P&T News: September 1996, Vol. 17, No. 3

Treatment Options for Penicillin-Resistant Streptococcus pneumoniae

Julie A. Peroutka, Pharm.D.
Peer Review Status: Internally Peer Reviewed by David J. Kusner, M.D., Ph.D., Assistant Professor, Division of Infectious Diseases, Department of Intemal Medicine and Ronald N. Jones, M.D., Director, Medical Microbiology Division, Department of Pathology

Penicillin interacts with penicillin-binding proteins of the bacterial cell wall, as do all beta-lactam antibiotics. This interaction inhibits bacterial cell wall synthesis, eventually causing the bacteria to lyse. Changes in these penicillin-binding proteins result in decreased susceptibility of the bacterium to all antimicrobials which act by this mechanism.8 Because penicillin-resistance in pneumococci is not dependent on the production of beta-lactamase, the addition of beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam) does not improve susceptibility.2 Pneumococcal resistance to penicillin may occur either on its own or in combination with resistance to other antimicrobial agents. Multidrug resistance has been described as resistance to antimicrobials of at least three different groups.4

The development of resistant strains has primarily been due to selective pressure exerted by the overuse of antimicrobials.27 In addition, successive genetic mutations have resulted in gradually increasing resistance.28 Resistant strains have been easily transported to geographically distant areas and now represent a worldwide problem.4 Resistant strains isolated from nasopharyngeal secretions are commonly spread, especially in children.28 This type of spread has led to cases of persistent pneumococcal-resistant otitis media in day-care centers.2

According to the National Committee for Clinical Laboratory Standards (NCCLS), strains of pneumococci with a minimum inhibitory concentration (MIC) to penicillin of < 0.06 mcg/ml are considered fully susceptible, an MIC of 0.12 to 1 mcg/ml is defined as intermediate susceptibility, and strains with an MIC 2 or more mcg/ml are considered highly or fully resistant. 2,4-6,13 This distinction becomes important when determining treatment options. Penicillin-resistant pneumococci, particularly highly-resistant strains, are also often resistant to non-beta-lactam antibiotics, including erythromycin, tetracycline, and trimethoprim/sulfamethoxazole.1,3 For cephalosporins (cefotaxime, ceftriaxone), strains with an MIC < 0.5 mcg/ml are considered fully susceptible, an MIC of 1 mcg/ml is regarded as having an intermediate susceptibility, and strains with an MIC 2 or more mcg/ml are defined as resistant.2,4-6,13 These latter interpretations are based on therapy for infections of the central nervous system (meningitis) only. The NCCLS's interpretative standards are outlined in Table 1.

Table 1. Minimum Inhibitory Concentration (MIC) (mcg/ml) Interpretive Standards for Streptococus pneumoniae*
ANTIMICROBIAL AGENT	SUSCEPTIBLE	INTERMEDIATE	RESISTANT
Penicillin#	0.006 or less	0.1 - 1	2 or less
Cefotaxime Ceftriaxone	0.5 or less	1	2 or less
Vancomycin	1 or less	----	----
Erythromycin	0.5 or less	1 - 2	4 or less
Ofloxacin	2 or less	4	8 or less
Trimethoprim/sulfamethoxazole	0.5/9.5 or less	1/19 - 2/38	4.76 or less
Imipenem-cilastatin	0.12 or less	0.25 - 0.5	1 or less
Rifampin	1 or less	2	4 or less
Chloramphenicol	4 or less	----	8 or less
Azithromycin or Clarithromycin	0.5 or less	1	2 or less
*Adapted from the National Committee for Clinical Laboratory Standards #A pneumococcal isolate that is susceptible to penicillin can be considered susceptible to anoxicillin, amoxicillin/clavulanate, ampicillin, ampicillin/sulbactam

Treatment
Treatment of resistant pneumococcal infections is complicated by numerous factors. These factors include the delayed recognition of the presence and degree of resistance of infecting strains, the variability of drug levels at different sites of infection, the natural history of disease at different sites and among different age groups, the stage of infection at which empiric therapy should be initiated, and the presence of underlying conditions such as malnutrition, immunodeficiency, or malignancy, which predispose the patient to pneumococcal infections.' To select appropriate antimicrobial agents for empiric treatment of patients with a pneumococcal infection, clinicians need data on the prevalence of drug resistant S, pneumoniae (DRSP) specific to their community. Until culture and sensitivity data are known, if the incidence of DRSP is high and the patient has a life threatening infection, combination therapy or alternative agents to penicillin should be considered. In communities known to have low levels of pneumococci-resistance, empiric use of alternative agents, such as vancomycin, should be avoided, thereby reducing the overuse of this agent. Because rapid increases in resistance patterns have occurred, empiric therapy must be based on the most recent data available.

Because an increase in the incidence of pneumococcal infection cases per month has been observed at the UIHC, along with an increased rate of resistance, various treatment options for pneumococcal infections will be discussed.

Meningitis
Penicillin-resistant pneumococcal infections of the central nervous system (CNS) are especially difficult to treat due to the limited penetration of the drug into the CNS. There have been numerous case reports of penicillin treatment failure in both adults and children. Larger doses of penicillin (500,000 units/kg/day) have been utilized in an attempt to increase the penicillin concentration at the site of infection, and thus overcome the resistance; however, this too has often led to clinical failures.2,9 Unfortunately, alternative agents commonly prescribed for empiric therapy also may now be ineffective due to the development of drug resistance.2

Cephalosporins
Cefotaxime or ceftriaxone is the preferred agent for initial empiric therapy for suspected pneumococcal meningitis until culture and susceptibility results are returned.1,2,8,9 It has been suggested that meningitis caused by strains for which the cephalosporin MIC was < I mcg/ml (intermediate susceptibility) may be treated adequately with one of these extended spectrum cephalosporins; however, there have been reports of patients poorly responding to therapy when the MIC was 0.5 to 1 mcg/ml.2,9 Pneumococcal strains with a cephalosporin MIC of 2 or more mcg/ml are defined as resistant and cephalosporin therapy should not be used alone. Due to a lack of studies, it is unknown whether increasing the dose of the cephalosporin will result in high enough cerebral spinal fluid (CSF) concentrations to overcome resistance. 9

Vancomycin
Vancomycin is the recommended therapy for meningitis due to penicillin-resistant pneumococci.10 Central nervous system concentrations of vancomycin are highly variable and the penetration into the CSF is dependent on the degree of meningeal inflammation. The highly variable drug levels of vancomycin in the CSF may be part of the cause of vancomycin treatment failures.9 Vancomycin therapy should be reserved for cases of high-level penicillin resistance. The effectiveness of intrathecally administered vancomycin for pneumococcal meningitis is not clearly delineated.9 Rifampin has been administered with vancomycin for patients who have failed cephalosporin therapy.9 In vitro, the addition of rifampin did not show either a synergistic or an antagonistic effect,9 although tests with UIHC strains observed antagonism. There have recently been reports of rifampin-resistant S. pneumoniae strains.2,9

Chloramphenicol
The addition of chloramphenicol has been recommended as part of the initial therapy of bacterial meningitis because it can easily achieve concentrations in the CSF that exceed the MICs for penicillin- resistant isolates. Although resistance to chloramphenicol is uncommon, its bactericidal activity against many penicillin-resistant strains is poor.2,8,9 Due to insufficient bactericidal activity in the CNS, poor clinical efficacy has been reported. The minimum bactericidal concentration (MBC) of chloramphenicol for penicillin-resistant isolates should be determined before initiating chloramphenicol therapy.2,9

Other Agents
Imipenem-cilastatin has been used successfully in patients with penicillin- and cephalosporin- resistant pneumococcal meningitis.9 Imipenem-cilastatin has the potential risk of causing drug- related seizures, therefore caution must be used when treating patients with meningitis.2,9

Combination Therapy
Many different antibiotic combinations have been tried in patients who have failed initial therapy for pneumococcal meningitis. Currently, there are no comparative clinical data on combination therapy. It appears, however, that cefotaxime or ceftriaxone in combination with vancomycin may have synergistic activity.9

Summary
Initial empiric therapy for bacterial meningitis should be based on the possibility that a penicillin- resistant pneumococci may be the etiology of the patient's illness. Therapy should be initiated with cefotaxime or ceftriaxone. Vancomycin, despite uncertainty about sustained drug levels in the CSF, should be considered for patients with a cephalosporin allergy or those patients not responding to the extended-spectrum cephalosporin alone. It is important to closely monitor patients for response to therapy. Repeated culture of the CSF 24 to 36 hours after the start of therapy is recommended if a patient has a penicillin-resistant pneumococcal meningitis. Alteration of the initial antimicrobial regimen should be based on the results of the CNS susceptibility studies and the clinical response.2,9

Sepsis and Pneumonia
S. pneumoniae is one of the most common pathogens in hospitalized patients with community-acquired pneumonia. An increasing number of these isolates have been defined as intermediate to highly- resistant to penicillin. The serum concentrations which are achieved with penicillin, however, are many times greater than the MICs for pneumococci with intermediate penicillin-resistance, as well as for many highly resistant isolates. Thus, it is likely that patients will respond to high doses of penicillin or cephalosporins.2,11,12

A recent review evaluated the clinical outcomes of patients with community-acquired bacteremic pneumococcal pneumonia.12 This review found that mortality due to pneumococcal pneumonia involving penicillin-resistant strains is similar to that involving susceptible strains. The authors concluded that high-dose intravenous penicillin G (150,000 to 200,000 units per kilogram per day) may be adequate in patients with pneumococcal pneumonia when the MIC to penicillin is 0.12 to 2 mcg/ml. If the MIC of penicillin is higher, cefotaxime or ceftriaxone should be considered as alternatives.4

Initial empiric therapy for community-acquired pneumonia should include high-dose penicillin G or ampicillin. In patients who have underlying conditions which compromise the immune system or have other risk-factors for pneumococci with a high level of resistance to penicillin, cefotaxime (1 gram every 8 hours) or ceftriaxone (1 gram every 24 hours) should be considered. If there is suspicion of a high-level cephalosporin resistance (MIC > 2 mcg/ml), alternative agents such as vancomycin or imipenem-cilastatin could be considered. Alternative antimicrobial agents are limited due to escalating resistance.2,11-l3 Thus, the judicious use of antimicrobials for the treatment of pneumonia is mandatory.

Prevention of pneumococcal pneumonia should be a primary goal. The increasing incidence of resistant S. pneumoniae requires that practitioners make a high priority of following the current guidelines for administration of the pneumococcal vaccine.2,11,13

Otitis Media
Penicillin-resistant pneumococci have been recognized as one of the causes of treatment failure in otitis media and chronic sinusitis. The incidence of resistant pneumococcal isolates is probably underestimated because of the infrequency with which diagnostic material is obtained from these sites. The penetration of orally administered drugs to the site of infection is usually low in relation to the MIC for the penicillin-resistant pneumococci which have been recognized as causes for treatment failure.1,2 Despite this fact, amoxicillin therapy is still recommended for initial empiric therapy because improved clinical outcomes have not been demonstrated with alternative "extended-spectrum" agents.1,2

Another cause for amoxicillin treatment failure may be the presence of beta-lactamase producing organisms (Haemophilus, Moraxella).2 Therefore, use of amoxicillin must be closely monitored, and alternative therapy chosen if a prompt clinical response does not occur. Most of the newer oral cephalosporin agents or amoxicillin/clavulanate are highly effective against these beta-lactamase- producing organisms; however, these agents have poor efficacy against penicillin-resistant pneumococci. In fact, these agents are significantly less active than amoxicillin for both penicillin- intermediate and penicillin-resistant S. pneumoniae. Therefore, highly penicillin-resistant strains unresponsive to amoxicillin will probably not be adequately treated with alternative beta-lactams (cephalosporins).2

Alternative agents for recurring or chronic otitis media include the non-beta-lactam drugs trimethoprim/sulfamethoxazole, erythromycin/sulfisoxazole, and clarithromycin. These agents are generally effective against both penicillin-resistant pneumococci and beta-lactamase producing organisms. There have been reports of penicillin-resistant pneumococci isolated from middle-ear fluid which have also been resistant to erythromycin and trimethoprim/sulfamethoxazole.2 Judicious use of these agents is required to reduce the further spread of resistance, reserving empiric use for those cases of amoxicillin treatment failures. Myringotomy may be appropriate for those patients who do not respond to antimicrobial therapy in order to permit the identification of the causative organism and test its antimicrobial susceptibility.2

Prevention of Pneumococcal Infections
Efforts to prevent pneumococcal infections in patients at high risk of developing an overwhelming pneumococcal sepsis (e.g., splenectomized patient, patients with hematologic malignancies or immunodeficiencies, elderly patients) should be undertaken. Antimicrobial prophylaxis with oral penicillin V or erythromycin has been effective; however, breakthrough bacteremia with DRSP has been documented.! Use of the 23-valent pneumococcal vaccine contains material from the 23 types of pneumococcal bacteria that cause 88% of pneumococcal bacteremias. The vaccine usually provides long-term protection; however, select patients should be considered for revaccination after six years. Guidelines for the use of pneumococcal vaccine are outlined in Table 2.

Table 2. Guidelines for the Use of Pneumococcal Vaccine14,15

1. All adults 65 or more years of age. 2. Immunocompetent adults who are at increased risk of pneumococcal disease or its complications because of chronic illnesses (e.g., cardiovascular or pulmonary disease, diabetes, alcoholism, cirrhosis, or CSF leaks). 3. Immunocompromised adults at increased risk of pneumococcal disease or its complications (e.g., splenic dysfunction, nephrotic syndrome, organ transplantation, hematologic malignancies, immunodeficiencies, asymptomatic or symptomatic HIV infection). 4. Children 2 or more years of age with chronic illnesses associated with increased risk of pneumococcal disease or its complications (e.g., anatomic or functional asplenia, nephrotic syndrome, CSF leaks, conditions associated with immunosuppression). 5. Children 2 or more years with symptomatic or asymptomatic HIV disease. 6. Persons living in environments with an identified increased risk of pneumococcal disease or its complications (e.g., nursing homes or institutional living).

Summary
A working group sponsored by the Centers for Disease Control and Prevention was formed in June 1994 to address the problem of drug resistant pneumococci. This working group has developed an initial strategy for surveillance, prevention, and control of DRSP. The conclusions of this group were published in the February 16, 1996, edition of Morbidity and Mortality Weekly Report.16 A summary of these findings was published in the January 17, 1996, edition of JAMA.3 The conclusions and recommendations of this working group to combat the spread of DRSP are summarized in Table 3.

Table 3. Conclusions and Recommendations to Combat the Spread of Drug Resistant S. pneumoniae3,16
CONCLUSIONS	RECOMMENDATIONS
The magnitude of the problem is unknown due to incomplete surveillance of DRSP prevalence data. The clinical impact of DRSP infections is currently unknown. National vaccination rates are low. Antimicrobial drugs are overprescribed and inappropriately used. Choice of empiric therapy for presumed pneumococcal infections is currently unclear.	Implement an electronic laboratory-based surveillance system for reporting invasive infections of DRSP. Promote appropriate interpretive standards for antimicrobial susceptibility of DRSP. Establish nationwide mandatory reporting of DRSP. Investigate risk factors and outcomes of pneumococcal infections. Improve pneumococcal immunization rates nationally. Promote the judicious use of antimicrobial agents. Establish treatment guidelines Periodically publish national and regional trends.

The increasing incidence of resistant S. pneumoniae to multiple antimicrobials is a cause for concern. A recent multicenter national surveillance study determined that the overall national prevalence of pneumococci strains which were not susceptible to penicillin was 23.6% (penicillin-intermediate and high-level resistant strains), with approximately two of every five nonsusceptible strains manifesting as penicillin-resistance. 17 The results of this study indicate that the prevalence of both penicillin-intermediate and penicillin-resistant strains of S. pneumoniae continues to increase in the U.S. Excessive oral antimicrobial use appears to have been the driving force for the spread of drug resistant pneumococci; therefore, judicious use is required. Penicillin resistance can, in certain conditions, be overcome with higher doses of penicillin. Penicillins remain the drug of choice for sepsis, pneumonia, and otitis for susceptible strains. In cases of meningitis, where the concentration of antimicrobial at the site of infection is not as high in relation to the MIC due to incomplete penetration, alternative agents should be utilized, most commonly a broad-spectrum cephalosporin. These recommendations are summarized in Table 4. Local and institution-specific antimicrobial susceptibility patterns must be known so that practitioners can provide the most effective therapy. Refer to the most recent "Guide to Choice of Antibiotic Therapy" for UIHC data.

Table 4. Treatment Recommendations for Pneumococcal Infections
SITE OF INFECTION	FIRST CHOICE	SECOND CHOICE	ALTERNATIVES#
Meningitis
Penicillin-susceptible	Penicillin G* 4 million units IV every 4 hours	Cefotaxime* 1 gram IV every 8 hours Ceftriaxone* 1 gram IV every 24 hours	Vancomycin
Penicillin-resistant	Vancomycin* 1 gram IV every 12 hours	Cefotaxime* 2 grams IV every 8 hours Ceftriaxone * 1 gram IV every 12 hours	Imipenem-cilastatinX Vancomycin + Rifampin Vancomycin + Cefotaxime or Ceftriaxone
Pneumonia/sepsis
Penicillin-susceptible	Penicillin G* 2 million units IV every 6 hours	Cefotaxime * 1 gram IV every 8 hours Ceftriaxone* 1 gram IV every 24 hours	Erythromycin Vancomycin Oral cephalosporin
Penicillin-resistant	Penicillin G* 2 million unitS IV every 4 hours 4 million units IV every 6 hours	Cefotaxime* 1 gram IV every 8 hours Ceftriaxone * 1 gram IV every 24 hours	Vancomycin Erythromycin
Otitis Media
Suspected penicillin-resistance	Amoxicillin~ 40 mg/kg/day PO divided in 3 doses	Oral cephalosporin~ cefpodoxime 10 mg/kg PO every 24 hours Amoxicillin/clavulanic acid~ 40 mg/kg (amoxicillin) PO divided in 3 doses Trimethoprim/sulfamethoxazole~ 8 mg TMP/40 mg SMX/kg/day PO divided in 2 doses Erythromycin/sulfisoxazole~ 40 mg/kg/day (erythromycin) PO divided in 4 doses	Azithromycin~ 10 mg/kg PO day l; 5 mg/kg PO days 2 through 5 Clarithromycin~ 7.5 mg/kg PO every 12 hours
#Contact the Infectious Diseases Division if dosages are needed. *Dosages suggested are for adults assuming normal renal fiunction and no severe hepatic dysfunction. XImipenem-cilastatin has the potential of causing drug-related seizures in patients with meningitis. ~Dosages suggested are for vediatrics assuming normal renal fiunction.

References

1. CID. 1992;15:119-27.

2. N EnglJMed. 1994;331:377-82.

3. JAMA. 1996;275:206-9.

4. CID. 1992;15:77-83.

5. Antimicrob Agents Chemother 1994;38:2905-7.

6. JAMA. 1994;271:1831-5.

7. N Engl J Med. 1995;333:481-6.

8. CID. 1992;15:84-94.

9. Antimicrob Agents Chemother 1995;39:2171-5.

10. Principles and Practice of Infectious Disease. 4th ed. New York Churchill Livingstone, Inc.; 1995.

11. N EnglJMed. 1995;333: 1618-24.

12. NEnglJMed. 1995;333:474-9.

13. Am Rcv Respir Dis. 1993;148 1418-26.

14. Ann Intern Med. 1994;121 540-1.

15. Merck & Co. Pneumovax 23. Package Insert. West Point, PA 1995

16. MMWR. 1996;45(RR-1):1-20.

17. Amimicrob Agents Chemother. 1996;40 1208-13.

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