A 7 year old male presents to his physician's office with thigh pain and fever since yesterday afternoon. He has a minimal limp and no history of trauma.
Exam VS T37.5, HR 90, RR 18, BP 110/70. He is alert and not toxic. His exam findings are only positive for tenderness in his mid femur region. His hip exam is normal. He has no skin sores, bruises or other areas of tenderness. His gait appears to be normal except for an occasional suggestion of a limp.
Plain radiographs of his femur and hip are normal. His CRP and ESR are high so a bone scan is obtained that afternoon which shows a hot spot in his mid femur. He is hospitalized for acute osteomyelitis. He is initially treated with IV vancomycin. An orthopedic procedure is performed to drain some pus and to obtain a culture and biopsy. On hospital day 3, his clinical condition is improved. Cultures of his blood and the bone aspirate grow Staph aureus which is sensitive to cephalosporins and methicillin. His antibiotics are changed to IV oxacillin. He continues to improve. Consultants recommend that he be treated for 6 weeks with IV antibiotics. His medical insurance company approves inpatient antibiotics for 7 days and requests that the remainder of his antibiotics be administered as an outpatient. Is there a rational method to provide him with inpatient levels of antibiotics as an outpatient?
Each bacteria has a level of antibiotic which will inhibit growth but not kill the organisms. This is called the minimum inhibitory concentration (MIC). Related to this, a higher antibiotic concentration will kill the organisms. This is called the minimum bactericidal concentration (MBC). By understanding the concepts in determining antibiotic concentrations compared to the MIC and MBC, we can make rational decisions in determining how successful antibiotic treatment is likely to be.
Pharmacologists have taught us that some antibiotics are "bactericidal" and some are "bacteriostatic". These terms are slight misnomers since all antibiotics are potentially bactericidal and bacteriostatic at different concentrations. The "bactericidal" and "bacteriostatic" terminology originates from whether the antibiotic's mechanism is based on inhibiting cell wall formation ("bactericidal") or inhibiting bacterial metabolism or ribosomal protein synthesis ("bacteriostatic"). The idea is that if cell wall formation is blocked, the organisms will lyse and perish, but if metabolism or protein synthesis is blocked, the organisms merely slow down. While this is true to some degree, bactericidal or bacteriostatic outcomes are dependent on the concentration of the antibiotic as well. A low dose of a "bactericidal" antibiotic may only inhibit bacterial growth, while a high dose of a "bacteriostatic" antibiotic will be bactericidal. Additionally, organisms which are not proliferating may not be significantly affected by anti-cell wall antibiotics, in which case anti-ribosomal antibiotics would be more effective.
An example of this is the effect of bug spray on a cockroach. A light spray will only slow the cockroach down (a cockroach-static level). By tomorrow, the cockroach will recover. However, if one drowns the cockroach in bug spray (a cockroach-cidal level), the cockroach will perish.
Modern laboratory methods can rapidly determine the MIC and MBC for cultured organisms for multiple antibiotics simultaneously. However, to understand this better, the following clinical example will be used to demonstrate these concepts. Refer to the table below:
The table above is an example which describes the result of MIC/MBC determinations for an organism from our patient with a hypothetical antibiotic. There are six tubes with varying concentrations of antibiotic in a bacterial culture broth. Tube 1 contains the highest concentration of antibiotic and tube 6 contains the lowest concentration of antibiotic. The organism is inoculated into all 6 tubes. After a 2 day incubation, the first 4 tubes are clear (which indicates that the organisms did not grow in these tubes). Tubes 5 and 6 are turbid due to bacterial growth which means that an antibiotic concentration of 0.5 is neither inhibitory nor bactericidal.
For tubes 1, 2, 3 and 4, it is not known whether the organisms present in these tubes have died (bactericidal concentration) or their growth is merely inhibited (inhibitory concentration). These tubes contain either dead organisms or viable growth-inhibited organisms. The next step is to centrifuge tubes 1 through 4. All solid debris (dead or alive organisms) will be centrifuged to the bottom of the tube. After centrifugation, the supernatant containing the antibiotic is poured off. Fresh broth without antibiotic is now added to the tubes. After another two days of incubation (on day 4), tubes 1 and 2 are clear, while tubes 3 and 4 are turbid. This means that tubes 3 and 4 contained viable organisms which were inhibited by the antibiotic, but now that the antibiotic is gone, they are able to grow. Tubes 1 and 2 are still clear which means that all organisms in these tubes were killed. Thus tubes 3 and 4 contain inhibitory concentrations of antibiotic, while tubes 1 and 2 contain bactericidal concentrations of antibiotic. Thus, the minimum inhibitory concentration (MIC) of this organism for this antibiotic is 1.0 (tube 4), while the minimum bactericidal concentration (MBC) of this organism for this antibiotic is 5.0 (tube 2).
Now that we know the MIC and MBC for this organism and this antibiotic, we can put the patient on oral antibiotics and see what antibiotic levels can be achieved in the patient's bloodstream. We could measure an antibiotic level 1-2 hours after an antibiotic dose is given (peak level) and one hour before the next antibiotic dose is given (trough level). At a minimum, the tough level should be above the MIC and the peak level should be above the MBC. In practice, the peak level should be several times higher (e.g., 8 times higher) than the MBC, depending on the type of infection. If such levels cannot be obtained by oral antibiotics, then IV antibiotics must be maintained for the duration of therapy.
Most clinical laboratories are not able to measure levels of all antibiotics. For example, a clindamycin or a trimethoprim/sulfamethoxazole level may not be available. If preliminary sensitivity testing shows drug sensitivities to such antibiotics, a different method may be necessary to determine if satisfactory MICs and MBCs can be obtained with these antibiotics. This is called the Schlichter test, which is demonstrated in the example below:
The tables above are an example which describes the result of MIC/MBC determinations for an organism from our patient with a hypothetical antibiotic for which, antibiotic levels are not routinely available in the clinical lab. There are six tubes with varying dilutions of the patient's serum mixed with culture broth. Tubes 1-6 are drawn just after the patient receives an antibiotic dose (peak level). Tubes A-F are drawn just before the patient receives an antibiotic dose (trough level). Tube 1 contains the highest concentration of antibiotic for the peak levels. Tube A contains the highest concentration of antibiotic for the trough levels.
The organism is inoculated into all 6 tubes for peak and tough. After two days of incubation, tube 6 is turbid for the peak tubes, and tubes E and F are turbid for the trough tubes. For these turbid tubes, we know that active bacterial growth has taken place so these dilutions are neither inhibitory nor bactericidal.
For tubes 1, 2, 3, 4, 5 for the peak tubes, and tubes A, B, C, D for the trough tubes, it is not known whether the organisms present in these tubes have died (bactericidal concentration) or their growth is merely inhibited (inhibitory concentration). These tubes contain either dead organisms or viable growth-inhibited organisms. The next step is to centrifuge tubes 1, 2, 3, 4, 5 for the peak tubes, and tubes A, B, C, D for the trough tubes. All solid debris (dead or alive organisms plus some blood cells) will be centrifuged to the bottom of the tube. After centrifugation, the supernatant containing the antibiotic (from the patient's serum) is poured off. Fresh broth without antibiotic is now added to the tubes.
For the peak and trough tubes, after another two days of incubation (on day 4), tubes 1, 2, 3, A, B are clear, while tubes 4, 5, C, D are turbid. This means that turbid tubes 4, 5, C, D contained viable organisms which were inhibited by the antibiotic (in the patient's serum), but now that the antibiotic is gone, they are able to grow. Tubes 1, 2, 4, A and B are still clear which means that all organisms in these tubes were killed. Thus tubes 4, 5, C and D contain inhibitory concentrations of antibiotic, while tubes 1, 2, 3, A and B contain bactericidal concentrations of antibiotic. Thus, the minimum inhibitory concentration (MIC) of this organism for this antibiotic is occurs at a 1:32 dilution (tube 5) at peak antibiotic levels, and 1:16 dilution (tube D) at trough antibiotic levels, while the minimum bactericidal concentration (MBC) of this organism for this antibiotic is 1:8 dilution (tube 3) at peak antibiotic levels, and 1:4 dilution (B) at trough antibiotic levels.
What does this mean? This data tells us that the antibiotic blood levels exceed the MBC 4 to 8 times from trough to peak. This is excellent. However, for an infection such as osteomyelitis, bone levels are not necessarily the same as blood levels. Thus, blood levels well in excess of MBC and MIC are desirable. If such levels can be demonstrated with oral antibiotics using these tests, then the patient can be treated with oral antibiotics as an outpatient, and therapeutic success is more certain. Thus our patient does not need to remain in the hospital for 6 weeks of IV antibiotics. He can be discharged and take antibiotics at home. This is much less costly and it should be just as effective as long as the patient is compliant.
The utilization of MIC/MBC data and the Schlichter test is complex and controversial. The most common infections which require very long antibiotic courses (4 to 6 weeks) are bone and joint infections (osteomyelitis and septic arthritis) and bacterial endocarditis. While still controversial, peak drug levels 8 times the MBC are felt to be the minimum levels to predict therapeutic success for these infections. Peak levels below this may be insufficient. In general, higher levels are better, and some organisms typically require higher levels than other organisms.
1. How does a bacteriostatic antibiotic behave in a bactericidal fashion?
2. How does a bactericidal antibiotic behave in a bacteriostatic fashion?
3. Do all infections require MIC/MBC or Schlichter tests? Why or why not?
4. When should a Schlichter test be performed?
5. When is it NOT possible to perform MIC/MBC determination testing?
6. If the infection is in bone (osteomyelitis), in joint fluid (septic arthritis), in urine (UTI), or in any body space, how can we be sure that adequate antibiotic levels are obtained if we are only able to measure MIC/MBC in the blood?
1. Starke JR. Chapter 32: Infective Endocarditis. In: Feigin RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 4th edition. 1998, Philadelphia: W.B. Saunders, pp. 315-338.
2. Baltimore RS. Chapter 38: Endocarditis and Intravascular Infections. In: Long SS, Pickering LK, Prober CG (eds). Principles and Practice of Pediatric Infectious Diseases. 1997, New York: Churchill Livingstone, pp. 289-298.
3. Krogstad P, Smith AL. Chapter 64: Osteomyelitis and Septic Arthritis. In: Feigin RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 4th edition. 1998, Philadelphia: W.B. Saunders, pp. 683-704.
Answers to questions
1. When the level of the antibiotic is so high that all organisms are killed.
2. When the level of the antibiotic is so low that organism growth is inhibited, but they are not killed.
3. No. MIC/MBC or Schlichter tests are only useful when a very long course of antibiotics are anticipated and the patient must be changed to oral antibiotics to complete the antibiotic course as an outpatient. These tests are necessary to determine if it is possible to attain sufficient blood levels with the oral antibiotics to predict therapeutic success. The most common clinical scenarios would be for osteomyelitis, septic arthritis and bacterial endocarditis.
4. A Schlichter test should be performed when the lab is unable to measure levels of the antibiotic that is to be used.
5. When we don't have an organism (cultures are negative).
6. We are never totally sure. We do know that compared to blood levels, most antibiotics have lower levels in bone and in joint fluid, but higher levels in urine.