Table 1 Definitions of Pneumococcal Resistance to ß-Lactam Antibiotics
Antibiotic
|
Definition by MIC (μg/ml) 1 |
||
Susceptible |
Intermediate |
Resistant |
|
Penicillin |
£ 0.06 |
0.1 - 1 |
³2 |
Amoxicillin |
£ 2 |
4 |
³ 8 |
Cefotaxime, Ceftriaxone, Cefepime: non-meningitis meningitis |
£ 1 £ 0.5 |
2 1 |
³ 4 ³ 2 |
Cefaclor |
£ 1 |
2 |
³ 4 |
Cefprozil |
£ 2 |
4 |
³ 8 |
Cefpodoxime |
£ 0.5 |
1 |
³ 2 |
Ceftibuten |
N/A |
N/A |
N/A |
Cefixime |
N/A |
N/A |
N/A |
Cefuroxime sodium (parenteral) |
£ 0.5 |
1 |
³ 2 |
Cefuroxime axetil (oral) |
£ 1 |
2 |
³ 4 |
Imipenem |
£ 0.12 |
0.25-0.5 |
³ 1 |
Meropenem |
£ 0.25 |
0.5 |
³ 1 |
Table 2. Pneumococcal (N=1531) Resistance (%) to Antibiotics in 33 Centers in the USA (1999-2000).
Antibiotic |
Intermediate 1 |
Resistant 1 |
Overall Nonsusceptible |
Penicillin |
12.7 |
21.5 |
34.2 |
Age 0-5 yr |
13.7 |
28.9 |
42.6 |
Cefaclor |
2.9 |
29.5 |
32.4 |
Ceftriaxone |
10.3 |
14.4 |
24.7 |
Cefuroxime |
2.0 |
25.3 |
27.3 |
Clindamycin |
0.3 |
8.9 |
9.2 |
Erythromycin2 |
0.5 |
25.7 |
26.2 |
Levofloxacin |
0.4 |
0.3 |
0.7 |
TMP-SMX |
5.6 |
30.3 |
35.9 |
Rifampin |
0 |
0.1 |
0.1 |
Vancomycin |
0 |
0 |
0 |
Data adapted from ref. 56
1. See table 2 for definitions.
2. Similar resistance rates observed with clarithromycin and azithromycin
Table 3. Representative Peak Serum Concentrations of ß-Lactam Antibiotics in Reference to in vitro Resistance in Adults.
Antibiotic
|
Definition by MIC (μg/ml) 1 |
Mean peak serum conc. in μg/ml 2 (Antibiotic dosage in g) |
Potency relative to penicillin3 |
||
Susceptible |
Intermediate |
Resistant |
|||
Penicillin |
£ 0.06 |
0.1 - 1 |
³2 |
|
|
Amoxicillin |
£ 2 |
4 |
³ 8 |
7.5 (0.5) |
± |
Cefotaxime, Ceftriaxone, Cefepime: non-meningitis meningitis |
£ 1 £ 0.5 |
2 1 |
³ 4 ³ 2 |
130 (2) 250 (2) 130 (2) |
+ + + |
Cefaclor |
£ 1 |
2 |
³ 4 |
16.5 (0.5) |
- - |
Cefprozil |
£ 2 |
4 |
³ 8 |
9.6-10.5 (0.5) |
- - |
Cefpodoxime |
£ 0.5 |
1 |
³ 2 |
4.2 (0.4) |
- |
Ceftibuten |
N/A |
N/A |
N/A |
15.0 (0.4) |
- - |
Cefixime |
N/A |
N/A |
N/A |
1.9 (0.2) |
- - |
Cefuroxime sodium (parenteral) |
£ 0.5 |
1 |
³ 2 |
100 (1.5) |
- |
Cefuroxime axetil (oral) |
£ 1 |
2 |
³ 4 |
4.4-9.0 (0.5) |
- |
Imipenem |
£ 0.12 |
0.25-0.5 |
³ 1 |
52 (1) |
++ |
Meropenem |
£ 0.25 |
0.5 |
³ 1 |
49 (1) |
+ |
1. Susceptibility definitions are from ref. 131.
2. Serum concentration data were obtained from ref. 13, 58, 64, 102, 110, 147.
3. ± indicates similar MICs; + indicates two- to four-fold lower MICs, ++ indicates 4-fold or lower MICs, - indicates two- to four-fold greater MICs,
and -- indicates 4-fold or greater MICs. N/A indicates that interpretive criteria are not available
Table 3-a: Time Above MIC for Three Oral and Four Parenteral β-lactam Antibiotics Tested against Penicillin-Intermediate and Penicillin-Resistant Strains of Streptococcus pneumoniae
Drug |
Regimen |
S Pneumoniae (I) |
|
S pneumoniae (R) |
|
|
|
MIC 50-90 (ug/ML) |
Time above MIC (%) |
MIC 50-90 (ug/ML) |
Time above MIC (%) |
Amoxicillin |
13.3 mg/Kg, t.i.d. |
0.25-1 |
80-55 |
1-2 |
55-43 |
Cefaclor |
13.3 mg/Kg, t.i.d. |
8-16 |
20-0 |
32-64 |
0 |
Cefuroxime |
15 mg/Kg b.i.d |
0.5-2 |
56-40 |
4-8 |
30-0 |
|
|
|
|
|
|
Ampicillin |
1 g q6h |
0.5-2 |
71-100 |
2-4 |
71-54 |
Penicillin |
2MU q6h |
0.5-1 |
58-66 |
2-4 |
50-41 |
Cefotaxime |
1g q8h |
0.25-1 |
87-63 |
1-2 |
63-52 |
Ceftriaxone |
1g q24h |
0.25-1 |
76-100 |
1-2 |
76-48 |
Table 4. Recommended Therapy for Penicillin-Susceptible and -Resistant Pneumococcal Infections.
Infection
|
Empiric Therapy1 |
Penicillin susceptibility known |
||
Susceptible |
Intermediate resistance |
PRSP |
||
Pneumonia or bacteremia |
Penicillin Ampicillin, cefuroxime, amoxicillin, cefotaxime, ceftriaxone |
Penicillin, ampicillin, amoxicillin, cefuroxime |
Penicillin, ampicillin, amoxicillin, cefuroxime |
High dose penicillin Cefotaxime, ceftriaxone, high dose ampicillin, newer fluoroquinolones |
Meningitis |
Cefotaxime or ceftriaxone + vancomycin2 |
Cefotaxime, ceftriaxone, ampicillin or penicillin |
Cefotaxime3 or ceftriaxone + vancomycin2 |
Cefotaxime3 or ceftriaxone + vancomycin2 + rifampin4, meropenem5 |
Otitis media |
Amoxicillin in high dose6 |
Amoxicillin |
Amoxicillin in high dose6. (Avoid oral cephalosporins) |
Amoxicillin in high dose6, clindamycin, ceftriaxone7 |
1. For suspected pneumococcal infection or confirmed pneumococcal infection pending susceptibility data.
2. Vancomycin (15 mg/kg/dose 6-hourly in children) should be combined with a cephalosporin in areas where cephalosporin resistance occurs.
Vancomycin therapy can be discontinued once the strain is confirmed to be cephalosporin susceptible.
3. High dosage (300 mg/kg/d) recommended.
4. Addition of Rifampin (10 mg/kg/dose 12-hourly) should be considered after 24 to 48 hours of therapy if the organism is susceptible to rifampin and
1) the patient’s clinical condition has worsened; or 2) the subsequent gram-stained smear or culture of CSF indicates failure to eradicate or to reduce
substantially the number of organisms; or 3) the organism has a cefotaxime or ceftriaxone MIC ³4 µg/ml.
5. Meropenem may be considered for cephalosporin-resistant infections in patients failing cephalosporin therapy although effectiveness has not been
established for such infections.
6. For example, 90 mg/kg/day.
7. If oral therapy fails, intramuscular ceftriaxone can be given daily for 3 - 5 days.
Table 5: Antimicrobial Therapy Recommendations for Children and Adults with Meningitis Caused by Streptococcus pneumoniae on the
Basis of Susceptibility Tests Results
Drug* |
Pediatric Dose (mg (u)/kg/day) |
adults Dose (total daily dose) |
Dose interval |
Empirical therapy |
Penicillin susceptibility |
Cephalosporin resistant |
||
susceptible |
Intermediate resistant |
Resistant |
||||||
Penicillin |
G 250,000- 4000,000u# |
16- 24,000,000u |
4-6 h |
No |
Yes |
No |
No |
No |
Ampicillin |
200-400 mg |
8-12 gr |
4-6 h |
No |
Yes |
No |
No |
No |
Cefotaxime |
200-300 mg |
2.0 gr |
4-6 h |
Yes |
Yes |
Yes |
Yes |
Yes@ |
Ceftriaxone |
100 mg |
2.0 gr |
12 h |
Yes |
Yes |
Yes |
Yes |
Yes@ |
Vancomycin& |
60 mg |
2-3 gr |
6 h |
Yes |
Yes |
Yes |
Yes |
Yes |
Rifampin |
20 mg |
600 mg |
12 h |
No |
No |
No |
No |
Yes@@ |
Cefepime |
150 mg |
6 gr |
8 h |
Yes |
Yes |
Yes |
Yes |
Yes@ |
Meropenem |
120 mg |
6 gr |
8 h |
Yes |
Yes |
Yes |
Yes |
Yes |
Chloramphenicol |
75-100 mg |
4 gr |
6 h |
No |
No |
No |
No |
No@@@ |
* Duration of treatment 10-14 days
#1u= 0.6 μg/mL
& Vancomycin should be given only in combination therapy
@ Combination therapy with vancomycin.
@@Addition of Rifampin should be considered after 24 to 48 hours of therapy if the organism is susceptible to rifampin and 1) the patient’s clinical condition has worsened;
or 2) the subsequent gram-stained smear or culture of CSF indicates failure to eradicate or to reduce substantially the number of organisms; or 3) the organism has a
cefotaxime or ceftriaxone MIC > 4 µg/ml.
@@@ In patients with sever Beta-lactam allergy should be considered in combination therapy with vancomycin and addition of rifampin.
Table 6. Recommended Daily Dosages of Agents Commonly Used for Treatment of Non-Meningeal Pneumococcal Infections.
See Table 4 For Selection Of Antibacterial Agent.
Agent |
Route |
Adult Dosage (g/day) |
Pediatric Dosage (mg/kg/day) |
Dosing Interval (h) |
Penicillin |
IV |
4-12 million U |
250,000-400,000 U/kg |
4-6 |
Ampicillin |
IV |
4-12 |
100-200 |
6 |
Cefazolin |
IV |
2-6 |
50-100 |
8 |
Cefuroxime |
IV |
2-4.5 |
100-150 |
6 |
Cefotaxime |
IV |
2-6 |
100-200 |
8 |
Ceftriaxone |
IV |
1-2 |
75-100 |
24 |
Vancomycin |
IV |
2 |
30-40 |
6-12 |
Levofloxacin |
IV/PO |
0.5 |
NE |
24 |
Gatifloxacin |
IV/PO |
0.4 |
NE |
24 |
Amoxicillin |
PO |
0.75-1.5 |
40-80 |
8 |
Cefuroxime |
PO |
0.5-1 |
100 |
12 |
Erythromycin |
PO |
1-2 |
40 |
6-8 |
Clarithromycin |
PO |
1 |
15 |
12-24 |
Azithromycin |
PO |
0.5 day 1 then 0.25 |
10 |
24 |
TMP/SMX |
PO |
0.16 |
8-12 (TMP) |
12 |
Clindamycin |
PO |
0.6-1.2 |
20-30 |
6-8 |
Moxifloxacin |
PO |
0.4 |
NE |
24 |
Telithromycin |
PO |
0.8 |
NE |
24 |
Use upper range dosages of ß-lactam antibiotics to cover penicillin-resistant strains
IV, intravenous; PO, per os; TMP/SMX, trimethoprim/sulfamethoxazole
NE = Not established
Table 7. Serum And Middle Ear Fluid Concentrations of Antimicrobial Agents that Have Been Used for
Therapy of Childhood Otitis Media and Comparative In Vitro Activity According to Pneumococcal Susceptibility to Penicillin.
Antibiotic |
Dose (mg/kg) |
Peak Concen-trations (μg/ml)1 |
MIC50,MIC90 (μg/ml) According to Penicillin Susceptibility2 |
|||
Serum |
MEF |
Susceptible |
Intermediate |
Resistant |
||
Amoxicillin |
15 |
13.6 |
5.6 |
0.01, 0.03 |
0.5, 1 |
4, 8 |
Cefaclor |
15 |
8.5 |
0.5 |
0.5, 1 |
4, 16 |
64, 64 |
15 |
16.8 |
3.8 |
||||
Cefixime |
8 |
2.5 |
1.3 |
0.25, 0.5 |
2, 32 |
32, 32 |
8 |
4.2 |
1.5 |
||||
Cefpodoxime |
5 |
2.0 |
0.2 |
0.03, 0.06 |
0.5, 2 |
4, 32 |
Cefprozil |
15 |
5.5 |
2.0 |
0.25, 0.25 |
1, 4 |
16, 32 |
15 |
12.1 |
2.0 |
||||
Ceftibuten |
9 |
6.7 |
4.0 |
4, 8 |
>32, >32 |
>32, >32 |
9 |
12.2 |
9.3 |
||||
Cefuroxime |
15 |
5.1 |
1.23 |
0.03, 0.12 |
1, 16 |
8, 16 |
Loracarbef |
15 |
9.3 |
3.9 |
1, 2 |
8, 32 |
32, 32 |
TMP/SMX |
4 |
2.0 |
1.4 |
0.25, 1 |
0.25, 4 |
2, 4 |
Erythromycin |
15 |
3.6 |
1.7 |
0.06, 0.06 |
0.25, 4 |
2, 16 |
Clarithromycin |
7.5 |
1.7 |
2.5 |
£ 0.03, 0.06 |
0.25, 8 |
1, 8 |
Azithromycin |
10®5 |
0.2 |
|
0.12, 0.12 |
2, 16 |
2, 32 |
10®5 |
|
9.4 |
||||
Ceftriaxone |
504 |
175 |
|
0.03, 0.06 |
0.012, 1 |
1.0, 2.0 |
MEF, middle ear fluid; MIC50, median MIC; MIC90, concentration inhibiting 90% of strains; TMP/SMX, trimethoprim/ sulfamethoxazole
2. MIC data are from middle ear isolates obtained from children in Kentucky (18) or Texas (132).
Additional data are from isolates recovered from outpatients (56)
3. After a single 250 mg dose in children aged 6 to 12 years.
4. Single intramuscular dose (22)
Table 8: Antimicrobial Therapy Recommendations for Children with Acute Otitis Media (AOM) caused by Streptococcus pneumoniae
on the Basis of Susceptibility Tests Results
Drug |
Dose (mg/kg/day ) |
Dose interval |
Penicillin susceptibility |
Macrolide resistant |
||
susceptible |
intermediate or resistant |
|||||
First line |
Amoxicillin |
40-50
|
8 h |
Yes |
No |
Yes |
Cefpodoxime proxetil |
10 |
12 h |
Yes |
No |
Yes |
|
Cefprozil |
30 |
12 h |
Yes |
No |
Yes |
|
Amoxicillin* |
70-90 |
8 h |
Yes |
Yes |
Yes |
|
Second line** |
Amoxicillin/clavulanate |
45/6.4 |
12 h |
Yes |
No |
Yes |
Amoxicillin/clavulanate* |
90/6.4 |
12 h |
Yes |
Yes |
Yes |
|
Cefuroxime-axetil |
30 |
12 h |
Yes |
Moderate |
Yes |
|
Ceftriaxone***
|
50 |
24 h |
Yes |
Yes |
Yes |
|
Type I allergy to penicillins |
Erythromycin |
30-50 |
8 h |
Yes |
Yes@ |
No |
Clarithromycin |
15 mg |
12 h |
Yes |
Yes@ |
No |
|
Azithromycin& |
5-10 |
24 h |
Yes |
Yes@ |
No |
|
Clindamycin |
30-40 |
8 h |
Yes |
Yes@ |
Yes$ |
* If recurrent AOM episodes or if patient has risk factors for infection with penicillin resistant S. pneumoniae
** If AOM persists after 48-72 hours of treatment tympanocentesis should be recommended to make a bacteriologic diagnosis.
@ In some cases penicillin and macrolides S. pneumoniae resistance are linked.
Table 9: Published Reports on Mono vs. Combo in Treatment of Pneumonia (listed in the order of time published)
Author/J/Time |
CAP vs pneumo |
Prospective /retrospective |
Patient number |
Controlled for severify of illness Y/N |
Combo is superior Y/N |
Gleason Arch Int Med 1999 |
CAP |
R |
12,945 |
N |
Y |
Mufson AM J Med 1999 |
Bacteremic pneumococcal pneumonia |
R |
328 |
N |
Y |
Waterer Arch Int Med 2001 |
Bacteremic pneumococcal pneumonia |
R |
225, |
Y |
Y |
Martinez CID 2003 |
Bacteremic pneumococcal pneumonia |
R |
409 |
N |
Y |
Weiss Can Respir J 2004 |
Bacteremic pneumococcal pneumonia |
R |
95 |
Y |
Y |
Baddour Am J Respir Crit Care Med 2004 |
bacteremia |
P |
844 |
Y |
Y |
Harbarth Eur J Clin Miceobiol 2005 |
Pneumococcal sepsis |
R |
107 |
Y |
N |
Garcia Vazquez Eur J Clin Micro 2005 |
CAP |
R |
1,391 |
Y |
Y |