Clindamycin-2-palmitate, a derivative of clindamycin, was microbiologically evaluated to obtain the following results:
1) Unlike that of clindamycin, the in vitro antibacterial activity of clindamycin-2-palmitate is very weak, i. e. M. I. C. against gram-negative and gram-positive organisms ranging from 12.5 to ≥ 100 mcg/ml.
2) Of 100 clinically isolated staphylococcal strains tested, 76% was sensitive to clindamycin, i. e. the M.I. C. ranging 0.045-0.19 mcg/ml with a peak at 0.09 mcg/ml; the rest, 24%, was high ly resistant (≥=100 mcg/ml).
3) As is the case with clindamycin, clindamycin-2-palmitate increased its in vitro activity in proportion to the shift of the pH of the medium used at the alkaline side. The derivative also resembles its parent compound in that it was not influenced much by the inocula sizes used.
4) Clindamycin-2-palmitate was found as effective as clindamycin in treating staphylococcal, streptococcal, and diplococcal infections experimentally induced in mice. The weak in vitro and strong in vivo activities of clindamycin-2-palmitate suggest that this antibiotic, once inside the body of mice, transforms itself, by metabolism, into clindamycin and works strongly.

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The pharmacological actions of clindamycin-2-palmitate (CL-Pl) were investigated.
Summary of pharmacological actions and minimal effective doses (MED) of CL-Pl was as follows: inhibition followed by acceleration on excised frog heart (10^-3g/ml), no effect on excised guinea-pig atrium and ECG of the rabbit (up to 2×10^-4g/ml and 20mg/kg, respectively), constriction on excised rabbit ear vessels (10^-2g/ml), acceleration on permeability of rabbit abdominal skin vessels (100mcg) and inhibition (1,000mcg), acceleration on excised rabbit intestine (10^-3g/ml), no effect on excised guinea-pig intestine and tracheal muscle, or on excised rat uterus (up to 2×10^-3g/ml and 2×10^-4g/ml, respectively), and fall on blood pressure and acceleration on respiration of the rabbit (40mg/kg).
Actions of CL-Pl were almost identical to the related antibiotics, clindamycin and lincomycin, and MED were almost equal or larger. These MED also were much larger than minimum inhibitory concentrations and maximum blood levels in clinical uses.
Therefore, it is concluded that CL-Pl is one of the antibiotics which have much less pharmacological actions.

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Clindamycin palmitate was administered to children with acute infections at the dose of 25-50mg/kg/day divided into 3 portions for 5-6 days. The therapy was effective in 24 of 33 cases of the upper respiratory tract infection and 5 of 11 cases of the lower respiratory tract infection treated.
No side effect was observed in all patients treated.

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Clinical studies were conducted on clindamycin-2-palmitate in the field of pediatrics and the following results were obtained.
1. A prompt improvement of laboratory data and clinical signs occurred in 23 cases out of 26 cases suspected bacterial infection.
2. It was very effective in 4 cases out of 6 cases of pneumonia due to Mycoplasma pneumoniae or cold-agglutination test positive pneumonia. The minimal growth inhibiting concentration against a Mycoplasma pneumoniae strain was 0.5 mcg/ml.
3. No particular side effects were detected in infants and children treated.

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[in Japanese]

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Clinical studies with clindamycin-2-palmitate, a preparation of clindamycin for pediatric use, were undertaken in children with acute infections, and the following results were obtained.
1. In vitro activity
The in vitro antibacterial activity of clindamycin was determined against 100 clinically isolated strains of staphylococcal organisms and compared with that of oleandomycin similarly tested. The range of minimal inhibitory concentrations (MIC) of clindamycin showed two distinct peaks: one at 0.08 mcg/ml and the other at 100 mcg/ml, though more than 80% of the organisms tested were inhibited at the drug concentration of 1.5 mcg/ml or less. The similar range of oleandomycin, on the otherh and, showed different peaks: one at 1.5-3.0 mcg/ml and the other at 100 mcg/ml. These results revealed that the tested Staphylococcal organisms were more sensitive to clindamycin than to oleandomycin.
2. Clinical trials
Clindamycin-2-palmitate was administered to 7 children with acute upper respiratory tract infection, 5 with acute bronchitis, 6 with bronchopneumonia and 4 with lymphadenitis purulenta, at thed ose equivalent to clindamycin base 20 mg/kg/day in general. The antibiotic dosed proved to be effective in 16 (72.7%) of the total 22 patients.
3. Adverse effects
The adverse effects which were considered ascribable to the antibiotic dosed consisted of slight GOT elevation in 3, diarrhea in 3, and exanthema in 1 of the 22 cases. This incidence of untoward effects, however, can not be said particularly high in comparison with other macrolide antibiotics.

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We treated 27 children casesw ith various infections (tonsilitis 22, abscess 2, pneumonia 1, pyothorax 1, stomatitis gangrenosa 1) with clindamycin-2-palmitate (20m g/kg).
One strain of Staphylococcus aureus from an abscess had high resistance to clindamycin (CLDM) and other various antibiotics. Except this case, clinicallygood results were observed in all cases treated with clindamycin-2-palmitate. In two cases, pneumonia and pyothorax, lincomycin (LCM) was also injected.
Bacteriologically5, of 17 strains of S. aureus were resistant to CLDM and LCM. Five strains of Diplococcus pneumoniaea nd 6 strains of β-Streptococcus had good sensitivityt o CLDM and LCM.

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The clinical response of children with scarlet fever was evaluated.
Twenty-four children with scarlet fever received oral clindamycin-2-palmitate at the rate of about 20mg/kg/day divided into 3 portions for 5 consecutive days. Of them, 14 cases (58.7%) showed good to excellent clinical response.
This result excelled those obtained with oral administration of benzathine penicillin (16/43, 37.2%), erythromycin (5/20, 25%), tetracycline (69/163, 42.3%), and spiramycin (11/20, 55%), though it was outstripped by that of parenteral penicillin G 300,000 units i. m.(80/92, 86%) and by that of oral clindamycin capsule (18/27, 66.7%).
No side effect was observed in all patients treated.

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Blood level and urinary excretion of clindamycin-2-palmitate after oral administration were determined, and clinical responses to this antibiotic were evaluated in acute bacterial upper-respiratory infections in children. The conclusions were as follows:
1. Average blood levels in 4 subjects after an oral administration of 4-5 mg/kg of clindamycin-2-palmitate were 2.8 mcg/ml after 1 hour, 2.9 mcg/ml after 2 hours, 1.7 mcg/ml after 3 hours and 0.9 mcg/ml after 6 hours. Peak of the blood level of this drug was lower than that of clindamycin capsule.
2. An average urinary recovery rate in 3 subjects was 14.0% in the first 8 hours.
3. Twenty-eight patients with lacunar tosillitis, scarlet fever, and cervical lymphadenitis were given 15 mg/kg/day orally for 7-14 days. The drug was effective in 24 patients and an efficacy rate was 85.7%. In 2 out of 6 patients with scarlet fever the causative organism reappeared after treatment with the drug.
4. One out of 28 patients temporarily developed soft stool during administration of the drug. None of the patients had skin rash.
5. A transient eosinophilia was noted in one patient and slight elevation of S-GOT in another. A minimum increase of BUN was observed in 4 patients. BUN returned to normal during administration in 2 patients and remained elevated in the other 2 even after withdrawal of the drug.
In one of the last 2 patients it became normal 4 months after cessation of treatment. As no abnormal urinary findings were found in the above 4 patients and their general condition was good, it could not be determined whether this elevation of BUN reflects the disturbance of renal function by this antibiotic.
6. Taste and flavor of clindamycin-2-palmitatew ere thought to be well acceptableb y children.
7. Based upon the above results clindamycin-2-palmitate is considered to be a useful antibiotic in the treatment of acute bacterial infections caused by the sensitive organisms and its trecommended dose is 20-30mg/kg/day.

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The authors have carried out the laboratory and clinical studies on clindamycin-2-palmitate. The results were as follow:
Sensitivities to clindamycin and clindamycin-2-palmitate of 30 strains of Staphylococcus aureus isolated from patients were determined by the plate dilution method. The growth of 60% of all strains was inhibited at concentration of 0.1 mcg/ml or less. No differences were observed in sensitivity to clindamycin between strains isolated in 1967-1968 and 1970-1972. Twenty-six of thirty strains of Staph. aureus were inhibited at concentrations of more than 50 mcg/ml.
Clindamycin-2-palmitate was given a single dose of 100-150 mg to 2 children. The peak blood level, 1.0 mcg/ml, was reached 1 hour after the administration. The blood level 8 hours after administration was 0.06-0.08 mcg/ml.
The excretion rate of clindamycin in the urine after a single dose was 9.4-10.9% in 8 hours post-administration.
Clindamycin-2-palmitate was effective in 9 of 11 cases with upper respiratory tract infections.
One patient exhibited a side effect of vomiting.

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Laboratory studies and clinical trials were conducted on clindamycin-2-palmitate to obtain the following results:
1. Antibacterial activity: The MIC against Staphylococcus and Streptococcus was below 0.05 mcg/ml for clindamycin and N-demethyl-clindamycin, over 6.25 mcg/ml for clindamycin sulfoxide and over 100 mcg/ml for clindamycin-2-palmitate. With most of gram-negative bacilli, all of these four clindamycins showed MIC of over 100 mcg/ml.
2. Sensitivity of clinically isolated Staph. aureus:Clindamycin and N-demethyl-clindamycin both reached the peak of MIC against clinically isolated Staphylococcus aureus at 0.1 mcg/ml and that of clindamycin sulfoxide did so at 1.56 mcg/ml. While these three analogues showed MIC higher than 100 mcg/ml in only 19 of the 54 strains tested, the MIC of clindamycin-2-palmitate was 100 mcg/ml in all of the 54 strains.
3. Blood level and urinary excretion: Blood level, determined in four adults each given a single oral administration of 300 mg of clindamycin-2-palmitate, reached the peak (average 1.13 mcg/ml) one hour after administration. Two-hour and six-hour values were 0.90 mcg/ml and 0.55 mcg/ml, respectively.
The urinary excretion determined simultaneously in the same four patients reached the peak (average 111.9 mcg/ml) two hours after the administration. The urinary recovery rate within six hours was 8.05%.(For determination, cup method with phosphate buffer solution as the standard was used.)
4. Tissue concentrations: Of the tissue concentrations determined in rats after a single oral administration of clindamycin-2-palmitate at the rate of 20 mg/kg, liver marked the highest, followed by kidneys, lungs, spleen, heart, muscle and serum.
5.In vivo metabolism: Study by thin-layer chromatography of in vivo metabolism of clindamycin-2-palmitate revealed that this product is transformed in the living body into clindamycin, N-demethylclindamycin and clindamycin sulfoxide.
6. Clinical trials: Clindamycin-2-palmitate was found effective in 22 of 24 surgical patients treated with it (success rate: 91.6%). Side effects were observed in none.

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Clindamycin-2-palmitate (CLDM-P), an analogue of clindamycin devised for the pediatric use, was employed for the treatment of pediatric surgical infections, and in vivo and in vitro studies were made with the following results.
1. Absorption and excretion
With the initial oral dose of 4.0 mg/kg to an infant of two months, the blood level attained the peak of 5.4 mcg/ml at 4 hour, and at 6 hour the drug was still detected at the level of 3.4 mcg/ml. In the same patient, at a certain point of a series of CLDM-P treatments, a lymph level of 4.8 mcg/ml was detected 2.5 hours after the administration of oral 4.0 mg/kg (concurrently determined blood level was 6.3 mcg/ml). Urinary recovery in 5 hours after the initial oral dose of 4.0 mg/kg in a 6-year-old patient was only 1.1 mg (0.7%), indicating a slow excretion rate.
2. Antibacterial spectrum
When CLDM HCI was used, the minimum inhibitory concentrations against 81% of 25 clinically isolated strains of Staphylococcus aureus were <0.2 mcg/ml.
In the case of CLDM-P, almost all of these strains were resistant to this drug.
3. Clinical results
Twenty-four pediatric patients with furuncle, abscess, cellulitis, lymphonoditis or suspected postoperative endocarditis, or for postoperative prophylaxis, were treated with CLDM-P, 1/3 or 1/4 dose of 8.3-50 mg/kg, 3 or 4 times a day. The response to the therapy was excellent in 6 cases, good in 15, fair in 2 and nil in 1. As untoward effects, diarrhea and anorexia were observed in one patient, and diarrhea in one.

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Basic and clinical evaluations of the new antibiotic clindamycin palmitate were performed with the results which may lead to the following conclusions:
1) In vitro antibacterial activity: The minimal inhibitory concentration of clindamycin was measured by an agar plate dilution method. Clindamycin inhibited the growth of 60 strains of coagulasepositive Staphylococcus aureus isolated from clinical specimens. The peak distribution of the Staphylococcus aureus susceptible to clindamycin was at ≤ 0.19 mcg/ml as the minimal inhibitory concentration.
2) Concentration in the blood: The maximal level reached 1.4 mcg/ml on the average one hour after administration of 150 mg in healthy children, and the level was still 0.1 mcg/ml 6 hour after the administration.
3) Concentration in tissues: Clindamycin palmitate activity was demonstrable in concentrations of 0.25 and 0.1 mcg/g in a human palatine tonsilla and pharyngeal tonsilla, maxillary sinus specimen respectively at one hour after administration of 150 mg, and serum levels of clindamycin palmitate were 1.4 and 1.5 mcg/ml respectively.
4) Clinical evaluation: In the clinical tests in otorhinolaryngical field infections, it was found that clindamycin palmitate showed good to excellent response it as many as 26 of the 30 patients by the administration (87% effectiveness).
5) Side effect: No side effects due to administration of this drug were noted in any of the cases.

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From the laboratory and clinical studies on clindamycin-2-palmitate, the following results were obtained.
1. The sensitivity of 28 strains, isolated from pathological materials in our clinic, to clindamycin was estimated by the plate dilution method. Growth of Staphylococcus strains was inhibited 66.7% by 0.19 mcg/ml or less. Clindamycin was found to have almost complete cross resistance with lincomycin.
2. Single oral dose of 5 mg/kg produced serum concentration of an average level of 1.66 mcg/ml in 9 patients.
3. Tissue concentrations of clindamycin-2-palmitate in tonsils were measured. An average tissue level in 1 hour after oral administration of 5 mg/kg was 0.88 mcg/g, and that in 2 hours was 1.69 mcg/g.
4. Clindamycin-2-palmitate was clinically used to 14 cases of ear and throat infections, and it was effective in 85.7% of them.

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1. The minimal inhibitory concentrations of clindamycin palmitate against 30 strains of Staphylococcus aureus were 0.36-0.2 mcg/ml.
2. Assays of the blood and aqueous humor levels after oral dose of 50 mg/kg of clindamycin palmitate were performed in rabbits. The peak of the blood level (3.4 mcg/ml) was reached in 1 hour and the aqueous humor level reached O.9mcg/ml in 2 hours.
3. Clindamycin palmitate was administered to children with acute infections at doses of 10-20mg/kg/day divided into 3 portions. By the treatment of clindamycin palmitate, 91.8% of these cases were improved.
4. Side effect such as exanthema and diarrhoea were observed in 3 of 37 patients treated with clindamycin palmitate.

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Bacteriala nd clinical experimentsf or ophthalmicu se of clindamycin-palmitate (C LDM-palm.) were performed and following results were obtained.
1) There was almost no bacteriostatic effect of CLDM-palm. against major causative organisms of ocular infections. CLDM showed a strong antibacterial activity against gram-positive cocci.
2) Minimum growth inhibitory concentration of CLDM-palm. was higher than 25 mcg/ml for 50 strains of Staphylococcus aureus isolated from the patients; meanwhilet hat of CLDM was lower than ≤0.19 mcg/ml for 92% of strains. Therefore it was proved that CLDM showed high sensitivity against S. aureus.
3) After oral administration of 100 mg/kg of CLDM-palm. to the rabbits, the concentration in the aqueous humor attained the peak after 3 hours, and remained relatively high level after 6 hours. After 2 hours the ocular tissue concentration showed the maximum level in the iris and ciliary body, then the eyelid, the conjunctiva, the extraocular muscles, the retina and choroid in order of decreasing concentration.
4) The concentration in the human eyelid revealed in the high level at 2 hours after administration of CLDM-palm.
5) The oral application of CLDM-palm. 100 mg/kg/day, against suppurative ocular infection revealed excellent effects in all of 2 cases with acute catarrhal conjunctivitis, 4 of 6 cases withh ordeolum externum, 3 of 4 cases with hordeolum internum, a case of lid abscess, one of 2 cases with dacryocystitis neonatorum and a case of idiopathic panophthalmitis.
Post-operative infection was prevented in all of 10 cases by the oral administration of CLDM-palm. 10-20 mg/kg/day.
6) Side effects: A case out of 26 cases complained diarrhoea, and was able to be treated continuously by the drug. These symptom immediately disappeared after cessation of the drug.
No other side effect was found in the other cases.

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