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

 ³ 2

 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

   1. Susceptibility definitions are from ref [150]

 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 [61]

   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 [150]

   2. Serum concentration data were obtained from ref[15, 64, 71, 118, 126, 168]

   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, Levofloxacin

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

   1. Data from ref.

   2. MIC data are from middle ear isolates obtained from children in Kentucky [19] or Texas [152].

      Additional data are from isolates recovered from outpatients [61]

   3. After a single 250 mg dose in children aged 6 to 12 years.

   4. Single intramuscular dose

 

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

 

Figure 1:  Algorithm for Testing Staphylococcus aureus Vancomycin Susceptibility (VISA or VRSA)