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1.  Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2387-2391.
The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcus faecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 micrograms/ml and 8 and 8 micrograms/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 micrograms/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) micrograms/ml. Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P less than 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.
PMCID: PMC172066  PMID: 2128443
2.  Antimicrobial therapy of experimental meningitis caused by Streptococcus pneumoniae strains with different susceptibilities to penicillin. 
The pharmacokinetics and bacteriological efficacies of penicillin G, ceftriaxone, vancomycin, and imipenem were determined in rabbits with experimental meningitis caused by Streptococcus pneumoniae strains with different penicillin susceptibilities. Drug dosages were adjusted to attain peak concentrations in serum that were similar to those observed in infants and children. In animals infected with a penicillin-susceptible (MBC, 0.008 micrograms/ml) pneumococcus, penicillin G and ceftriaxone reduced the number of organisms in cerebrospinal fluid (CSF) by greater than or equal to 4.14 log10 CFU/ml after single doses and after 9-h continuous infusions. A single large dose (50 mg/kg) of penicillin G was comparatively ineffective (-2.15 log10 CFU/ml) against a relatively penicillin-resistant (MBC, 0.5 micrograms/ml) strain, whereas ceftriaxone therapy resulted in a 3.66- and 4.77-log10 CFU/ml reduction after single doses and 9-h continuous infusions, respectively. In animals in which meningitis was caused by a penicillin-resistant (MBC, 8.0 micrograms/ml) pneumococcus, a single dose of penicillin (50 or 150 mg/kg) or of ceftriaxone failed to lower the number of organisms in CSF. Vancomycin and imipenem reduced the counts in CSF by at least 2.19 and 4.10 log10 CFU/ml after single doses and 9-h infusions, respectively. In all experiments, a bactericidal titer of greater than or equal to 1:8 in CSF was necessary to achieve a maximal bacteriological effect.
PMCID: PMC176226  PMID: 3845793
3.  Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens. 
Penicillin-"virgin" strains of Enterococcus faecalis collected from a population of individuals with no previous antibiotic exposure were subjected in vitro to penicillin delivered as repeated pulses, stepwise increasing concentrations, or sustained levels of a single concentration. Changes in resistance to penicillin were assessed by determination of MICs, and time-kill studies were performed to evaluate changes in tolerance to the bactericidal effects of penicillin. Isogenic clones, derived from various exposure regimens, which exhibited changes in either resistance or tolerance were further examined for changes in penicillin-binding proteins. Exposure to repeated pulses of penicillin resulted in the development of tolerance to penicillin without changes in the level of resistance. Clones derived from a regimen of stepwise increases in the penicillin concentration acquired both increased penicillin resistance and tolerance. Clones selected after prolonged continuous exposure to a fixed concentration of penicillin displayed minimally increased resistance to penicillin, but they retained the lytic, nontolerant response to the bactericidal effect of penicillin. Clones which acquired tolerance to the bactericidal effect of penicillin without changes in penicillin resistance exhibited a penicillin-binding protein pattern identical to that of the parental strain. Increased labeling of several penicillin-binding proteins accompanied the development of increased penicillin resistance in both penicillin-tolerant and nontolerant strains. Exposure of E. faecalis to penicillin in repeated pulses of brief duration, for prolonged periods at a constant concentration, or in stepwise graded concentrations can result in the selection of clones with increased resistance to the inhibitory or bactericidal effects of penicillin, or both. These observations may be relevant to the selection of dosing regimes for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.
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PMCID: PMC189238  PMID: 1590676
4.  Serum and Subcutaneous Chamber Fluid Dynamics of Penicillins After Single Large Parenteral Doses 
Serum and subcutaneous chamber fluid (CF) dynamics of penicillin G, ampicillin, and amoxicillin were studied in rabbits after single large parenteral doses comparable to doses used in treating gonorrhea and endocarditis. The effects of parenteral probenecid and of injection of an antibiotic directly into a subcutaneous chamber (“intrachamber” injection) also were studied. Peak serum antibiotic concentrations exceeded peak CF concentrations and occurred sooner. Antimicrobial activity persisted longer in CF than in serum. Percent penetration [100 × (CF peak/serum peak)] of CF was least after intramuscular ampicillin and amoxicillin, was greatest after intrachamber ampicillin and intrąmuscular aqueous procaine penicillin G, and was related to duration of antibiotic concentration gradients from serum to CF. Intramuscular aqueous crystalline penicillin G resulted in higher serum and CF penicillin G concentrations than intramuscular aqueous procaine penicillin G, which prolonged the duration of penicillin G in serum and CF. Amoxicillin diffused into CF more readily than ampicillin. Probenecid resulted in higher early serum and CF antibiotic concentrations, but had little or no effect on duration of antibiotic activity. Intrachamber ampicillin resulted in more prolonged serum and CF ampicillin activity than intramuscular ampicillin, but much lower peak serum concentrations. The data suggest a possible means by which probenecid improves the efficacy of gonorrhea therapy with aqueous procaine penicillin G. Intrachamber administration of penicillins could be useful in treating experimental infections requiring prolonged therapy.
PMCID: PMC283763  PMID: 7387144
5.  Parenteral sparfloxacin compared with ceftriaxone in treatment of experimental endocarditis due to penicillin-susceptible and -resistant streptococci. 
Antimicrobial Agents and Chemotherapy  1994;38(12):2683-2688.
A new, investigational, parenteral form of sparfloxacin was compared with ceftriaxone in the treatment of experimental endocarditis caused by either of three penicillin-susceptible streptococci or one penicillin-resistant streptococcus. Both drugs have prolonged half-lives in serum, allowing single daily administration to humans. Sparfloxacin had relatively low MICs (0.25 to 0.5 mg/liter) for all four organisms and was also greater than or equal to eight times more effective than the other quinolones against 21 additional streptococcal isolates recovered from patients with bacteremia. Ceftriaxone MICs were 0.032 to 0.064 mg/liter for the penicillin-susceptible strains and 2 mg/liter for the resistant isolate. Both antibiotics resulted in moderate bacterial killing in vitro. Rats with catheter-induced aortic vegetations were inoculated with 10(7) CFU of the test organisms. Antibiotic treatment was started 48 h later and lasted either 3 or 5 days. The drugs were injected at doses which mimicked the kinetics in human serum produced by one intravenous injection of 400 mg of sparfloxacin (i.e., the daily dose expected to be given to human adults) and 2 g of ceftriaxone. Both antibiotics significantly decreased the bacterial densities in the vegetations. However, sparfloxacin was slower than ceftriaxone in its ability to eradicate valvular infection caused by penicillin-susceptible bacteria. While this difference was quite marked after 3 days of therapy, it tended to vanish when treatment was prolonged to 5 days. In contrast, sparfloxacin was very effective against the penicillin-resistant isolate, an organism against which ceftriaxone therapy failed in vivo. No sparfloxacin-resistant mutant was selected during therapy. Thus, in the present experimental setting, this new, investigational, parenteral form of sparfloxacin was effective against severe infections caused by both penicillin-susceptible and penicillin-resistant streptococci.
PMCID: PMC188270  PMID: 7695248
6.  Effect of gentamicin dosing interval on therapy of viridans streptococcal experimental endocarditis with gentamicin plus penicillin. 
This study compares the effects of a total daily dose of gentamicin given once a day (q.d.) or three times a day (t.i.d.) in the therapy of experimental endocarditis in rabbits caused by penicillin-susceptible, penicillin-tolerant, or penicillin-resistant viridans streptococci. Four isolates were used in vivo: one penicillin susceptible (MIC < or = 0.03 microgram/ml), one penicillin tolerant (MBC/MIC, < or = 0.03/ > 32 micrograms/ml), and two penicillin resistant (MICs = 0.5 and 2 micrograms/ml). Animals were infected with one of the four isolates and assigned to one of the following treatment regimens: no treatment, procaine penicillin at 1.2 million IU intramuscularly (i.m.) t.i.d., procaine penicillin plus gentamicin at 1 mg/kg of body weight i.m. t.i.d., procaine penicillin plus gentamicin at 3 mg/kg i.m. q.d., or procaine penicillin plus gentamicin at 1 mg/kg i.m. q.d. (only animals infected with the penicillin-susceptible isolate). Serum drug concentrations measured 30 min after administration of 1.2 million IU of penicillin and 1 or 3 mg of gentamicin per kg were 22.6, 3.8, and 8.5 micrograms/ml, respectively. The reduced total daily dose of gentamicin was ineffective among animals infected with penicillin-susceptible viridans streptococci; treatment with 1 mg of gentamicin per kg per day plus penicillin was less effective (P < 0.05) than was treatment with 3 mg of gentamicin per kg per day plus penicillin. The 1-mg/kg/day gentamicin treatment regimen was not further studied. The gentamicin dosing interval did not significantly affect (q.d. versus t.i.d., P > 0.05) the relative efficacy of penicillin plus gentamicin for treatment of experimental endocarditis among animals infected with each of the four isolates tested.
PMCID: PMC162888  PMID: 8540723
7.  Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy 
Introduction
The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated.
Methods
In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance.
Results
The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the macrolide resistance mutation (A2058G). In subgroup analyses confined to the 75 patients infected with T. pallidum lacking resistance mutation, a statistically significantly lower risk for the Jarisch-Herxheimer reaction following azithromycin treatment was noted.
Conclusions
Treatment with azithromycin was associated with a lower risk for the Jarisch-Herxheimer reaction than that with benzathine penicillin G in HIV-positive patients with early syphilis. Previous benzathine penicillin G therapy for syphilis decreased the risk, whereas higher RPR titres increased the risk, for the reaction.
doi:10.7448/IAS.17.1.18993
PMCID: PMC4150017  PMID: 25174641
sexually transmitted diseases; spirochetal disease; macrolides; macrolide resistance; immunomodulation
8.  Comparison of fleroxacin and penicillin G plus probenecid in the treatment of acute uncomplicated gonococcal infections. 
Genitourinary Medicine  1992;68(5):317-320.
OBJECTIVE--To investigate the activity of fleroxacin in acute uncomplicated infections with N. gonorrhoeae in comparison with conventional penicillin G plus probenecid treatment. DESIGN--Multicentre open label randomised parallel group study. SUBJECTS--Male patients aged 18 years or over from university departments of urology, epidemiology and dermatology and a clinic for sexually transmitted diseases. INTERVENTIONS--Two hundred and sixty male patients were randomly assigned to treatment with either a single oral dose of fleroxacin 400 mg (130 patients) or a single intramuscular dose of penicillin G (2.4 or 5.0 mega units) plus a single oral dose of probenecid 1 gram (130 patients). Efficacy and safety assessments were undertaken at follow-up (3-14 days after treatment). Efficacy was assessed as bacteriological outcome of treatment. Safety was assessed by evaluation of adverse events, laboratory abnormalities and changes in vital signs. RESULTS--Two hundred and twenty four patients (114 in the fleroxacin group and 110 in the penicillin plus probenecid group) were evaluated for efficacy. Bacteriological cures were achieved in 100% of patients in the fleroxacin group and 97% of patients in the penicillin plus probenecid group. There was no statistically significant difference between the two groups in this respect (Fisher exact test, p = 0.25). Clinical cures were achieved in 100% of patients receiving fleroxacin and 95% of patients receiving penicillin plus probenecid. Safety analyses were undertaken on 255 patients (126 in the fleroxacin group and 129 in the penicillin plus probenecid group). No adverse events were reported for either treatment group, and no clinically relevant laboratory abnormalities were apparent. Thus, there appeared to be no difference in the efficacy or safety of these two treatments when used to treat acute, uncomplicated urethral gonorrhoea in males. CONCLUSIONS--In this study fleroxacin proved to be highly effective therapy for uncomplicated gonococcal urethritis in males and may provide a favourable alternative to standard treatment.
PMCID: PMC1195987  PMID: 1427804
9.  Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review 
Pharmaceuticals  2010;3(8):2568-2591.
Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2), clearance (Cl), and volume of distribution (Vd) change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides) AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based.
doi:10.3390/ph3082568
PMCID: PMC4033939
penicillins; cephalosporins; aminoglycosides; pharmacokinetics; neonate
10.  Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats. 
A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.
PMCID: PMC163797  PMID: 9087492
11.  Survival of treponemes after treatment: comments, clinical conclusions, and recommendations. 
Genitourinary Medicine  1985;61(5):293-301.
Treponemes may persist after treatment that has been accepted as effective; the reasons for this are discussed. Nevertheless, the epidemic of syphilis after the second world war was not followed by an epidemic of late syphilis, and the results of treatment with penicillin are excellent. Neurological signs may progress in some treated patients, and the standard doses of soluble penicillin and any dose of benzathine penicillin (even with added probenecid by mouth) cannot be relied on to achieve treponemicidal concentrations in the cerebrospinal fluid (CSF). There are no large scale studies of CSF findings after treatment of early syphilis with benzathine penicillin. Standard dosage, such as procaine penicillin G 600 000 international units (IU) by intramuscular injection for 10 days, is the treatment of choice for the patient suffering from uncomplicated early syphilis; this should be preferred to benzathine penicillin, which should only be used when standard treatment as above cannot be given. Treponemicidal concentrations of penicillin should be achieved in the CSF of patients suffering from neurosyphilis by schedules of probenecid by mouth and procaine penicillin by single daily intramuscular injections; treatment should last for 17 to 21 days. Benzathine penicillin should not be used for the treatment of patients suffering from neurosyphilis or from the iritis of late syphilis including that accompanying interstitial keratitis. Treatment for interstitial keratitis should initially be as for neurosyphilis, but in recurrent cases it may have to be prolonged to eradicate Treponema pallidum that is dividing slowly. Doxycycline 200 mg by mouth daily for 21 days provides a supervisable outpatient schedule for patients allergic to penicillin. Cephaloridine (and probably cefuroxime and the new cephalosporins) may be useful for patients who are allergic to penicillin but have not developed anaphylactic allergy. If erythromycin is used for treating syphilis in pregnant women who are allergic to penicillin, then the newborn babies should be treated with penicillin.
PMCID: PMC1011842  PMID: 3899905
12.  Optimal aminoglycoside dosing regimen for penicillin-tobramycin synergism in experimental Streptococcus adjacens endocarditis. 
Antimicrobial Agents and Chemotherapy  1992;36(11):2403-2407.
The combination of penicillin and aminoglycoside is the recommended therapy for endocarditis caused by nutritionally variant streptococci (NVS). However, the optimal aminoglycoside dosing regimen remains controversial. We compared the efficacies of four regimens of tobramycin alone or combined with procaine penicillin in the therapy of rabbits with endocarditis caused by Streptococcus adjacens, a new species of NVS. Animals were injected intramuscularly for 4 days with procaine penicillin (150,000 U/kg of body weight twice daily) or tobramycin at a low dose (3 mg/kg every 24 h) or a high dose (12 mg/kg every 24 h) either once or three times daily (t.i.d.) alone or in combination with procaine penicillin. Additional groups of animals were treated with the combination regimens for a shorter period of time (2 days) in order to demonstrate a possible difference in the rapidity of efficacy between the regimens. The MICs and MBCs were 0.015 and 1 micrograms/ml and 8 and 16 micrograms/ml for penicillin and tobramycin, respectively. The mean peak tobramycin levels in plasma were 2.4 +/- 1.3 (1 mg/kg t.i.d.), 5.4 +/- 3.7 (4 mg/kg t.i.d.), and 25 +/- 9.3 (12 mg/kg once daily). The mean penicillin levels in serum were always above the MIC. In vitro kill curves plotted at the time that peak concentrations were reached in plasma showed a concentration-dependent killing effect of tobramycin alone but not in combination with penicillin. In vivo, low-dose tobramycin was significantly less effective than the high dose. Results for the combinations of the different dosing regimens of tobramycin with procaine penicillin were not significantly different. Our results suggest that (i) against susceptible strains of streptococci, aminoglycoside alone exhibits a concentration-dependent killing effect both in vitro and in vivo; (ii) against NVS strains, combinations of penicillin and high- or low-dose tobramycin are equally effective; and (iii) aminoglycoside given once daily or at a low dose t.i.d. with penicillin could be a cost-effective alternative with reduced toxic risk for patients with NVS endocarditis when the bacteria are susceptible to the killing activities of both compounds.
PMCID: PMC284343  PMID: 1489184
13.  Penicillin Therapy of Experimental Endocarditis Induced by Tolerant Streptococcus sanguis and Nontolerant Streptococcus mitis 
The response of tolerant Streptococcus sanguis and nontolerant Streptococcus mitis infections to penicillin therapy was compared in the rabbit model of endocarditis. The minimal inhibitory and bactericidal concentrations of penicillin were 0.1 and 0.1 μg/ml, respectively, for S. mitis and 0.05 and 6.2 μg/ml, respectively, for S. sanguis. Time-kill studies done in vitro with penicillin concentrations of 2 and 20 μg/ml demonstrated minimal killing of the tolerant strain, with a 3 log difference in survival between the two strains after 24 and 48 h. Both strains produced endocarditis with comparable bacterial densities on the valvular vegetations. Rabbits were treated with procaine penicillin G in two dosage regimens, 80,000 or 5,000 U/kg given every 8 h. There was no difference between bacterial densities in valvular vegetations removed from rabbits infected with either strain after 2, 4, or 6 days of treatment with the high-dose regimen (serum penicillin concentration at 0.5 h, 9.4 μg/ml), despite the fact that serum bactericidal activity against the tolerant strain at 0.5 h was minimal. With the low-dose penicillin regimen (serum concentration at 0.5 h, 2.5 μg/ml), therapy was significantly less effective in the tolerant group only after 6 days of treatment. Similar results were obtained when penicillin was administered in low and high doses to prevent infection. In this animal model of infection, penicillin tolerance was associated with a diminished response to penicillin therapy only when the dose was severely restricted. In the high-dose regimen, there was no difference in the response to penicillin therapy between animals infected with either strain, despite the presence of only minimal serum bactericidal activity in the rabbits infected with the tolerant strain.
PMCID: PMC184619  PMID: 6830210
14.  In vivo efficacy of azithromycin in treatment of systemic infection and septic arthritis induced by type IV group B Streptococcus strains in mice: comparative study with erythromycin and penicillin G. 
We compared the activities of azithromycin, erythromycin, and penicillin G in a mouse model of systemic infection and septic arthritis induced by type IV group B streptococci (GBS). The in vitro and in vivo efficacy data for these drugs were analyzed relative to the pharmacokinetics of the drugs in sera, joints, and kidneys. Adult CD-1 mice were infected intravenously with 10(7) CFU of type IV GBS. Intraperitoneal drug administration was initiated with different dose regimens at different times after infection. A single dose of azithromycin (100 mg/kg) strongly reduced the incidence of articular lesions with respect to that with erythromycin or penicillin G. Treatment with azithromycin (three intraperitoneal administrations of 50 mg/kg at 12-h intervals) resulted in the complete prevention of arthritis. In contrast, erythromycin was poorly effective and penicillin G was effective only if inoculated 30 min after infection and at high doses (400,000 or 600,000 IU/kg). Furthermore, azithromycin was able to cure about 70% of the mice when administered 7, 8, and 9 days after GBS infection. Azithromycin was much more active than erythromycin and penicillin G with respect to bacterial killing in the joints and kidneys. In fact, cultures from these tissues were always negative no matter what treatment schedule was employed. The pharmacokinetics of azithromycin account for its superior in vivo efficacy against type IV GBS. A longer half-life and higher levels of this drug in serum and tissues with respect to those for erythromycin or penicillin G were achieved. The high affinity of azithromycin for the joints strongly supports its potential value for therapy of septic arthritis, which is a severe and frequent clinical manifestation of GBS infection.
PMCID: PMC162860  PMID: 8540695
15.  Comparison of single and combination antimicrobial agents for prevention of experimental gas gangrene caused by Clostridium perfringens. 
The treatment of experimental gas gangrene caused by Clostridium perfringens was investigated by using combinations of antimicrobial agents. This study demonstrated that rifampin, penicillin, metronidazole, and clindamycin were all bactericidal against standard inocula (10(5) to 10(6) CFU). These antimicrobial agents were then administered to mice beginning 30 min after intramuscular injection of 10(9) CFU of C. perfringens type A. The highest doses used produced levels of drug in blood which exceeded the MIC by at least a factor of 40. In addition, other groups of mice received monotherapy at full dose or one-fourth full dose or combination antimicrobial therapy at full or one-fourth full dose. Among the single and combination antimicrobial treatments, metronidazole alone, clindamycin alone, and clindamycin plus penicillin were the most efficacious (P less than 0.05). Although the survival of mice treated with clindamycin plus penicillin was greater than that of mice treated with clindamycin alone, the difference did not reach statistical significance (P greater than 0.05). In contrast, mice treated with a combination of metronidazole and penicillin demonstrated greater mortality than those treated with metronidazole alone (P less than 0.05). In summary, combination antimicrobial therapy of experimental C. perfringens infection did not improve survival compared to that achieved with metronidazole or clindamycin alone, and some combinations significantly reduced survival (P less than 0.05).
PMCID: PMC174712  PMID: 2882732
16.  Community acquired pneumonia in adults: a study comparing clinical features and outcome in Africa (Republic of Guinea) and Europe (France). 
Thorax  1996;51(4):385-388.
BACKGROUND: Community acquired pneumonia is the most common cause of death from infectious disease both in western and developing countries. A study was carried out in Conakry, Republic of Guinea and Tours, France in order to compare signs, symptoms, severity of illness, risk factors, and clinical outcome of community acquired pneumonia in adult patients admitted to hospital. METHODS: The study was performed in the cities of Conakry and Tours over the same one year period. Patients with nosocomial pneumonia, tuberculosis, and those who were HIV positive were excluded. Data were recorded on the same forms in both centres. A severity score was calculated according to American Thoracic Society criteria. Follow up was evaluated at days 2, 7 and 15. RESULTS: A total of 333 patients (218 from Conakry, 115 from Tours) were included in the study with a diagnosis of community acquired pneumonia, with or without lung abscess or pleural effusion. Mean age was higher and pre-existing illness rate, dehydration, agitation, and stupor were more frequent in patients in Tours. Respiration rates of > 30 breaths/min and the incidence of crackles were identical in the two centres. Fever above 39 degrees C, initial shock, chest pain, and herpes were significantly more frequent in Conakry. Initial chest radiographic abnormalities were similar in the two groups, ranging from unilateral pleuropulmonary involvement (89% and 83% in Conakry and Tours, respectively) to diffuse patchy parenchymal disease. Parapneumonic effusion was present in 17% and 16% of the patients of Conakry and Tours, respectively. Pneumonia was considered to be severe in 33% and 42% of the patients, respectively. In Conakry first line antibiotic therapy was penicillin alone (2 million units a day) for 197 patients (90%) and second line antibiotic therapy was prescribed for 25 patients (12%). In Tours first line therapy consisted of a single antibiotic (amoxicillin, third generation cephalosporins) for 65 patients (57%) and second line antibiotic therapy was prescribed for 55 patients (48%). The clinical outcome was similar in Conakry and Tours: 88% and 85% of patients, respectively, were afebrile or clinically cured at day 15. The mortality rate was similar (6% and 8%, respectively). CONCLUSIONS: The problems encountered in the management of community acquired pneumonia are quite different in western and developing countries. This study shows that low doses of penicillin can cure 90% of African patients with pneumonia as effectively as more aggregative treatments in European patients who are both older and have greater comorbidity. Although pneumococci with reduced penicillin sensitivity occur in western countries, this does not seem to be the case in black Africa. For these reasons, low doses of penicillin or amoxicillin remain good first line treatment.
PMCID: PMC1090673  PMID: 8733490
17.  Tolerance and efficacy of parenterally administered penicillin-streptomycin and orally administered amoxicillin or penicillin V for prophylaxis of experimentally induced streptococcal endocarditis. 
A regimen of a single intramuscular dose of penicillin G-streptomycin was compared with regimens of three oral doses of amoxicillin and two oral doses of penicillin V to prevent Streptococcus sanguis endocarditis in rabbits with experimentally induced valvular heart lesions. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis highly tolerant to penicillin and amoxicillin were used. The combination of penicillin and streptomycin was the only regimen tested that provided full protection even against the highest inoculum concentration. A single oral dose of penicillin V (36 mg/kg) or amoxicillin (50 mg/kg), two oral doses of penicillin V (36 and 18 mg/kg with a 7-h interval between doses), or six oral doses of amoxicillin (50 mg/kg followed by 8.5 mg/kg at 8-h intervals) protected recipients of the lowest inoculum concentration; protection diminished with increasing inocula. In contrast, administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses provided full protection against challenge doses of 10(4) and 10(6) CFU, preventing endocarditis in 10 (66%) of 15 recipients of 10(8) CFU. All regimens evaluated were highly effective in preventing endocarditis when rabbits were challenged with 10(4) CFU. The combination of penicillin and streptomycin was the best regimen tested. Administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses led to significantly fewer infections when compared with the other oral regimens when rabbits were challenged with 10(6) and 10(8) CFU.
PMCID: PMC171580  PMID: 2109579
18.  Bactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniae in an in vitro pharmacodynamic infection model. 
We examined the bactericidal activities of penicillin, cefprozil, cefixime, cefaclor, and loracarbef against three clinical isolates of Streptococcus pneumoniae which were susceptible, moderately susceptible, and resistant to penicillin. An in vitro two-compartment glass infection model was used to simulate human pharmacokinetics in the presence of bacteria. Also, changes in organism susceptibility and development of resistant subpopulations were evaluated. Simulated pediatric dosage regimens and target peak concentrations in the central compartment were as follows: penicillin V-potassium, 26 mg/kg of body weight every 6 h (q6h) and 14 micrograms/ml; cefaclor, 13.4 mg/kg q8h and 16 micrograms/ml; loracarbef, 15 mg/kg q12h and 19 micrograms/ml; cefprozil, 15 mg/kg q12h and 11 micrograms/ml; and cefixime, 8mg/kg q24h and 4 micrograms/ml. Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h for cefprozil; and 3.5 h for cefixime. Growth controls were performed at two different pump rates, 0.8 and 2.0 ml/min (half-lives = 3.5 and 1 h, respectively). Each isolate demonstrated autolysis at the lower rate which was attributed to a decreased supply of fresh nutrients available to the organisms in the infection compartment. Against the susceptible isolate, the time to 99.9% killing was statistically significant between penicillin V-potassium and both cefaclor and cefixime (P < 0.029). Loracarbef never achieved a 99.9% reduction in the inoculum. At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. Against the intermediately resistant isolate, cefprozil was superior to all other regimens with respect to rate of killing (P < 0.013) and extent of killing at 24 h (P < 0.0003). At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. All of the regimens exhibited inferior activity against this penicillin-resistant isolate. A 99.9% kill was never obtained with any of the regimens, nor was there an appreciable decrease in the colony counts. In conclusion, it appears that cefprozil, penicillin, and cefaclor are effective therapies against sensitive and even intermediately sensitive isolates of S. pneumoniae. However, none of the oral therapies appear to be of any benefit against penicillin-resistant isolates. The in vitro model may be an effective tool in evaluating other multiple-dose therapies against this fastidious organism, since the continual supply of fresh medium maintains the viability of S. pneumoniae with minimal stationary-phase autolysis.
PMCID: PMC163281  PMID: 8723456
19.  In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model. 
The increasing emergence of penicillin-resistant (Pr) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against Pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (Ps) strain (MICs of < 0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a Pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the Ps strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the Pr strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the Ps strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly Pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.
PMCID: PMC284667  PMID: 7811003
20.  Penicillin resistance in the subgingival microbiota associated with adult periodontitis. 
Journal of Clinical Microbiology  1986;23(6):1127-1133.
In this investigation, the penicillin-resistant and beta-lactamase-producing subgingival microbiota associated with adult periodontitis was identified, and the impact of a recent exposure to penicillin on the recovery of resistant organisms from this microbiota was assessed. Subjects with adult periodontitis were examined clinically and microbiologically. Twenty-one subjects had a documented history of penicillin therapy within the previous 6 months whereas an additional 21 subjects had no history of antibiotic use within 1 year. Subgingival plaque samples were cultured anaerobically on nonselective and penicillin-containing elective media. MICs and beta-lactamase production were determined for the isolates from the elective medium. The penicillin-resistant microbiota consisted primarily of gram-negative organisms, including Bacteroides, Veillonella, Haemophilus, Eikenella, and Capnocytophaga species. The prevalence (P less than 0.05) and proportions (P less than 0.005) of both penicillin-resistant pigmented Bacteroides and Veillonella species were significantly greater in subjects with recent penicillin exposure. Of the penicillin-resistant genera identified, beta-lactamase production was detected in species of pigmented Bacteroides, Capnocytophaga, and Streptococcus. The prevalence of beta-lactamase-producing Bacteroides species was significantly greater in subjects with recent penicillin exposure (P less than 0.05). Of the antibiotics examined, no single agent was uniformly effective against all of the penicillin-resistant strains, but metronidazole and clindamycin were active against all of the penicillin-resistant pigmented Bacteroides strains.
PMCID: PMC268807  PMID: 3486882
21.  Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models 
XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 106.8 to 108.4 CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and −1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 106.1 to 107.8 CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 μg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs ± standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 ± 10 and 31 ± 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.
doi:10.1128/AAC.50.1.243-249.2006
PMCID: PMC1346813  PMID: 16377693
22.  AN EXPERIMENTAL ANALYSIS OF THE CURATIVE ACTION OF PENICILLIN IN ACUTE BACTERIAL INFECTIONS  
The results of the experimental analysis reported in this and the two preceding papers (10, 11) indicate that in murine pneumococcal infections penicillin per se destroys the invading organisms only in those parts of the lesions where the bacteria are multiplying rapidly and are thus maximally susceptible to the bactericidal action of the drug. In areas where the bacterial growth rate is slowed, either because the pneumococci have reached a maximum population density, or because the accumulated exudate affords a relatively poor medium for rapid growth, the destructive effect of the antibiotic is greatly diminished. In such portions of the lessions the cellular defenses of the host are observed to play a major role in eliminating the bacteria. In sites where frank suppuration has developed, however, even the combined actions of the penicillin and the cellular defenses of the host are relatively ineffective in ridding the tissues of bacteria. Here, because of the poor medium provided by the pus, the pneumococci remain metabolically sluggish and therefore are not killed rapidly by the penicillin. At the same time the leucocytes in the necrotic exudate have deteriorated to the point where they cannot effectively perform their phagocytic functions. As a result, bacteria persist in such lesions for many days in spite of the most intensive penicillin treatment administered both locally and systemically. A strict analogy cannot be drawn between the action of penicillin upon specific pneumococcal lesions produced in the laboratory and its effect upon acute bacterial infections in man. Host-parasite relationships in acute bacterial infections are determined not only by the strain of parasite and the specific host involved, but also by the site in the body at which the infection occurs (16). Nevertheless, in spite of the number of variables involved, it may be possible, by means of selected laboratory models, to illustrate general principles of infection which in all probability apply to human disease. Bearing in mind the limitations of the methods employed in the present experiments, it would appear justifiable to draw the following conclusions concerning the clinical use of penicillin in acute infections caused by penicillin-sensitive bacteria. The earlier that treatment is begun the more likely is penicillin to effectuate a rapid cure. When therapy is started before the bacteria have reached a maximum population density in any part of the lesion, and before a cellular exudate is formed, the great majority of the infecting organisms will be in a state of active multiplication and thus will be killed promptiy by the bactericidal action of the drug. If, on the other hand, treatment is delayed until the bacterial growth has attained its maximum in older parts of the lesion, and the inflammatory reaction has become well advanced, the resultant slowing of bacterial metabolism will so interfere with the bactericidal action of the penicillin that ultimate destruction of many of the bacteria will have to depend upon the slower clearing effect of the phagocytic cells. In such instances of delayed therapy specific antibody, which is formed relatively slowly, may play an important role in recovery (6). If relapse is to be avoided, however, penicillin therapy must often be continued longer in well established infections than in those treated at a very early stage. Still further delay in treating infections which are prone to cause tissue destruction and suppuration, may lead to the establishment of abscesses. Fully developed abscesses often will not respond to chemotherapy alone; they will ultimately require drainage. As shown by the present murine experiments, the relative ineffectiveness of penicillin under these circumstances is due not only to the failure of the drug to kill the metabolically sluggish bacteria surviving in the pus, but also to the ineffectiveness of the phagocytic cells, most of which are non-motile or dead. Even if specific antibody gains access to such purulent foci, many of the bacteria will continue to survive because of the degenerated state of the leucocytes. It is evident, therefore, that the stage of the infection at which penicillin treatment is begun is often crucial. Equally critical may be the location of the infection. Bacterial lesions in different sites of the body vary greatly in their responses to penicillin therapy. This inconstancy of therapeutic effectiveness is due primarily to the participation of host factors of defense which differ widely in various tissues and at the same time play a major role in the curative action of the antibiotic. In cases of pneumococcal pneumonia, for example, in which each milliliter of the patient's blood contains more than 1000 pneumococci, blood cultures may become negative in a matter of minutes after the start of intensive treatment (17). The remarkable promptness with which penicillin therapy controls such acute bacteriemia is due, first, to its suppressive effect upon the primary infection in the lungs and regional lymph nodes from which the bacteria are being poured into the blood stream (16) and, secondly, to its synergistic action with the cellular defenses of the circulation. The latter are known to be extraordinarily efficient, perhaps more so than in any other tissue of the body (18). Assisting them in destroying the circulating bacteria is the penicillin's own bactericidal effect, which operates rapidly upon the metabolically active organisms in the plasma. Rarely, if ever, as they often do in other tissues of the body (10), do bacteria in the bloodstream reach such numbers, or do inflammatory cells accumulate intravascularly to such an extent, as to create metabolic conditions which depress the bactericidal actions of the antibiotic. In contrast, more prolonged and extensive penicillin therapy is needed to cure pneumococcal endocarditis (19), meningitis (19, 20), or infections of the serous cavities (3, 4). The cellular defenses of the heart valves and of the "open" fluid-containing cavities of the body are relatively inefficient as compared to those that operate in the bloodstream and in tissues with tightiy knit architectures such as the lungs and lymph nodes (16). In endocarditis relatively few phagocytic cells ever reach the site of the offending bacteria (21), and in infections of fluid-containing cavities, the phagocytic efficiency of the mobilized leucocytes is seriously interfered with by the "dilution effect" of the fluid (22, 23). Accordingly, final destruction of the bacteria must depend primarily upon the bactericidal effect of the antibiotic itself, since little assistance is provided by phagocytosis. It is no wonder, therefore, that such infections, as compared to bacteriemia, are relatively refractory to penicillin therapy. Certainly penicillin, in spite of its remarkable therapeutic properties, falls far short of being a therapia sterilans magna (24). Its effectiveness does not depend solely upon the inherent susceptibility of the infecting agent to its antimicrobial action. How readily it will cure a given infection is determined also by the state of growth of the bacteria in the various zones of the lesions, the influence of the purulent exudate upon the bactericidal action of the drug, and the destructive effect of the inflammatory phagocytes upon the invading bacteria. Optimal use of penicillin as a therapeutic agent requires due consideration of all of these factors. Finally, it should be emphasized that the conclusions drawn from this experimental analysis cannot be applied to antibiotic therapy in general. They pertain only to the action of penicillin in acute infections caused by penicillin-sensitive bacteria which act in the host as extracellular parasites (16). The most common human infections included in this category are those caused by pneumococci and Group A beta hemolytic streptococci.7 Whether they apply also to infections due to penicillin-sensitive staphylococci may be questioned because of recent evidence that certain pathogenic strains will survive phagocytosis (27). In diseases such as tuberculosis, brucellosis, and typhoid fever, which are treated with antibiotics having properties different from those of penicillin (28) and which are caused by bacteria capable of intracellular parasitism (28), factors other than those considered in the present analysis must certainly be involved in the curative effect of antimicrobial therapy.
PMCID: PMC2180355  PMID: 13306859
23.  Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models 
Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 μg/ml and the other for which the penicillin MIC was 1.0 μg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (Cmaxs) and times that the concentrations were greater than the MIC (T>MICs). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T>MIC and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (∼6 log10 CFU/ml), followed by the thigh (∼3 log10 CFU/thigh), and being the lowest in the lung (∼1 log10 CFU/lung). In the rabbit model the maximal effect was ∼6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T>MIC was ≥65% of the experimental time and Cmax was ≥15 times the MIC, and in the rabbit model bactericidal activity became marked when T>MIC was ≥35%, Cmax was ≥5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio and T>MIC, the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.
doi:10.1128/AAC.45.4.1078-1085.2001
PMCID: PMC90427  PMID: 11257018
24.  Comparison of Serological Response to Doxycycline versus Benzathine Penicillin G in the Treatment of Early Syphilis in HIV-Infected Patients: A Multi-Center Observational Study 
PLoS ONE  2014;9(10):e109813.
Background
While doxycycline is recommended as an alternative treatment of syphilis in patients with penicillin allergy or intolerance, clinical studies to compare serological response to doxycycline versus benzathine penicillin in treatment of early syphilis among HIV-infected patients remain sparse.
Methods
We retrospectively reviewed the medical records of HIV-infected patients with early syphilis who received doxycycline 100 mg twice daily for 14 days (doxycycline group) and those who received 1 dose of benzathine penicillin (2.4 million units) (penicillin group) between 2007 and 2013. Serological responses defined as a decline of rapid plasma reagin titer by 4-fold or greater at 6 and 12 months of treatment were compared between the two groups.
Results
During the study period, 123 and 271 patients in the doxycycline and penicillin group, respectively, completed 6 months or longer follow-up. Ninety-one and 271 patients in the doxycycline and penicillin group, respectively, completed 12 months or longer follow-up. Clinical characteristics were similar between the two groups, except that, compared with penicillin group, doxycycline group had a lower proportion of patients with secondary syphilis (65.4% versus 41.5%, P<0.0001) and a higher proportion of patients with early latent syphilis (25.3% versus 49.6%, P<0.0001). No statistically significant differences were found in the serological response rates to doxycycline versus benzathine penicillin at 6 months (63.4% versus 72.3%, P = 0.075) and 12 months of treatment (65.9% versus 68.3%, P = 0.681). In multivariate analysis, secondary syphilis, but not treatment regimen, was consistently associated with serological response at 6 and 12 months of follow-up.
Conclusions
The serological response rates to a 14-day course of doxycycline and a single dose of benzathine penicillin were similar in HIV-infected patients with early syphilis at 6 and 12 months of follow-up. Patients with secondary syphilis were more likely to achieve serological response than those with other stages.
doi:10.1371/journal.pone.0109813
PMCID: PMC4195693  PMID: 25310367
25.  Studies on the Antibacterial Effects of Statins - In Vitro and In Vivo 
PLoS ONE  2011;6(8):e24394.
Background
Statin treatment has been associated with a beneficial outcome on respiratory tract infections. In addition, previous in vitro and in vivo experiments have indicated favorable effects of statins in bacterial infections.
Aim
The aim of the present study was to elucidate possible antibacterial effects of statins against primary pathogens of the respiratory tract.
Methods
MIC-values for simvastatin, fluvastatin and pravastatin against S. pneumoniae, M. catarrhalis and H. influenzae were determined by traditional antibacterial assays. A BioScreen instrument was used to monitor effects of statins on bacterial growth and to assess possible synergistic effects with penicillin. Bacterial growth in whole blood and serum from healthy volunteers before and after a single dose of simvastatin, fluvastatin and penicillin (positive control) was determined using a blood culture system (BactAlert).
Findings
The MIC-value for simvastatin against S pneumoniae and M catarrhalis was 15 µg/mL (36 mmol/L). Fluvastatin and Pravastatin showed no antibacterial effect in concentrations up to 100 µg/mL (230 µmol/L). Statins did not affect growth or viability of H influenzae. Single doses of statins given to healthy volunteers did not affect growth of pneumococci, whereas penicillin efficiently killed all bacteria.
Conclusions
Simvastatin at high concentrations 15 µg/mL (36 µmol/L) rapidly kills S pneumoniae and M catarrhalis. However, these concentrations by far exceed the concentrations detected in human blood during simvastatin therapy (1–15 nmol/L) and single doses of statins given to healthy volunteers did not improve antibacterial effects of whole blood. Thus, a direct bactericidal effect of statins in vivo is probably not the mechanism behind the observed beneficial effect of statins against various infections.
doi:10.1371/journal.pone.0024394
PMCID: PMC3166163  PMID: 21912631

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