- derlying conditions (e.g., COPD, diabetes, malignancies, heart failure, chronic renal failure, splenectomy, cirrhosis, or chronic erythromycin 500 mg/6 hr or i.m. penicillin procaine 1.2 mU/12 hr Severe pneumonia Primary i.v.ceftriaxone 1-2 g/24 hr or i.v.cefotaxime 1-2 g/8 hr or i.v.amoxicillin-clavulanate 2 g/8 hr (+/-) i.v.erythromycin 1 g/6 hr Alternative i.v.cefpirome 1-2 g/12 hr or i.v.cefepime 1-2 g/8-12 hr or i.v.imipenem 500 mg/ 6 hr or i.v.meropenem 1 g/8 hr or i.v.vancomycin 1 g/12 hr (+/-) i.v.erythromycin 1 g/6 hr or a new quinoline 2. TheraDV when in vitro studies are known (severe Dneumonia) i.m., Intramuscular; i.V., intravenous; MICs, minimal inhibitory concentrations.Dosage recommendations are approximate values for an adult patient of 60-70 kg.
Dosage and intervals can be different in infants and children and should be calculated according to their age and specific conditions.In addition, pédiatrie patients may have pathogens causing pneumonia different than those in adults and thus it should be considered in selecting empirical antibiotic therapy.
Primary therapy is the treatment of choice suggested.
Alternative therapy should be selected according to (i) the patterns of antibiotic resistance in the patient's geographic area or when the culture results are known should be based on the in vitro susceptibility studies; (ii) history of allergy; (iii) toxicity; and (iv) costs.alcoholism); previous pneumonia <1 year ago; altered mental status; respiration rate > 30/min; blood pressure <90/60; tem- perature >10PF; WBC <4000 or >30,000/mm3; Pa02 <60 mmHg (<90% O2 saturation); PaCÛ2 >50; needs mechanical ventilation; chest X-ray >1 lobe; pleural effusion; Hct <30; sepsis; and extrapulmonary disease (e.g., meningitis).One im- Susceptible strains to penicillin (MICs <0.06 pg/ml) Primary i.v.penicillin G 1 mU/4 hr or i.v.ampicillin 1 g/6hr Alternative i.v.cefuroxime 1.5 g/8 hr or i.v.ceftriaxone 1 g/24 hr or i.v.cefotaxime 1 g/8 hr or i.v.erythromycin 1 g/6 hr Strains with decreased susceptibility to penicillin penicillin MICs 0.12 to 2.0 pg/ml Primary i.v.penicillin G 2 mU/4 hr or i.v.ampicillin 2g/6hr Alternative i.v.ceftriaxone 1-2 g/24 hr or i.v.cefotaxime 1-2 g/8 hr or i.v.erythromycin 1 g/6hr Penicillin MICs &4.0 pg/ml Primary Continue with the initial empirical therapy if the clinical response is satisfactory Alternative i.v.imipenem 500 mg/6 hr or i.v.meropenem 1 g/8 hr or i.v.erythromycin 1 g/6 hr or i.v.vancomycin 1 g/12 hr or a new quinoline portant clinical consideration is that in a patient with severe pneumococcal pneumonia, the possibility of having associated meningitis should be evaluated carefully because the treatment options are substantially different (see treatment of meningitis).
To treat pneumococci and other common bacteria (e.g., H. influenzae or other Gram-negative bacilli), the initial empirical therapy for severe pneumonia should include an appropriate cephalosporin or amoxicillin-clavulanate (Table 2).Addition- ally, erythromycin should be added in cases in which Legionella or another atypical pathogen cannot reasonably be ruled out.
In patients with severe underlying diseases (e.g., neutropenic patients) in whom some fastidious organisms such as Pseudomonas also needs to be treated, the combination of cef- pirome or cefepime or imipenem or meropenem with erythromycin should be considered.It is important to know that ceftazidime has little activity against penicillin-resistant pneu- mococci (Table 1).
There is little experience in treating patients with pneu- mococcal pneumonia with vancomycin alone and this drug has no activity against other pathogens such as Gram-negative bacilli.Thus, when vancomycin is selected for empirical therapy of severe pneumonia (e.g., allergy to /3-lactams or in places in which a very high level cephalosporin resis- tance has been detected) a combination with other drugs (e.g., aztreonam or ciprofloxacin) should be considered.Serum vancomycin levels should be monitored in these patients.In our opinion, and based on the current levels of antibiotic-re- sistant pneumococci, vancomycin should not be widely used for treating pneumonia.
The newest quinolones (e.g., trovafloxacin, sparfloxacin, grepafloxacin) may play an important role in the empirical treat- ment of severe pneumonia cases in the near future.

Therapy for known pneumococcal pneumonia
When culture results (e.g., positive cultures from blood, pleural fluid, or a lower respiratory tract specimen) and in vitro studies are known, any change in antibiotic therapy should be based on the results of susceptibility tests and on the light of clinical evolution of the patient.
Penicillin or ampicillin (at standard dosage) remains the ther- apy of choice for susceptible strains.Alternative drugs (see Table 2) may be necessary in penicillin-allergic patients.
Patients infected with strains having penicillin MICs of 0.12-2.0pglml may respond to penicillin or ampicillin ther- apy, although the administration of high dose (for example, 150,000-200,000 U/kg per day of penicillin G) would be pru- dent to achieve higher serum and pulmonary levels of the drug.
It is not well known whether patients infected with strains for which penicillin MIC s 4 pglml could respond to intra- venous (i.v.) penicillin therapy.In these patients, consecutive therapy should be based on the response to the initial empirical therapy and the results of the in vitro studies.In the case that the patient is doing well with a cephalosporin or amoxi- cillin-clavulanate, this therapy should be continued.On the con- trary, if the clinical response is not satisfactory, other drugs such as imipenem, meropenem, erythromycin, vancomycin, or a new quinoline should be considered according to the results of the in vitro studies.

THERAPY FOR MENINGITIS
Response to therapy in penicillin-resistant and cephalosporin-resistant pneumococcal meningitis is different to that in nonmeningeal infections.We believe that clinicians should have in mind some important considerations when selecting antibi- otic therapy for pneumococcal meningitis: (i) There have been numerous case reports of failure of penicillin therapy in patients with pneumococcal meningitis caused by intermediate or high-level penicillin-resistant strains. 1,6,22,24,27,38,46,47,62,72,77,79,92Thus, because penicillin-resistant strains are spread worldwide, the initial therapy for pneu- mococcal meningitis should not be penicillin or ampicillin.
(ii) Several patients with pneumococcal meningitis infected with strains showing decreased susceptibility to cephalosporins failed cefotaxime or ceftriaxone treatment.3,8,9,18,23,51,53,58,81In most of them, cefotaxime or ceftriaxone were administered at the standard dosage for meningitis.iii) Vancomycin could be a good alternative for pneumo- coccal meningitis caused by penicillin-and cephalosporin-resistant strains.Nevertheless, the administration of vancomycin at 30 mg/kg per day (the dosage recommended for adult pa- tients) was associated with several failures in adult pneumo- coccal meningitis.89These failures could be due to the highly variable concentrations of vancomycin achieved in the CSF, es- pecially when dexamethasone was given concomitantly.How- ever, we are unaware of any reported vancomycin failure in pneumococcal meningitis in pédiatrie patients in whom van- comycin is administered at higher dosages (60 mg/kg per day).56 (iv) In penicillin-resistant pneumococcal meningitis, chlor- amphenicol treatment may not be appropriated.Several penicillin-resistant pneumococci are also resistant to chlo- ramphenicol.In addition, unsatisfactory results with chlo- ramphenicol (despite the strains that were susceptible to this drug based on the MICs) in penicillin-resistant pneumococ- cal meningitis have been reported.32These failures could be due to a poor bactericidal activity of chloramphenicol in such strains.32 We suggest the following antibiotic therapy for pneumo- coccal meningitis (Table 3).

Initial empirical therapy
This terminology refers to the initial treatment for a patient with pneumococcal meningitis (a purulent meningitis and a CSF Gram stain showing typical Gram-positive diplococci).How- ever, in cases with purulent meningitis and a CSF Gram stain showing no microorganisms, several possible pathogens should be considered in selecting the initial therapy, depending on the clinical suspicion in each case.
These suggested antibiotic regimens are for treating patients with pneumococcal meningitis in regions in which penicillinresistant pneumococci are reported.Dosage recommendations are approximate values for an adult patient of 60-70 kg.
Dosage and intervals can be different in infants and children, and should be calculated according to their age and specific conditions.In addition, pédiatrie patients may have pathogens causing meningitis different from those in adults and thus it should be considered in selecting empirical antibiotic therapy, particularly in cases of purulent meningitis with no microor- ganisms in the CSF Gram stain.
Primary therapy is the treatment of choice suggested.Alternative therapy should be selected according to (i) the patterns of antibiotic resistance in the patient's geographic area or when the culture results are known should be based on the in vitro susceptibility studies; (ii) the pharmacokinetics of the drugs; (iii) history of allergy; (iv) toxicity; and (v) costs.cefpirome appear to be promising for resistant pneumococcal meningitis.
In places where high-level cephalosporin resistance (MICs of cefotaxime >2 /xg/ml) has been detected, cefotaxime may be administered in combination with vancomycin.However, it is important to have in mind some considerations regarding this combination: (i) some studies of animals with cephalosporinresistant meningitis have suggested that the combination of cephalosporin and vancomycin is more effective than either drug alone,35 however, to our knowledge little clinical experi- ence with this combination has been published56; (ii) even if the combination is given, in adult patients cefotaxime should be administered at a high-dosage regimen because vancomycin (at the recommended dosage) may achieve insufficient CSF lev- els89; (iii) by contrast, in children in whom vancomycin may be administered at higher dose and this drug alone may be ef- fective for pneumococcal meningitis, the concomitant admin- istration of high-dose cefotaxime might be less important than in adults, and the standard dose of cefotaxime or ceftriaxone might be enough; (iv) vancomycin should be discontinued when in vitro studies are known and the pneumococcus is susceptible to penicillin or cephalosporins.
An alternative regimen for the empirical therapy may be van- comycin with or without rifampin.Vancomycin alone may be appropriate for pédiatrie patients.However, in adults the com- bination of vancomycin and rifampin may be more appropriate (see comments on vancomycin dosage and levels above).
The combination of cefotaxime or ceftriaxone and rifampin appeared to be promising.However, some in vitro studies in the laboratory have shown an antagonistic effect between ri- fampin and ß-lactams, although this has not been confirmed in animal studies.87To date, the relevance of this phenomenon in clinical practice is not well known, although some data in chil- dren with meningitis have suggested that this combination may enhance CSF bactericidal activity compared with that of cef- Primary Oral amoxicillin  mg/kg per day (1 g/6-8 hr) or oral amoxicillin-clavulanate 1 g/8 hr Alternative Oral cefuroxime 750 mg/8-12 hr or i.m. ceftriaxone 1 g/24 hr or oral erythromycin 500 mg/6 hr or oral clarithromycin 500 mg/12 hr or oral azithromycin 1 g/24 hr or oral TMP-SMZ 160/800 mg/12 hr i.m., Intramuscular; TMP-SMZ, trimethoprim-sulfamethoxazole.
Dosage recommendations are approximate values for adult patients.Doses/intervals in parenthesis are those recommended for an adult patient of 60-70 kg.
Dosage and intervals can be different in infants and children, and should be calculated according to their age and specific conditions.
Primary therapy is the treatment of choice suggested.Alternative therapy should be selected according to (i) the patterns of antibiotic resistance in the patient's geographic area or if the culture results are known should be based on the in vitro susceptibility studies; (ii) history of allergy; (iii) toxicity; and (iv) costs.triaxone alone.56Rifampin cannot be used as monotherapy be- cause of the rapid development of resistance.

Therapy for known pneumococcal meningitis
When culture results (positive CSF and/or blood cultures) and in vitro studies are known, any change in antibiotic ther- apy should be based on the results of susceptibility tests and on the light of clinical evolution of the patient.A control lumbar puncture should be performed 24-36 hr after the start of an- tibiotic therapy in all patients with resistant pneumococcal meningitis.
Penicillin remains the therapy of choice for susceptible strains, and alternative drugs are only necessary in penicillin al- lergic patients.
Patients infected with strains with decreased susceptibility to penicillin (MICs a 0.12 pglml) should not be treated with penicillin.In such cases, cefotaxime or ceftriaxone, using the stan- dard dose for meningitis, may be the therapy of choice for those with MICs of cefotaxime s 0.25 pg/ml.
Based on the concept that to kill a pathogen the antibiotic concentration in CSF should exceed by 8-to 10-fold the min- imal bactericidal concentration (MBC) of the drug, it may be prudent to suggest high-dose cefotaxime for those cases with MICs of cefotaxime 0.5-1.0pg/ml.This is because the cefo- taxime MBC may be one dilution higher than the cefotaxime MIC, and clinical failures have been reported in patients in- fected with strains having cefotaxime MICs as small as 0.5 pg/ml who were treated with standard dose of cefotaxime or ceftriaxone.3,8,9,18,23'51,53,58,81Ceftriaxone administered at a dose higher than 4 g/day is not recommended because of po- tential side effects (e.g., biliary stones).To date, there is no ex- perience with other drugs such as cefpirome or cefepime.
Up to now, several failures have been reported in cephalosporin-resistant pneumococcal meningitis (MICs of ce- fotaxime > 2 pg/ml) using standard dose of cefotaxime or cef- triaxone.88However, there are some reported cases with MICs of cefotaxime of 2 pg/ml that were cured with high-dose ce- fotaxime.2,88,90In cases in which the pneumococcus has an MIC of cefotaxime s 2 pg/ml and the patient is doing well with the initial empirical therapy (e.g., high-dose cefotaxime with or without vancomycin), this therapy should be continued.On the other hand, if the patient has no good clinical response, an al- ternative therapy should be considered in the light of the results of a second lumbar puncture.These regimens may include van- comycin with or without rifampin (or intrathecal vancomycin) or alternatively meropenem or imipenem or chloramphenicol (based on in vitro studies), or perhaps new compounds (e.g., clinafloxacin).
The MICs of meropenem may be smaller than those of ce- fotaxime in cephalosporin-resistant strains, but the doses rec- ommended and the CSF levels achieved appear not to be very promising.25Although imipenem may have MICs smaller than those of meropenem and some patients with meningitis have been cured with this drug, the potential risk of seizures should be taken into account.In addition, meropenem and imipenem may produce hypersensitivity reactions in /31actam-allergic patients.In the case that chloramphenicol is se- lected as an alternative therapy, MBCs determinations should be performed.32THERAPY FOR OTITIS MEDIA AND SINUSITIS Acute otitis media and acute sinusitis are most commonly caused by S. pneumoniae, H. influenzae, or Moraxella ca- tarrhalis.15,26'40'44,49 In acute otitis media, response to antibi- otic therapy is often difficult to interpret due to a high rate of spontaneous resolution.15,34  Some case reports of "standard dose" amoxicillin treatment, failure have been reported in pneumococcal otitis media, par- ticularly in cases with high-level penicillin resistance. 19,34,49owever, it has been suggested that the administration of high doses of amoxicillin might be effective at least in those cases with intermediate penicillin resistance.19Because in most cases microbiological cultures are not avail- able, empirical antibiotic therapy should be selected to treat the most important microorganisms.It is important to know the prevalence of pneumococci resistant to penicillin and other an- tibiotics, as well as the prevalence of strains of H. influenzae and M. catarrhalis producing /3-lactamase in the patient's ge- ographic area.
As shown in Table 4, the treatment of choice for acute oti- tis media and acute sinusitis may be amoxicillin.In regions in which penicillin-resistant pneumococci is prevalent, the ad- ministration of high-dose amoxicillin may be prudent.In places with a high percentage of H. influenzaea and M. catarrhalis producing /3-lactamase, amoxicillin-clavulanate or cefuroxime may be preferred.
Because of the low penetration of the antibiotics in the mid- dle ear, otitis media caused by high-level penicillin-resistant pneumococci may not respond to standard doses of amoxicillin or amoxicilli-clavulanate.34If a patient with acute otitis media has a clinical failure after 48 hr of amoxicillin-clavulanate, amoxicillin at 30-40 mg/kg per day may be added to obtain higher amoxicillin dose (total 80 mg/kg per day) while not in- creasing the total clavulanate dose.19Other alternative drugs (e.g., ceftriaxone, macrolide, or TMP-SMZ) may also be con- sidered.Tympanocentesis may be required in patients who do not respond to therapy and this technique would allow the iden- tification of the causative organism and susceptibility studies.

Table 1 .
In Vitro Activity of Several Antibiotics in 952 Penicillin-Resistant Streptococcus pneumoniae3

Table 4 .
Suggested Antibiotic Regimens for Otitis Media and Sinusitis